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Diseases of the Fallopian Tube and Paratubal Region

  • Russell VangEmail author
Living reference work entry

Abstract

The Italian physician and anatomist Gabriele Falloppio provided the first detailed and accurate description of the oviducts in humans in 1561 A.D. and designated it the Uteri Tuba (Graham 1951). This organ was eventually named after him. Since that time, a wide variety of nonneoplastic and neoplastic diseases of the fallopian tube has become recognized, but it is only recently that the pathogenesis of fallopian tube carcinoma is beginning to be understood.

The Italian physician and anatomist Gabriele Falloppio provided the first detailed and accurate description of the oviducts in humans in 1561 A.D. and designated it the Uteri Tuba (Graham 1951). This organ was eventually named after him. Since that time, a wide variety of nonneoplastic and neoplastic diseases of the fallopian tube has become recognized, but it is only recently that the pathogenesis of fallopian tube carcinoma is beginning to be understood.

Surgical specimens removed specifically for lesions of the fallopian tube are much less common than specimens from other sites in the gynecologic tract; nonetheless, the fallopian tube is frequently examined by the surgical pathologist because it accompanies specimens which were removed for lesions of other gynecologic organs, and the tube plays an important role in reproduction, including problems related to infertility. The majority of fallopian tube lesions examined by the surgical pathologist are nonneoplastic. Benign and malignant tumors of the fallopian tube are uncommon, but, as discussed below, early carcinomas of the fimbriated end of the fallopian tube are becoming more frequently recognized because of complete examination of all fallopian tube tissue submitted as part of prophylactic bilateral salpingo-oophorectomy specimens or major resections for ovarian carcinoma. Also, intraepithelial carcinomas are detected as incidental findings in a small subset of routine specimens when the fallopian tubes are completely submitted for histologic examination.

This chapter provides a detailed discussion of normal fallopian tube (embryology, gross anatomy, and histology) and gross examination, nonneoplastic lesions, benign and malignant tumors, and gestational trophoblastic disease of the fallopian tube. Paratubal/para-ovarian and pelvic ligament lesions are presented as well.

Normal Fallopian Tube and Gross Examination

Embryology

Regardless of genetic sex, the paired müllerian (paramesonephric) ducts develop on the anterolateral surface of the paired urogenital ridges in both females and males beginning in the sixth week of embryonic life (O’Rahilly 1983, 1989; Robboy et al. 1982). At the cranial end of the urogenital ridge, the peritoneum gives rise to a population of epithelial cells which segregate from the peritoneal layer (Guioli et al. 2007). This new population proliferates and forms the longitudinally oriented müllerian ducts (Guioli et al. 2007; Orvis and Behringer 2007). The mesenchyme surrounding the luminal epithelial layer of the müllerian duct is also derived from the peritoneum. Cranially, the ducts open into the peritoneal cavity. Each of the paired ducts grows caudally in the urogenital ridge immediately lateral to and using the wolffian (mesonephric) duct as a guide. Spatially lateral to the cranial aspect of the wolffian ducts, the müllerian ducts then ventrally cross the wolffian ducts. The longitudinally oriented and caudal portions of the müllerian ducts now lie medial to the wolffian ducts as they enter the pelvis. The caudal ends of the müllerian ducts abut on the posterior wall of the urogenital sinus immediately between the two wolffian ducts. In the eighth week of embryonic life, these caudal ends of the paired müllerian ducts fuse with each other but are still separated by a septum (Figs. 1 and 2). All these developments occur in both female and male fetuses and are completed before the testis (if the embryo is male) begins to secrete müllerian inhibiting substance (MIS), also known as anti-müllerian hormone (In the absence of MIS, the müllerian ducts develop passively to form the fallopian tubes, uterus, and vaginal wall. Likewise, in the absence of testosterone, the wolffian ducts regress.) In the development of the female, the first two parts of the müllerian duct (the cranial longitudinal segment which opens into the peritoneal cavity and the transverse portion which crosses the wolffian duct) form the fallopian tube. The cranial-most aspect of the first part forms the fimbriated end, and the caudal-most segment of the müllerian duct (the fused portion) forms the uterus. During the growth of the second portion of the müllerian duct (the transverse segment which crosses the wolffian duct), the urogenital ridges form a transverse pelvic fold. After the fusion of the caudal segment of the müllerian duct, the transverse pelvic fold extends laterally from the fused müllerian duct toward the pelvic sidewall (Fig. 2). This fold forms the broad ligament, to which the fallopian tube is attached.
Fig. 1

(a) Diagram of ventral aspect of coronal section through female embryo at the end of the eighth week. The arrangement of the müllerian (red) and wolffian (mesonephric) [blue] ducts is shown. The cranial portion of the müllerian duct is lateral to the wolffian duct. The former grows in a caudal direction and crosses ventral to the latter and is in a medial position at the caudal end. The caudal ends of the müllerian ducts fuse, which eventually form the uterus. (b) The developed fallopian tube with accompanying wolffian remnants. The red and blue structures correspond to their precursors in (a). (From Sadler TW. Langman’s Medical Embryology, 6th Edition. Baltimore: Williams & Wilkins; 1990:Fig. 15–22. Printed with permission from Lippincott Williams & Wilkins)

Fig. 2

Diagram of transverse section of female embryo. (a) through (c) show progressively lower levels through urogenital ridge. The müllerian (paramesonephric) ducts (orange) eventually fuse and are then located medial to the wolffian ducts (blue). The fusion of the müllerian ducts creates a transverse fold which becomes the broad ligament (c). (From Sadler TW. Langman’s Medical Embryology, 6th Edition. Baltimore: Williams & Wilkins; 1990:Fig. 15–23. Printed with permission from Lippincott Williams & Wilkins)

The lumen of the fallopian tube is initially oval to round and lined by immature columnar epithelium, but the mucosa forms plicae at week 14. In week 16, the fallopian tube begins an active growth phase and starts to coil. Smooth muscle appears in the walls of the genital canal between 18 and 20 weeks. The fallopian tube muscular wall develops only around the müllerian duct, so that the wolffian duct remnants are external to the true wall of the canal. From the 22nd to 36th weeks, there is an increase in the growth and coiling of the fallopian tube at a rate of approximately 3 mm/week (Hunter 1930). Fimbriae do not develop until the 20th week, at which time only 3–4 are present in each fallopian tube (Sulak et al. 2005). The fimbriae increase in number throughout gestation, and at term, 6–8 are present in each tube. The number continues to increase after birth.

Important genes in the embryologic development of the müllerian duct include the Wnt family, Lim1, Pax2, and Emx2 (Yin and Ma 2005). In addition, the Hox family of genes (Hox in mice, HOX in humans) is particularly essential for development of this anatomic structure (Du and Taylor 2004; Taylor et al. 1997; Yin and Ma 2005). The Hox family represents four clusters of genes (Hoxa through Hoxd) which encode transcription factors that direct embryogenesis. Their main function is to control patterning and positional identity along a developing axis, such as the hindbrain, axial skeleton, and limbs. One of the anatomic sites controlled by the Hoxa cluster during embryogenesis is the müllerian duct, in which each Hoxa gene controls the morphogenesis of different segments along the developing axis of the müllerian duct. Hoxa-9 through Hoxa-13 are sequentially located in tandem with one another in the same region of the chromosome. It has been shown in mice that the physical order of the Hoxa genes on the chromosome corresponds to the same spatial order of the different segments of the developing müllerian duct (i.e., Hoxa-9 is expressed in the fallopian tube, Hoxa-10 and Hoxa-11 in the uterine corpus, Hoxa-11 in the uterine cervix, and Hoxa-13 in the upper vagina). This same spatial organization of Hoxa genes with their respective derivatives of the different segments of the müllerian duct is also maintained in humans (Taylor et al. 1997). Thus, interaction between HOXA-9 and presumably several other non-HOX genes determines the proper development of the human fallopian tube.

Gross Anatomy

The fallopian tube is located anterior to the ovary. The tube extends medially from the area of its corresponding ovary to its origin in the posterosuperior aspect of the uterine fundus. In an adult during the reproductive years, its length is usually between 9 and 12 cm. The tube at the ovarian end opens to the peritoneal cavity and is composed of about 25 finger-like extensions of the tube – the fimbriae. The fallopian tube consists of five main segments. From medial to lateral, they are the intramural (interstitial) portion, isthmus, ampulla, infundibulum, and fimbriated end (Fig. 3). The fimbriae attach to the expanded end of the tube, the infundibulum, which is about 1 cm long and 1 cm in diameter. The infundibulum lies within a few millimeters of the lateral or tubal end of the ovary. It narrows gradually to about 4 mm in diameter and merges medially with the ampullary portion of the tube, which extends about 6 cm, passing anteriorly around the ovary. At a point characterized by relative thickening of the muscular wall along with a smaller diameter compared with the ampulla, the isthmic portion begins and extends about 2 cm toward the uterus. Within the myometrium, the tube extends as a 1 cm-long intramural segment until it joins the extension of the endometrial cavity at the uterotubal junction. Throughout its extrauterine course, the tube lays in a peritoneal fold along the superior margin of the broad ligament – the mesosalpinx.
Fig. 3

Posterior aspect (upper) and coronal section (lower) of fallopian tube including anatomic relationships with adjacent structures. All five segments of the fallopian tube (intramural segment, isthmus, ampulla, infundibulum, and fimbriated end) are illustrated. (From Netter FH. Atlas of Human Anatomy. West Caldwell: CIBA-GEIGY Corporation; 1989:Plate 350. Printed with permission from Elsevier, Inc. All rights reserved)

The arterial blood supply has a dual origin from branches of the ovarian and uterine arteries. Tubal branches of the uterine artery pass in the mesosalpinx laterally from the cornu of the uterus to anastomose with tubal branches of the ovarian artery. Venous drainage parallels the arterial supply via anastomosing tubal branches of uterine and ovarian veins, also located in the mesosalpinx. The arterial and venous distributions for lateral portions of the tube are supplied by the ovarian vessels whereas the uterine vessels supply the medial portions of the tube. Drainage from the ovarian veins is to the inferior vena cava on the right and renal vein on the left. Drainage from the uterine plexus is to the internal iliac vein. Tubal lymphatics typically drain into ovarian and uterine vessels. The former and latter drain into the para-aortic and internal iliac lymph nodes, respectively.

The nerve supply of the tube is both sympathetic and parasympathetic. Sympathetic fibers from T10 through L2 synapse in the celiac, aortic, renal, inferior mesenteric, cervicovaginal, and possibly presacral plexuses. Sensory pain fibers pass along with the sympathetic nerves to the spinal cord at the level of T10-T12. Parasympathetic fibers from the vagus nerve supply the lateral portion of the tube via postganglionic fibers from the ovarian plexus whereas the medial portion is innervated via S2-S4 parasympathetic fibers synapsing in the pelvic plexuses.

Histology

A mucosa, wall of smooth muscle (muscularis or myosalpinx), and serosa constitute the three layers of the fallopian tube. The mucosal layer lies directly on the muscularis. It consists of a luminal epithelial lining and a scanty underlying lamina propria containing vessels and spindle or oval mesenchymal cells. Although the lamina propria may be small in area, this is the site of decidua in 5–12% of postpartum tubes (Fig. 4), and decidua may be seen in 80% of tubes removed for ectopic pregnancy (Green and Kott 1989). The stroma of the plicae of the fallopian tube tends to be more fibrotic in the postmenopausal years. The mucosa increases significantly in its gross structural complexity as the lumen enlarges from the uterine to the ovarian ends. The interstitial/intramural portion contains a mostly flat mucosa with minimal undulation. It is lined by endometrium in the most proximal portion at the junction of the endometrial cavity and tubal ostium. Farther away from the tubal ostium, the mucosa of the interstitial/intramural portion is lined by an epithelial lining that is more typical of distal portions of the tube but with lesser numbers of ciliated cells. The isthmus shows slightly greater undulation than is seen in the interstitial/intramural portion and contains a limited number of blunted plicae (Fig. 5). In the ampulla, the plicae are frond-like and delicate, and both secondary and tertiary branches may be appreciated (Fig. 6). The infundibular and fimbriated end plical patterns are similar to that of the ampulla except that the plicae of the fimbriated end are essentially exophytic and have no underlying smooth muscle wall. A distinct fimbria, the fimbria ovarica, runs from the tubal ostium to one pole of the ovary and is involved in ovum pick-up, in which there appears to be a realignment of fimbriae in their relationship to the ovary itself. However, it should be noted that histologic characterization of this structure is very limited (Okamura et al. 1977).
Fig. 4

Decidua. The plicae are expanded due to decidual change within the lamina propria. The decidual cells have cytologic features similar to those of endometrial decidua. Scattered lymphocytes are present in the background

Fig. 5

Isthmus. The appearance is similar to the interstitial (intramural) segment except that the mucosa shows slightly more undulation with a limited number of blunted plicae

Fig. 6

Ampulla. In comparison with the interstitial (intramural) segment and isthmus, the ampulla has a greater diameter of the entire cross section of the tube, greater diameter of the lumen, and thinner muscularis. The plical architecture of the ampulla is more complex than that of the interstitial (intramural) segment and isthmus

The epithelium of the mucosa is composed of a single layer of cells, or it may be pseudostratified. It predominantly consists of ciliated and secretory cells; the latter are more numerous (Fig. 7). A third cell, the intercalated (“peg”) cell, is thought to exist. Some believe that this is a variant of the secretory cell, but it is not reliably identified on H&E sections. Ciliated cells are more abundant in the lateral portions of the tube, and the secretory cells are more numerous in the medial portions. The ciliated cell is columnar or round and has a mild to moderate amount of eosinophilic or clear cytoplasm. The nucleus is oval to round, and the chromatin is moderately granular and slightly basophilic. Ultrastructurally, each of the cilia is composed of a central pair of microtubules that is surrounded by nine outer doublet microtubules. In Kartagener’s syndrome, where cilia are scanty and structurally/functionally defective, fertility is impaired but not abolished (Halbert et al. 1997). The reader is referred elsewhere for additional details regarding the structure and physiology of fallopian tube cilia (Lyons et al. 2006).
Fig. 7

Mucosal epithelium of the fallopian tube. The epithelium contains a mixture of ciliated (arrow) and secretory (arrowhead) cells

The secretory cell also is columnar and approximately the same height as the ciliated cell but often narrower with scant eosinophilic cytoplasm. Its nucleus is columnar, and it is thinner and slightly darker than the nucleus of the ciliated cell. Immunohistochemically, the normal mucosal epithelium of the fallopian tube frequently and diffusely expresses WT-1, ER, and PR. The Ki-67 labeling index is typically <10% (George et al. 2012; Kuhn et al. 2012a), but it is higher in the proliferative compared with secretory phase of the menstrual cycle (George et al. 2012). The secretory cell exhibits the immunophenotype HMFG2(+)/PAX8(+)/p73(-), while the opposite pattern is characteristic of ciliated cells (Bowen et al. 2007; Lee et al. 2007; Roh et al. 2009).

The morphologic characteristics of the tubal epithelium change during life. Ciliated cells appear during early fetal development and persist until the postmenopausal years. At this time, as circulating estrogen levels drop, the cilia are gradually lost. Estrogen therapy in postmenopausal women, however, restores both the cilia and the ability to transport particulate matter. The presence of estrogen receptor in the fallopian tube also supports that estrogen is involved with ciliogenesis. The characteristics of the tubal epithelium change during the course of the menstrual cycle (Donnez et al. 1985). Early in the cycle, the cells are of low height, and the secretory cells appear relatively inactive. As ovulation approaches, probably under the influence of an increasing amount of estrogen, the secretory cells become prominent and actually project above the luminal border of the ciliated cells. In association with the effects of estrogen and progesterone, changes in cilial maturity and repeated ciliation and deciliation occur during the menstrual cycle, including maximal ciliation around the time of ovulation (Donnez et al. 1985; Verhage et al. 1979). Additional details of fallopian tube physiology are available elsewhere (Jansen 1984).

In addition to the three epithelial cell types described above, scattered lymphocytes may be seen located basally above the basement membrane. Immunohistological analysis of these lymphocytes indicates a preponderance of the T-cytotoxic/suppressor subtype, consistent with formation of mucosal-associated lymphoid tissue (MALT) (Morris et al. 1986). In addition, the inflammatory component of normal tubal mucosa includes macrophages and dendritic cells (Ardighieri et al. 2014).

The tubal muscularis generally has two layers: an inner circular layer and outer longitudinal layer. The circular layer forms the major muscle mass of the tube. Its thickness varies, being greater in the isthmus and lesser in the ampulla/infundibulum. The outer longitudinal layer is easily overlooked, as it is composed of inconspicuous bundles of smooth muscle interspersed with loose connective tissue containing numerous small blood vessels. At the uterine end, beginning in the intramural tube and extending laterally about 2 cm, there is, in addition, an inner longitudinal layer. The serosa is lined by flattened mesothelial cells. The interface between the mesothelial lining of the serosa and epithelium of the mucosa has been referred to as the tubo-peritoneal junction (Fig. 8) (see section on “Histologic Features” of “Intraepithelial Carcinoma”) (Seidman 2015). Beneath the mesothelium lies a small amount of connective tissue containing a few collagen fibers and blood vessels.
Fig. 8

Tubo-peritoneal junction. The flat mesothelial layer of the serosa (left) shows an abrupt transition (center) with the tall epithelium of the mucosa (right)

The wolffian or mesonephric duct develops in close proximity to the fallopian tube, and remnants from it normally persist throughout adult life. These remnants consist of 10–15 mesonephric tubules lying within abundant muscular stroma just peripheral to the fallopian tube. The tubules (epoöphoron) are lined by a single layer of low-columnar or cuboidal epithelium containing non-ciliated or ciliated cells (Fig. 9).
Fig. 9

Wolffian (mesonephric) duct remnants. The tubules are invested by abundant muscular stroma. Inset: They are round and lined by a single layer of bland cuboidal cells. This example is non-ciliated, but other cases may contain cilia

Gross Examination

Salpingectomy for Benign Disease, with or Without Hysterectomy

In hysterectomies with benign disease, both fallopian tubes should be measured in the longitudinal and transverse dimensions. The serosa should be examined for gross lesions. The patency of the fimbriated end can be determined with a blunt probe. If a lesion is present, it should be measured, its location (corneal/intramural, isthmic, ampullary, infundibular, or fimbriated end) noted, and its relationship to the lumen and serosa described. The entire length of the tube should be transversely cut (“bread loafed”) to identify lesions within the lumen. Grossly visible lesions should be sampled. For grossly unremarkable tubes, standard sections include ≥1 block from each side, but submission of the fimbriated end is recommended.

Hysterectomy and/or Oophorectomy with Salpingectomy for Non-fallopian Tube Malignant Disease

In hysterectomies for malignant disease, attention should be given to identifying involvement of the fallopian tubes, especially since focal disease may upstage the patient. The tubes should be examined, measured, and cut as described above. In cases of ovarian, peritoneal, or endometrial serous carcinomas, it is advisable to submit all tissue from both fallopian tubes for histologic examination to identify serous tubal intraepithelial carcinoma (STIC), especially in the fimbriated end (see “Carcinoma” section below). A number of studies have shown the clinical and diagnostic value of submitting all tubal tissue in this setting (Koc et al. 2018; Lengyel et al. 2013; Singh et al. 2015).

Total or Partial Salpingectomy for Tubal Ectopic Pregnancy

The external appearance of the specimen should be carefully examined, and blood distending the lumen should be sought and sampled. If the tubal pregnancy is apparent, its site and location should be noted as described previously and sampled. A rupture site if present should be described and sampled. If the ectopic pregnancy is not obvious, extensive sampling may be necessary. Even a tubal abortion leaves foci of trophoblast at the implantation site. Blood clot in the tube or as a separate specimen should be sampled for microscopic examination to identify trophoblastic cells or chorionic villi.

Bilateral Partial Salpingectomy for Tubal Sterilization

The most important goal in this setting is to document that the tube has been completely transected. This requires complete cross sectioning of the entire tube and submitting the entire specimen for histologic examination. For instances where a complete transection cannot be demonstrated on the original H&E slides, it may be necessary to have the tissue reoriented in the paraffin block and then cut multiple deeper H&E levels exhausting the entire paraffin block.

Prophylactic Bilateral Salpingo-Oophorectomy

Measurements should be made as specified above. The SEE-FIM (Sectioning and Extensively Examining the FIMbria) protocol for complete examination of the fallopian tube is recommended (Medeiros et al. 2006). Accordingly, the fimbriated end should be amputated from the rest of the tube and serially sectioned at 2 mm intervals along the long axis. The entire length of the remaining tube should be cut perpendicular to the long axis (“bread loafed”) at 2 mm intervals (Fig. 10). The ovary should also be cut perpendicular to the long axis (“bread loafed”) at 2 mm intervals. All fallopian tube and ovarian tissue should be submitted for histologic examination.
Fig. 10

Sectioning of fallopian tube from a prophylactic bilateral salpingo-oophorectomy specimen. (a) Diagram of fallopian tube prior to (upper) and during (lower) sectioning. From the proximal-most end of the fallopian tube to the beginning of the fimbriated end, transverse sections (solid, vertical/diagonal, and red lines) should be cut at 2 mm intervals. The fimbriated end should be amputated (dashed, vertical, and red lines). The fimbriated end should be cut at 2 mm intervals parallel to the long axis of the fallopian tube (solid, horizontal, and red lines). All gross tissue should be submitted for histologic examination. (b) Gross photograph of fallopian tube after complete sectioning as per (a)

Although there is no standard in terms of how many H&E slides need to be prepared from each block, our routine practice is 1 H&E slide per block; however, it has been recognized that in anecdotal cases, additional deeper H&E levels may identify a small tubal intraepithelial carcinoma not present on the initial H&E level. Nonetheless, based on the findings in one study, it has been proposed that routine performance of multiple deeper H&E levels for risk-reducing specimens is not necessary (Rabban et al. 2009b).

Salpingectomy for Tubal Neoplasms, with or Without Hysterectomy and/or Oophorectomy

A protocol for gross examination of a tube with carcinoma has been developed by the Association of Directors of Anatomic and Surgical Pathology (Longacre et al. 2007). That protocol also lists the essential clinical, gross, and histologic information which should be included in the pathology report. Similarly, the International Collaboration on Cancer Reporting has also published their recommendations for which elements should be provided in a pathology report for tubal carcinoma (McCluggage et al. 2015a).

The size of the specimen and tumor should be recorded, as should the exact location of the tumor within the tube. The external surface should be examined for visible disease, and any lesions should be sampled. It is important to note whether the fimbriated end is open or closed, the latter being determined by having a hydrosalpinx-like, hematosalpinx-like, or pyosalpinx-like gross appearance. At least three sections from the tumor should be obtained. Sections should show the relationship of the tumor with mucosa, depth of invasion, and serosa.

Nonneoplastic Lesions of Fallopian Tube

Metaplasia, Hyperplasia, and Other Epithelial Changes

The tubal epithelium may undergo various metaplastic changes, including squamous, transitional, mucinous, or oncocytic type (Fig. 11) (Egan and Russell 1996; Rabban et al. 2009a; Seidman 1994). Mucinous metaplasia may be associated with Peutz-Jeghers syndrome and can also accompany chronic inflammation. Arias-Stella reaction can occur with intrauterine pregnancy. Mucosal hyperplasia of variable degree and extent, which may be bilateral, is frequent (Moore and Enterline 1975; Robey and Silva 1989; Yanai-Inbar and Silverberg 2000; Yanai-Inbar et al. 1995). It is nonspecific, without clinical significance, and can be associated with various conditions and lesions. The hyperplastic epithelium can show stratification, loss of cell polarity, crowding of cells, and small papillary tufts; however, mitotic activity is usually low. In the setting of inflammation, mucosal distortion (including plical blunting and stromal fibrosis) may be seen. Nuclear atypia can be present but is typically mild (Hunt and Lynn 2002). In some cases, particularly those associated with marked salpingitis, the degree of hyperplasia (including cribriform architecture) can simulate carcinoma (Fig. 12) (Cheung et al. 1994b; Dougherty and Cotten 1964). This differential diagnosis is diagnosed below in the section on “Carcinoma”. A particular form of hyperplasia, designated papillary tubal hyperplasia, is characterized by epithelial stratification, small detached papillary clusters, more papillary branching than seen normally, and psammoma bodies (see below) within either stroma and/or detached papillary clusters (Fig. 13) (Kurman et al. 2011). It has been suggested that papillary tubal hyperplasia can be an etiology for ovarian atypical proliferative (borderline) serous tumors and implants in some cases although further academic investigation is warranted. Severe epithelial changes that mimic early adenocarcinoma may be produced by thermal artifact (Fig. 14).
Fig. 11

Squamotransitional cell metaplasia. The upper center portion shows more squamous differentiation while the lower left portion shows more transitional cell differentiation. Other cases may be of pure squamous or transitional cell type

Fig. 12

Mucosal hyperplasia. In the setting of inflammation, mucosal distortion may be seen. (a) Marked distortion of the plicae is present in this case of florid salpingitis. Other foci (b) show glandular epithelium with cribriform architecture. The nuclei exhibit only mild atypia and are mitotically inactive. Ciliated cells can still be identified

Fig. 13

Papillary tubal hyperplasia. (a) The mucosa exhibits epithelial stratification, detached epithelial clusters, and psammoma bodies within the stromal cores of small papillae. (b) Numerous small papillae with stromal cores are present within the lumen, and some appear to bud-off from larger papillae

Fig. 14

Thermal artifact. This appearance may falsely suggest adenocarcinoma because of the distorted and stratified epithelium with darkly staining nuclei. However, closer magnification will show nuclei with the streaming effect that is characteristic of thermal injury

Psammoma bodies (“salpingoliths”) are an occasional finding. They are often nonspecific and can be seen with normal-appearing epithelium or in various miscellaneous settings, such as chronic salpingitis associated with IgG antibodies to Chlamydia, ovarian serous tumors, papillary tubal hyperplasia (Fig. 13; see above), or otherwise normal epithelium (Martin et al. 1995; Seidman et al. 2002).

Nests of cells morphologically similar to ovarian hilus cells have been described in the tube (Hirschowitz et al. 2011). In the absence of either Reinke crystals or close association with nonmyelinated nerve fibers, it is difficult to exclude the possibility of an adrenal rest. Hilus cell nests with Reinke crystals may be seen, however, in fimbrial stroma. Ectopic pancreatic tissue or sex cord inclusions (Fig. 15) can rarely occur (Longworth et al. 2018; McCluggage et al. 2015b).
Fig. 15

Sex cord inclusions in the fimbriated end of the fallopian tube. Immunohistochemical stains for inhibin and calretinin were diffusely positive. The ovaries were thoroughly sampled, and an ovarian mass was not present. (Photo courtesy of Dr. Kathleen Cho (Univ. of Michigan Medical School))

The tubal serosa, by invagination, may give rise to a number of benign inclusion cysts. The simplest is a 1- to 2-mm unilocular cyst lying directly beneath the serosal surface lined by one or more layers of mesothelial cells – a mesothelial inclusion cyst. By a process of transitional cell metaplasia, small Walthard nests can arise as 1- to 2-mm yellow-white nodules beneath the serosa. Histologically, the Walthard nest may be solid or cystic and resemble urothelium (Fig. 16). The cells have nuclei which are irregularly ovoid with a longitudinal nuclear groove, giving them a coffee-bean appearance. Both mesothelial inclusion cysts and Walthard nests are common incidental findings of no clinical importance.
Fig. 16

Walthard nests. Walthard nests may be either solid or cystic. Closer magnification will show nuclei which are bland with transitional (urothelial) cell differentiation

Endometriosis and Endosalpingiosis

Normally, endometrial tissue can be found within the mucosa of the intramural and isthmic portions of the fallopian tube. The presence of endometrial tissue within the lumen has been referred to as “endometrial colonization”; however, it is unclear whether this is a variant of normal as opposed to true endometriosis. Endometriosis of the tube can be found within the lumen or myosalpinx or on the serosa. In occasional cases, the configuration of endometriosis may produce a mass clinically or grossly simulating a tumor (“polypoid endometriosis”) (Parker et al. 2004). A form of endometriosis designated “post-salpingectomy endometriosis” occurs in the tip of the proximal stump of the fallopian tube years after tubal ligation (Clement 2007). This form is apparently common. Endosalpingiosis is ectopic tubal-type epithelium involving the serosal surface of the tube. Both endometriosis and endosalpingiosis are discussed in detail in the chapter on “Diseases of the Peritoneum”.

Salpingitis Isthmica Nodosa

Salpingitis isthmica nodosa (SIN) is a pseudoinfiltrative lesion consisting of diverticula of tubal epithelium in the isthmus. It occurs in women between the ages of 25 and 60 years (average, 30 years). SIN is often bilateral. The external gross appearance is that of one or more nodularities in the isthmus, ranging up to 1–2 cm in diameter. The serosa is smooth. Grossly, the tissue is firm, and careful inspection may disclose some of the dilated diverticula.

Histologically at low-power magnification, round to elongated dilated glands proliferate through the muscularis, which is usually accompanied by nodular smooth muscle hyperplasia and mural thickening (Fig. 17). The glands proliferate in a circumferential and swirling pattern around the centrally dilated lumen of the fallopian tube. In some sections, it may be possible to appreciate a communication with the central lumen, indicating a diverticular process. The glands are composed of a single layer of bland tubal-type epithelium. An altered stromal reaction is typically absent. However, SIN is frequently associated with chronic salpingitis (Kutluay et al. 1994). Endometrioid stromal cells lying beneath the diverticula may be abundant; however, they are usually sparse or absent. If both glands and stroma are present, it may be difficult to distinguish SIN from tubal endometriosis in some cases.
Fig. 17

Salpingitis isthmica nodosa. Glands extend into the wall in a circumferential and swirling manner around the central lumen in the fallopian tube. The glands are mostly rounded, and some are cystically dilated. Occasional glands show mild contour irregularities. Some glands contain blood within the lumens. Closer magnification will show glands lined by a single layer of bland tubal epithelium

The etiology is unknown, but post-inflammatory distortion and an adenomyosis-like process are possibilities (Bolaji et al. 2015). An important complication of SIN is infertility, and there is a strong association with ectopic tubal pregnancy (Green and Kott 1989; Homm et al. 1987; Majmudar et al. 1983; Persaud 1970; Saracoglu et al. 1992). A rare complication that we have seen is rupture of a deep diverticulum through the serosa, with subsequent mild intra-abdominal bleeding and pelvic pain.

Ectopic Pregnancy

An ectopic pregnancy occurs when the developing blastocyst implants at a site other than the endometrium of the fundus or lower uterine segment. Because more than 95% of ectopic pregnancies occur in the fallopian tube, the terms ectopic pregnancy and tubal pregnancy are nearly synonymous. However, implantation on both tubal fimbriae and ovary or in the interstitial segment of the fallopian tube (intramural pregnancy) or cornu, abdominal cavity, cervix, or retroperitoneum also may occur, in descending order of frequency (Breen 1970). Hepatic, diaphragmatic, and splenic pregnancies are extremely rare (Delabrousse et al. 1999).

Etiology

The mechanisms responsible for ectopic pregnancy are largely unknown, but any disease process that alters the normal tubal anatomy seems to increase the frequency. Although delay in entering the uterine cavity may predispose the blastocyst to tubal nidation, experimentally delayed conceptuses in rabbit, guinea pig, and mouse oviducts degenerate and fail to implant. However, ectopic pregnancy is reported uncommonly in nonhuman primates. As many as 88% and 43% of carefully studied tubes with an ectopic pregnancy will show chronic salpingitis and salpingitis isthmica nodosa, respectively (Green and Kott 1989). Ultrastructural studies have demonstrated that the mucosa of fallopian tubes in women with ectopic pregnancies have lower numbers of ciliated cells compared with women that have intrauterine pregnancies (Vasquez et al. 1983). Risk factors for ectopic pregnancy are (in descending order of magnitude): prior ectopic pregnancy, prior tubal surgery, smoking (>20 cigarettes/day), pelvic inflammatory disease, multiple spontaneous abortions (≥3), increasing age (>40 years), prior medically induced abortion, infertility (>1 year), multiple sexual partners (>5), and previous IUD use (Bouyer et al. 2003).

Clinical Features

Currently, ectopic pregnancy accounts for 1–2% of clinically known pregnancies (ACOG 2008; Farquhar 2005; Van Den Eeden et al. 2005). Simultaneous ectopic and intrauterine implantations (heterotopic pregnancy) used to occur in 1 in 30,000 pregnancies decades ago; however, the frequency now can be as high as 0.75–1% of pregnancies after undergoing assisted reproductive technology (Habana et al. 2000; Marcus et al. 1995). The classic presentation of ectopic pregnancy includes amenorrhea with subsequent vaginal bleeding and/or abdominal pain. Tubal rupture is associated with intra-abdominal hemorrhage. The frequency of left- versus right-sided ectopic tubal pregnancies is similar, but they are slightly more common on the right (Breen 1970; Brenner et al. 1980). Rare cases are bilateral.

Serial serum beta-human chorionic gonadotropin (β-hCG) measurements and transvaginal ultrasonography are important parts of the clinical evaluation. Management typically consists of either surgery (salpingectomy or salpingostomy) or medical therapy (methotrexate). Incomplete removal of trophoblastic tissue may result in persistent ectopic pregnancy, which occurs in 2–11% and 4–20% of cases after laparotomy with salpingostomy and laparoscopic salpingostomy (Farquhar 2005; Fylstra 1998). These figures are similar to the frequency of failure with systemic methotrexate therapy. In some cases, persistent ectopic pregnancy may be a result of spillage of gestational tissue from disruption/morcellation of the specimen after salpingostomy or salpingectomy. In such instances, the lesional tissue may be found as nodules/implants on pelvic, omental, or uterine serosal surfaces (Cataldo et al. 1990; Doss et al. 1998).

Pathologic Features

The unruptured tubal pregnancy is characterized grossly by a somewhat irregular elongated dilatation of the tube, with a blue discoloration caused by hematosalpinx (Fig. 18). Within the tube, most ectopic pregnancies are found in the ampulla (~80%), isthmus (12%), and fimbriae (5%) (Breen 1970).
Fig. 18

Ectopic pregnancy. External view of dilated fallopian tube containing an ectopic pregnancy. The cross section will show a hemorrhagic cut surface

Nearly two-thirds of cases contain a grossly or microscopically identifiable embryo. Chorionic villi usually are found in the blood-filled and dilated tubal lumen and, in 75% of cases, appear viable. Implantation is deeper and more apt to be associated with a viable pregnancy when the placentation occurs on the mesosalpingeal side of the tube as compared with the anti-mesosalpingeal side (Kemp et al. 1999). The extra-villous intermediate trophoblast of the conceptus penetrates deep in the tubal wall. On occasion, this proliferation may exhibit diffuse sheet-like architecture, which can raise concern for a gestational trophoblastic neoplasm or hydatidiform mole (Burton et al. 2001; Sebire et al. 2005); however, this appearance is within the range of proliferation that can be encountered in ectopic pregnancies (Fig. 19). Perhaps because of the limited ability of the endosalpingeal stroma to undergo decidualization, and analogous to a placenta increta, the chorionic villi invade muscularis and then serosa (Pauerstein et al. 1986). Another major difference compared with uterine implantation is the failure of tubal trophoblast to differentiate into chorion frondosum and chorion laeve (Randall et al. 1987), but a gestational sac can be seen (Pauerstein et al. 1986). Vascular changes in mid-sized tubal arteries adjacent to ectopic pregnancies are similar to those found in the vessels near uterine implantations, with invasion by intermediate trophoblast, proliferation of the vascular intima, and accumulation of foam cells in the intima.
Fig. 19

Exuberant intermediate trophoblast proliferation in an ectopic pregnancy. The sheet-like architecture and atypical epithelioid cells should not be mistaken for a gestational trophoblastic neoplasm or hydatidiform mole. Chorionic villi are present on the left side of the photograph

Chronic salpingitis is found in nearly half the patients, with a reported range of 29–88% (Green and Kott 1989). Salpingitis isthmica nodosa may also be present. Arias-Stella reaction can be seen in the fallopian tube mucosa (Milchgrub and Sandstad 1991). Clear cell hyperplasia has been reported (Tziortziotis et al. 1997).

The clinicopathologic features of extratubal ectopic pregnancy vary according to the site (Oliver et al. 2007). Cornual or interstitial pregnancies may expand up to about 12 weeks, when rupture may lacerate one of the uterine arteries as well as the entire side of the uterus. Cervical ectopic pregnancy presents with bleeding similar to an incomplete abortion. Because of the nature of the cervical tissue underlying placental implantation, control of bleeding may be difficult. Ovarian pregnancy is clinically similar to tubal pregnancy, including frequent preoperative rupture. More than half the patients in one series had a history of previous reproductive tract disease or infertility (Grimes et al. 1983). Macroscopic examination typically reveals a hemorrhagic mass replacing the ovary. Pathologic criteria for ovarian pregnancy have been proposed: (1) the tube must be intact and separate from the ovary; (2) the gestational sac must occupy the normal position of the ovary; (3) the gestational sac must be connected to the uterus by the utero-ovarian ligament; and (4) ovarian tissue must be demonstrated within the wall of the sac (Grimes et al. 1983). Pathologic documentation of ovarian tissue within the pregnancy may be difficult or impossible if treatment consists of conservative resection or if the pregnancy has extensively replaced the ovarian tissue.

Sequelae

The natural history of tubal ectopic pregnancy includes spontaneous expulsion from the fimbriated end (tubal abortion), as well as embryonal death and involution of the conceptus. Typically, however, continued growth of the trophoblast leads to increasing dilatation and weakening of the muscularis, with rupture at about the eighth week. About 25% of tubal pregnancies have ruptured by the time of diagnosis (Falcone et al. 1998). Hemorrhage due to rupture may be massive, and ectopic pregnancy is a major cause of maternal mortality during pregnancy. Rare ectopic pregnancies have proceeded to term with fetal viability.

In grossly normal fallopian tubes, chorionic villi or placental site nodules may be found, indicative of a prior unsuspected ectopic pregnancy (Jacques et al. 1997; Nayar et al. 1996). A subset of tubal pregnancies forms a mass that, with involution of trophoblast and reestablishment of the menstrual cycle, may present problems in differential diagnosis. This convoluted, blood-filled tube (including organization, variable inflammation, and adhesions), often with involved ipsilateral ovary, may simulate a tumor or an endometrioma. Most, but not all, patients will have detectable serum β-hCG. Extensive microscopic sampling of this so-called chronic ectopic pregnancy may be required to demonstrate trophoblastic tissue, which may consist of nonviable chorionic villi (Ugur et al. 1996). In more advanced pregnancy, death of the fetus with retention in the extrauterine location may be followed by calcification of the fetus (lithopedion) or both membranes and fetus (lithokelyphopedion).

Polyps

Polyps of the fallopian tube have been classified as tumors in other textbooks on gynecologic pathology; however, they are included in the nonneoplastic section of this chapter for conceptual purposes. They are found in approximately 1–3% of women undergoing hysterosalpingography for infertility and may cause proximal tubal occlusion (David et al. 1981; Fernstrom and Lagerlof 1964). Their causality of and relationship with infertility has been debated in the literature. They are typically small and preferentially occur in the intramural segment of the fallopian tube, particularly at the tubal ostium. Polyps are frequently bilateral. Although they are removed for microscopic examination only rarely, histologically they are of endometrioid type and resemble endometrial polyps (Lisa et al. 1954). Given that endometriosis of the tubal mucosa is found in some patients, it is possible that tubal polyps might represent a microscopic form of polypoid endometriosis.

Infertility

Most of the diseases discussed in this chapter may result in sufficient anatomic distortion to cause tubal infertility. In contrast, purely physiologic tubal dysfunction is not well defined but may be illustrated by the immotile cilia of Kartagener’s syndrome that can lead to reduced fertility – only 3 of 12 women in one series succeeded in becoming pregnant (Afzelius and Eliasson 1983). Paratubal or fimbrial adhesions secondary to endometriosis, prior pelvic inflammatory disease, or appendicitis may interfere with normal tubal motility and ovum pick-up. For a detailed discussion of the pathophysiology of fallopian tube cilia in various diseases in relation to infertility, the reader is referred elsewhere (Lyons et al. 2006). Obliterative fibrosis (possibly secondary to inflammation within the uterus) or polyps at the uterine tubal ostium may lead to obstruction at the uterotubal junction (Fortier and Haney 1985; Lee et al. 1997).

Issues Related to Sterilization Procedures

Sterilization by interference with tubal function involves procedures designed to damage or obstruct the mucosa or lumen of the fallopian tube by surgical removal of a segment of the tube (bilateral partial salpingectomy), rings/clamps, electrocoagulation, intratubal chemical methods (e.g., silicone plugs and methylcyanoacrylate), or intratubal mechanical devices (e.g., Essure System) (Clark et al. 2017; Donnez et al. 1979; Stock 1983). Tubal resection should be confirmed by histologic demonstration of a cross section of the fallopian tube including the entire lumen. On occasion, histologic sections may only show fibromuscular/fibrovascular tissue without fallopian tube mucosa. Such cases may represent pelvic ligaments or vessels which were clinically mistaken for a fallopian tube. In order to completely evaluate those cases, it may be necessary to cut deeper levels from the paraffin block, including the possibility of reorienting and reembedding the tissue in the block so as to entirely cut through it and find a fallopian tube lumen. The above protocol also applies to cases in which a fallopian tube is definitely present histologically but for which a complete cross section of the lumen is not seen on the H&E slide.

In women that were initially treated by surgical resection, spontaneous reanastomosis or fistula formation, which may lead to fertilization and ectopic or intrauterine pregnancy, are common mechanisms of sterilization failure (Soderstrom 1985). To identify the cause of failure of tubal sterilization procedures, careful gross examination of the specimen, occasionally specimen salpingography, longitudinal orientation of the tubal segment in the paraffin block, and meticulous sectioning techniques may be necessary.

Salpingitis

Salpingitis consists of three major types: acute, chronic, and granulomatous/histiocytic. On occasion, some cases will have mixed features, but this section is arranged according to the predominant histologic appearance.

Acute Salpingitis

Acute salpingitis is a purulent inflammatory process usually secondary to the passage of bacteria from the cervix and uterine cavity into the tubal lumen (Lareau and Beigi 2008; McCormack 1994). It is the pathologic correlate of the clinical entity, pelvic inflammatory disease. It typically occurs in young, sexually active, and reproductive-age women. Important risk factors include patterns of sexual behavior and contraceptive use.

Grossly, the fallopian tube is enlarged and edematous (Fig. 20). The serosa is erythematous and may be covered with fibrinopurulent exudates. Pus may also fill the lumen. Histologically, the fallopian tube lumen, mucosa, and wall contain neutrophils, fibrinous debris, and ulceration (Fig. 21). Edema and lymphocytes may be present as well. Mucosal hyperplasia and distortion can be seen. The histologic appearance varies according to the severity and phase of the disease. The appearance may also vary somewhat based on the specific causative microbial agent, as discussed below. Significant fallopian tube-specific sequelae include infertility and ectopic pregnancy.
Fig. 20

Gross appearance of fallopian tube containing acute salpingitis. The tube is enlarged with a dilated lumen and erythematous mucosa. The wall is edematous and thickened. Other examples may contain pus in the lumen

Fig. 21

Acute salpingitis. (a) The mucosa shows distorted architecture and abundant inflammation, including pus in the overlying lumen. (b) The inflammatory component is mixed but mostly composed of abundant neutrophils

It is not clear if organisms are carried upward by sperm or trichomonads as vectors or whether some form of passive transport is in effect (Keith et al. 1984). The bacteria implicated in acute salpingitis appear to be from two sources: sexual transmission and lower genital tract flora. Although Neisseria gonorrhoeae and Chlamydia trachomatis have been considered the most common causative organisms, meticulous bacteriologic studies indicate that most cases are polymicrobial and that anaerobic bacteria, especially Bacteroides species and peptostreptococci, frequently are present, as well as aerobes such as Escherichia coli. The presence of serum antibodies against gonococcal pili in some of these women, however, suggests that gonococci may initiate the process, only to be supplanted by anaerobes. The role of mycoplasmas in acute salpingitis is controversial, and viruses do not appear to be etiologic. However, Herpes simplex virus infection involving the mucosa of a prolapsed tube with mixed acute and chronic inflammation has been reported (Lefrancq et al. 1999).

The gonococcus gains access to the tube most readily at the time of menstruation. This situation corresponds to the typical clinical presentation in which the onset of acute pain occurs a few days after menses. The onset of non-gonococcal, non-chlamydial acute salpingitis is not, however, clearly related to the recent onset of menses (Sweet et al. 1986). Elegant in vitro studies by Ward et al. (1974) have clarified the likely initial steps in gonococcal infection, and the molecular mechanisms involved have been reviewed elsewhere (Edwards and Apicella 2004; Lyons et al. 2006). N. gonorrhoeae perfused through the lumen of cultured whole tubes attach only to non-ciliated cells. Within 3 h, microvilli from the cells appear to embrace the gonococci and adhere to them. The bacteria then penetrate both the cells and intercellular junctions, with cell lysis and sloughing. Adjacent ciliated cells are also destroyed but are not invaded directly. Gonococcal lipopolysaccharide and gonococcal-induced tumor necrosis factor-alpha and various other cytokines cause much of the epithelial damage (Maisey et al. 2003; McGee et al. 1999), and the degree of pathogenicity likely depends on the bacterial as well as the host genome (Arvidson et al. 1999). After cell lysis, the bacteria penetrate the subepithelial connective tissue. In vivo, this process is considerably modified by the host response.

N. gonorrhoeae spreads via the epithelial surface and thus causes mucosal damage. A brisk diapedesis of granulocytes from capillaries into the mucosa and lumen occurs, and there is vascular engorgement and edema of all tubal layers. As the lumen fills with granulocytes and cellular debris, and as the tube distends, pus may be seen dripping from the fimbriated end in patients undergoing laparoscopy. In severe cases, transudation of plasma proteins results in a fibrinous exudate on the serosal surface, which is erythematous because of vascular dilatation. The cell necrosis, distension of the tube, and focal peritonitis account for the symptoms of abdominal and pelvic pain. Over time, repeated infections result in recurrent symptoms as well as the anatomic changes of chronic salpingitis, discussed below.

Chlamydia trachomatis is cultured frequently from the cervix, uterus, and fallopian tubes in women with acute salpingitis (Kristensen et al. 1985; Mardh et al. 1977). It is thought that the damage of the fallopian tube by Chlamydia is due to the 60 kDa chlamydial heat shock protein (hsp60), as well as other various cytokines (Hafner 2015; Lyons et al. 2006). The histologic appearance of tubes removed during the acute or subacute phase of chlamydial salpingitis is virtually identical to that caused by the gonococcus. There is an initial transmural and mucosal infiltration of neutrophils with an intraluminal exudate. Subsequently, there is a lymphoplasmacytic response with variable numbers of residual granulocytes. Chlamydial inclusion bodies have been identified within the epithelial cells (Winkler et al. 1985). On occasion, the lymphofollicular response may be so florid as to suggest lymphoma (Wallace and Hart 1991).

As a result of acute salpingitis (usually in the context of gonococcal or chlamydial disease), fibrinous adhesions develop between the fallopian tube serosa and surrounding peritoneal surfaces. Peritoneal inflammation may be widespread, and thin so-called violin-string adhesions may form between the liver and anterior abdominal wall as part of the Fitz-Hugh-Curtis syndrome.

In severe cases of acute salpingitis (as well as with chronic or granulomatous salpingitis) with involvement of the ovary regardless of the specific microorganism, both the ovary and tube are attached to one another by adhesions and create a mass in the form of a tubo-ovarian abscess (Fig. 22). Tubo-ovarian abscesses can be unilateral or bilateral. Histologically, the inflammatory component may be predominantly composed of neutrophils or contain a mixture of neutrophils, lymphocytes, histiocytes, and plasma cells. Widespread necrosis is common. The background fallopian tube and ovarian parenchyma will be markedly distorted, and abundant fibrous and edematous stroma may be present. Although N. gonorrhoeae and C. trachomatis are common bacterial causes of acute salpingitis, they are isolated in culture only rarely from tubo-ovarian abscesses. Both aerobic and anaerobic cultures of any tubo-ovarian abscess should be obtained in the operating room or laboratory. Prior treatment with antibiotics possibly may eliminate culturable organisms, but anaerobes are commonly isolated. E. coli, Bacteroides fragilis and other Bacteroides species, Peptostreptococcus, Peptococcus, and aerobic streptococci are the most commonly found organisms (Landers and Sweet 1983). Typically, these infections are polymicrobial.
Fig. 22

Gross features of tubo-ovarian abscess. In this case, bilateral tubo-ovarian abscesses are composed of fibroinflammatory masses, and the ovary and fallopian tube on each side are attached to one another by adhesions. The cut surface will show distorted fibrous tissue with edema, hemorrhage, and necrosis

Another organism that can result in tubo-ovarian abscess is Actinomyces israelii, which is part of the indigenous female genital tract flora (Persson and Holmberg 1984). Actinomycotic infections of the tube are associated with intrauterine contraceptive devices (IUDs) (see chapter on “Benign Diseases of the Endometrium”) (Dische et al. 1974). Anaerobic culture is necessary to permit growth of Actinomyces israelii. Microscopically, fragments of gram-positive filaments and sulfur granules may be recognized within pus. Pseudoactinomycotic radiate granules should not be mistaken for the sulfur granules of actinomycosis (Bhagavan et al. 1982; Pritt et al. 2006).

An asymptomatic form of acute salpingitis (“physiologic salpingitis”) is seen in tubes removed during postpartum ligation. Beginning about 5 h after delivery and present up to 7–10 days later, a small number of acute or mixed acute and chronic inflammatory cells are found in the mucosa or lumen of 10% or more of specimens (Fig. 23). Attempts to culture aerobic or anaerobic bacteria have been almost uniformly unsuccessful. The process may be secondary to the trauma of delivery or intrauterine tissue necrosis and is apparently of no clinical significance.
Fig. 23

Physiologic “salpingitis.” A mild amount of acute inflammation is present within the vascular spaces in the mucosa. Other cases may have mild acute inflammation within the mucosal epithelium or lamina propria

Chronic Salpingitis

As a result of acute salpingitis, the proximity of the ovary to the fimbriae allows multiple tubo-ovarian adhesions to form, which may also cause occlusion of the tubal ostium. If the fimbriae close before the ovary is involved as part of a tubo-ovarian abscess, the inflamed and dilated tube can form a pyosalpinx full of acute and chronic inflammatory cells. When acute salpingitis resolves, the acute and most of the chronic inflammatory cells gradually disappear, and the patient is left with either a severely scarred tube in the form of chronic salpingitis or a hydrosalpinx. C. trachomatis DNA has even been detected in fallopian tubes in a subset of cases that contained only chronic salpingitis (Hinton et al. 2000). Thus, the finding of chronic salpingitis may imply previous pelvic inflammatory disease in some patients.

In chronic salpingitis, the mucosal plicae are often adherent to one another secondary to surface fibrin deposition from acute salpingitis. This may be focal or extensive. If it is severe enough, the bases of the fimbriae may coalesce in the center with the fimbriae radiating outward, or the tips of the fimbriae may adhere blocking the lumen and causing a blunted end – the so-called clubbed tube (Fig. 24). Healing and organization in the non-fimbriated portions of the tube also lead to permanent bridging between folds. Classically, this results in so-called follicular salpingitis (Fig. 25); however, that term is a misnomer as it suggests a pattern of inflammation characterized by lymphoid follicles. In chronic salpingitis, plicae may retain much of their size and shape, but plasma cells, lymphocytes, or both are still present in the mucosa (Fig. 26). Often the height of the folds appears reduced, and the plicae may become blunted and have fibrous stroma. Therefore, the once orderly pattern of the mucosa becomes distorted. The mucosa may also be hyperplastic.
Fig. 24

So-called clubbed tube. The fimbriated end is closed because of fimbrial adhesions, creating a blunted end

Fig. 25

So-called follicular salpingitis. The plicae are adherent to one another, creating follicle-like spaces in the setting of chronic salpingitis

Fig. 26

Chronic salpingitis. (a) Fibrotic and blunted plicae. (b) The distorted plicae show the lamina propria filled with lymphocytes and plasma cells

Hydrosalpinx is characterized by obliteration of the fimbriated end and dilation of the tube, usually the ampullary and infundibular portions (Fig. 27). If the ovary is first involved by tubo-ovarian adhesions, the ovary may be compressed by the dilated tube. Because a luminal communication usually can be demonstrated between dilated and non-dilated portions of the tube, the etiology of the dilatation can be obscure. The dilated tube can become cystic and filled with serous fluid, and the wall is generally white, thin, and translucent with occasional fibrous adhesions on the external surface. The muscle wall is either thin and atrophic or replaced by fibrous tissue. Most of the epithelial lining consists of low-cuboidal cells, but an occasional plica may persist with columnar epithelium containing histologically normal ciliated and secretory cells (Fig. 28). A few lymphocytes may be found in the wall of the hydrosalpinx but are more commonly absent.
Fig. 27

Gross features of hydrosalpinx. The fallopian tube is massively dilated, producing a large cystic mass

Fig. 28

Hydrosalpinx. Most of the dilated fallopian tube contains a thin wall and atrophic mucosa. Residual small plicae are present. Note smooth muscle within the wall

Granulomatous/Histiocytic Salpingitis and Foreign Bodies

Granulomatous and histiocytic inflammation of the fallopian tube may result from infection by a number of different organisms or be induced by a variety of noninfectious processes, some of which include tissue reactions due to microscopic foreign bodies.

Pseudoxanthomatous/Xanthogranulomatous Salpingitis
Pseudoxanthomatous salpingitis (variably referred to as “pigmentosis tubae”) is characterized by lipofuscin- and hemosiderin-laden macrophages within the lamina propria of the mucosa of the fallopian tube, including distension of the plicae, and is associated with endometriosis (Fig. 29) (Clement et al. 1988; Furuya et al. 2002; Herrera et al. 1983; Munichor et al. 1997; Seidman et al. 1993; Seidman and Woodburn 2015). The tubes may be enlarged and edematous, with the mucosa having a dark brown polypoid gross appearance. Despite the association with endometriosis, this process also might result from salpingitis with associated bleeding (Clement et al. 1988; Seidman et al. 1993). It has been suggested that pseudoxanthomatous salpingitis should be distinguished from xanthogranulomatous salpingitis because of the latter’s association with pelvic inflammatory disease and lack of association with endometriosis (Furuya et al. 2002). In contrast with pseudoxanthomatous salpingitis, xanthogranulomatous salpingitis has mucosa which is usually grossly yellow and purulent, macrophages which are foamy (as opposed to the dark brown macrophages in pseudoxanthomatous salpingitis), and other types of inflammatory cells, including multinucleated giant cells (Furuya et al. 2002; Ladefoged and Lorentzen 1988). A potentially related lesion that has been described in the tube is xanthelasma (Chetty et al. 2003).
Fig. 29

Pseudoxanthomatous salpingitis. The plicae are expanded and distorted due to sheets of histiocytes with eosinophilic cytoplasm in the lamina propria. This should not be mistaken for decidualization

Tuberculous Salpingitis

Mycobacterium tuberculosis historically has been the predominant etiologic agent of granulomatous salpingitis. The frequency of tuberculous salpingitis in women studied for tubal causes of infertility ranges from much less than 1% in the United States to nearly 40% in India (Parikh et al. 1997). Twenty percent of women who die of tuberculosis have tubal involvement (Schaefer 1970). Primary infection of the genitalia, as by coitus with a partner with genitourinary tuberculosis, is extremely rare. Secondary spread via a hematogenous route, usually from a primary pulmonary infection, is the usual route of infection. For unclear reasons, the blood-borne organism prefers the tubes rather than other parts of the female genital tract. The primary pulmonary lesion may not be radiologically evident, but extrapulmonary involvement of the peritoneum, kidneys, or other sites may be present. Lymphatic spread from primary intestinal tuberculosis or direct spread from the urinary bladder or gastrointestinal tract may occur. Tubal involvement is usually bilateral. Although the earliest pathologic lesions are microscopic, with advancing disease the tube increases in diameter and may become nodular, mimicking salpingitis isthmica nodosa. In the more common adhesive form of the disease, multiple dense adhesions may form between the tube and ovary, and the fimbriae and ostium may be obliterated (Haines 1958). With the exudative form of disease, progressive distension mimics bacterial pyosalpinx. Hematosalpinx, hydrosalpinx, tubo-ovarian abscesses, or a so-called frozen pelvis may be found late in the disease process (Parikh et al. 1997). In either form, serosal tubercles may be present.

In early disease, microscopic lesions are mucosal-based with a typical granulomatous reaction of epithelioid histiocytes and lymphocytes arranged in a nodular configuration. Multinucleated giant cells are often seen, and focal or massive central caseation may be present (Fig. 30). Immunosuppression can modify cellular immunity to a point where granulomas fail to form, and with this clinical information, the mere finding of acute and chronic inflammatory cells should lead to consideration of staining for acid-fast organisms. From the mucosa, extension to the muscularis and serosa may occur. As the tubercles enlarge and coalesce, they may erode through the mucosa and discharge their contents into the tubal lumen, and the tube may then become dilated. The mucosal inflammatory reaction leads to progressive scarring, with plical distortion and agglutination. Calcification can occur in areas of fibrosis. Because tubercles may not be present in a given section, the presence of caseation, fibrosis, or calcification in a tube may be the only histologic finding that suggests the need for more thorough evaluation. Notable mucosal distortion may result in hyperplasia mimicking carcinoma.
Fig. 30

Granulomatous salpingitis due to tuberculosis. Noncaseating granulomas are present in the mucosa. Note calcifications and multinucleated giant cells. Other cases may contain caseating granulomas

There are several complications of tuberculous salpingitis. Alteration in function is expected, and sterility is almost universal because of the common bilaterality of the disease. Because of repeated seeding of the endometrium from the infected tubes, mycobacterial culture and the histologic finding of endometrial granulomas on curettage are diagnostically useful (see chapter on “Benign Diseases of the Endometrium”).

Parasitic Salpingitis
Pinworm (Oxyuriasis)
The pinworm, Enterobius vermicularis, may migrate up the female genital tract, embed in the tube, and cause an inflammatory reaction. The tube can be involved with the ovary as a tubo-ovarian abscess, or a fibrous nodular area may be present. Acute and chronic inflammatory cells may be found together with eosinophils and portions of a gravid female worm. Ova can be released into the tissue, where they provoke a granulomatous reaction (Fig. 31), but identification of ova can be obscured by calcification and granulomas.
Fig. 31

Granulomatous salpingitis due to pinworm. This caseating granuloma contains abundant eosinophils. A pinworm egg (arrow) is present within the necrotic zone

Schistosomiasis (Bilharziasis)

Although tubal schistosomiasis may be one of the more common causes of granulomatous salpingitis worldwide, it is rare in the United States. In Africa, the fallopian tube is involved by schistosomiasis in 22% of all infected women (Gelfand et al. 1971). The ova of Schistosoma haematobium are most common, but Schistosoma mansoni eggs may be present in some women. Gross findings appear to be related to fibrosis surrounding the ova, producing a nodular or fibrotic tube. Histologically, the inflammatory reaction is typically granulomatous and may contain eosinophils, neutrophils, plasma cells, lymphocytes, and macrophages, including multinucleated giant cells. Some granulomas may be present within the stroma of the plicae and produce plical expansion. Ectopic pregnancy has been reported as occurring synchronously with tubal schistosomiasis in some patients.

Other Parasites

Where the condition is common, hydatid disease secondary to Echinococcus granulosus infection may involve the female genital tract, including the adnexae. Cysticercosis (Taenia solium) also has been described in the tube (Abraham et al. 1982). Other rare parasites that have been reported in the fallopian tube include Entamoeba histolytica (amebiasis). Liesegang rings should not be mistaken for parasites (Clement et al. 1989).

Fungal Salpingitis

Other fungi which rarely can cause tubo-ovarian abscesses or granulomatous salpingitis include Blastomyces dermatitidis, Coccidioides immitis, Candida, and Aspergillus. These may be secondary to hematogenous spread or disseminated disease.

Sarcoidosis

Sarcoidosis of the tube is rare (Boakye et al. 1997). Histologically, noncaseating granulomas may be seen in the mucosa. Culture, histochemical stains, and clinical information are necessary to exclude other granulomatous diseases.

Crohn’s Disease

Crohn’s disease of the ileum, colon, or appendix may secondarily involve the tube and ovary to produce a granulomatous salpingitis and tubo-ovarian abscess. Noncaseating granulomas can involve the entire thickness of the tubal muscularis as well as the mucosa. The mucosa may exhibit hyperplasia with reactive atypia (Brooks and Wheeler 1977). Fistulas from bowel to tube also can occur.

Other Types of Granulomatous/Histiocytic Lesions and Foreign Bodies

Malakoplakia has rarely been reported in the fallopian tube. Some vasculitides have a granulomatous pattern (see “Vasculitis” section below) (Bell et al. 1986). Foreign body granulomas due to starch and talc, as well as pulse granulomas (Rhee and Wu 2006), can occur in the tube. In order to detect some foreign bodies, granulomatous or histiocytic reactions should be examined under polarized light. Extruded keratin from endometrioid carcinomas with squamous differentiation of the endometrium or ovary can produce keratin granulomas on the serosa or fimbriated end of the tube, as well as within the tubal lumen (Kim and Scully 1990). It should be noted, however, that not all foreign bodies produce a significant granulomatous or histiocytic response. Gelatin microsphere embolization particles (Embospheres®/EmboGold®) used in uterine artery embolization for treatment of uterine leiomyomas may sometimes be found in the fallopian tubes or ovaries because of the vascular anastomosis between the uterine and ovarian arteries (Kim et al. 2007). In the fallopian tube, these particles are typically found within arterial lumens in the outer wall of the tube or para-tubal locations. They usually elicit only a mild lymphocytic response with rare multinucleated giant cells as opposed to the marked multinucleated giant cell reaction with a granulomatous or histiocytic component seen with other foreign bodies.

Torsion, Prolapse, and Intussusception

Among the various anatomic displacements of the tube, torsion is the most common. The usual predisposing factor is cystic enlargement of the ipsilateral ovary. A benign ovarian cyst or tumor is present in the majority of patients, but in a minority, a malignant ovarian tumor is the cause. Para-ovarian cysts also are associated with torsion. Tubal enlargement secondary to hydrosalpinx or pyosalpinx, or previous gynecologic surgery (especially sterilization), are additional etiologies, but torsion may occur in the absence of apparent adnexal disease (Bernardus et al. 1984). The typical patient is in the reproductive years, occasionally pregnant, and complains of the sudden onset of lower abdominal pain. At operation, the adnexa on one side is twisted, usually once or twice. Venous outflow is compromised early, and the resulting congestion may lead to arterial compression. The adnexa often is enlarged, edematous, and dark and shows hemorrhagic infarction. If surgical intervention is prompt, the tube may be preserved. Asymptomatic or undiagnosed torsion can occur.

Tubal prolapse into the vagina may occur rarely as a complication of vaginal or abdominal hysterectomy (See chapter on “Diseases of the Vagina”) (Ouldamer et al. 2013; Ramin et al. 1999). Clinically, this is characterized by dyspareunia, vaginal bleeding/discharge, or abdominal pain beginning a few days to several years after hysterectomy. However, some women may be asymptomatic. On clinical examination, an excrescence is seen in the vaginal vault, suggestive of granulation tissue or carcinoma. Fimbriae may be apparent grossly. Severe acute and chronic inflammation can be present microscopically, and papillary architecture or pseudogland formation by the tubal epithelium can mimic adenocarcinoma. Due to admixed granulation tissue, it may be difficult to recognize the lesional tissue as a distorted segment of fallopian tube (Song et al. 2005); however, close scrutiny should reveal papillae lined by benign tubal epithelium. Depending on the specific differential diagnosis, immunohistochemical staining for WT-1, ER/PR, CK7, CK20, p16, and/or Ki-67 may be of help.

Intussusception of the tube is rare. In one case, a para-ovarian cyst was engulfed by the end of the tube, and the fimbriated end was pulled into the ampulla (Adams 1969).

Congenital Anomalies

Structural congenital anomalies of the fallopian tube are rare. Diethylstilbestrol (DES) use during pregnancy was discontinued decades ago, but surgical specimens from patients that were born during the DES era may still be examined today. In utero exposure to DES produces shortened, sacculated, and convoluted fallopian tubes. The fimbriae are constricted, and the os is pinpoint (DeCherney et al. 1981). The mucosa may be absent, or when it is present, the plicae do not develop (Robboy et al. 1982).

Tubal duplication and accessory fallopian tubes are uncommon, but the latter occur more frequently (Beyth and Kopolovic 1982; Coddington et al. 1990; Daw 1973; Gardner et al. 1948). Absence of various segments of the fallopian tube (also variably referred to as atresia, hypoplasia, or interruption), absence of the ampullary muscularis, and complete absence of the tube have been described. These may be unilateral or bilateral, and they can occur with or without uterine anomalies, such as unicornuate or bicornuate uterus (reviewed in Nawroth et al. (2006)).

Vasculitis

The fallopian tube can be involved by vasculitis as part of localized or systemic disease, and involvement of the tube is less frequent compared with other sites within the gynecologic tract. Vasculitis involving the female genital tract can be of polyarteritis nodosa or giant cell arteritis types, but the former is more common (Ganesan et al. 2000; Hernandez-Rodriguez et al. 2009; Hoppe et al. 2007). Either one or multiple arterioles/small arteries may be involved. Clinical correlation is needed to determine whether or not vasculitis is localized to the gynecologic tract; however, it is uncommon for patients with vasculitis involving the female genital tract to have either a previous diagnosis of systemic disease or subsequent development of systemic disease (Ganesan et al. 2000; Hoppe et al. 2007).

Neoplasms of the Fallopian Tube

The neoplasms arising in the fallopian tube include benign and malignant types, but malignant tumors are more common than benign ones; however, both are infrequent. They are commonly mistaken for chronic salpingitis or pyosalpinx, both preoperatively and during the operative procedure itself. Many benign tumors are small enough to be incidental findings at laparotomy. The WHO Classification of fallopian tube tumors is listed in Table 1 (Crum et al. 2014). Most of these are nonspecific histologic types since the same ones can be seen in other gynecologic sites, especially the ovary.
Table 1

2014 WHO classification of tumors of the fallopian tube

Epithelial

Benign

 Papilloma

 Serous adenofibroma

Precursor lesion

 Serous tubal intraepithelial carcinoma

Borderline tumor

 Serous borderline tumor/atypical proliferative serous tumor

Malignant

 Low-grade serous carcinoma

 High-grade serous carcinoma

 Endometrioid carcinoma

 Undifferentiated carcinoma

 Others

  Mucinous carcinoma

  Transitional cell carcinoma

  Clear cell carcinoma

Mixed epithelial-mesenchymal

Adenosarcoma

Carcinosarcoma (malignant müllerian mixed tumor; MMMT)

Mesenchymal

Leiomyoma

Leiomyosarcoma

Others

Mesothelial

Adenomatoid tumor

Germ cell

Teratoma

 Mature

 Immature

Lymphoid and myeloid

Lymphomas

Myeloid neoplasms

Benign Neoplasms

Adenomatoid Tumor

Adenomatoid tumor (benign mesothelioma) is the most frequent type of benign tubal tumor. Previously reported lymphangiomas probably represent examples of this entity. They are usually only 1–2 cm in diameter, appearing as a nodule beneath the tubal serosa, and are yellow or white-gray on cross section. Rare cases are bilateral. Similar lesions may be found in the uterus, cul-de-sac, or ovary (see chapter on “Mesenchymal Tumors of the Uterus”). Their origin is presumed to be from the cells of the serosal mesothelium. A fortuitous section may demonstrate a connection between serosa and tumor, but usually the serosa covers the lesion.

Microscopically, the tumor may be large enough to displace the tubal lumen eccentrically and may grow into the supporting stroma of the luminal folds in an infiltrating manner. Multiple, small, slit-like, or ovoid tubules proliferate through the muscular wall of the fallopian tube; however, the stroma may be fibrous or hyalinized (Fig. 32). Foci of chronic inflammation can also be present. The tubules are lined by a single layer of low-cuboidal or flattened epithelial-like cells which contain abundant eosinophilic cytoplasm with variably sized vacuoles and round and bland nuclei. Mitotic figures are rare. The tubules may be empty or contain pale fluid. Infarction may occur in adenomatoid tumor. When this occurs, and when marked, there is the potential for confusion with other lesions, such as adenocarcinoma, because of the obscured junction between adenomatoid tumor and nonneoplastic tissue, pseudoinfiltration, solid patterns in viable tumor, and reactive atypia (Skinnider and Young 2004).
Fig. 32

Adenomatoid tumor. (a) Nodular configuration in the wall of the fallopian tube. (b) Diffuse proliferation of tubules which infiltrate the myosalpinx. Foci of chronic inflammation are also present. (c) The tubules are lined by a single layer of flat eosinophilic cells with cytoplasmic vacuoles and bland nuclei. The lumens of the tubules are empty. An intra-lumenal thin cytoplasmic strand, which can be focally seen in some cases, is present (arrow)

Histochemical studies have shown alcian blue-positive, hyaluronidase-digestible material in the cells and spaces; however, this material may be absent after routine processing for histologic sections. No significant glycogen or intracellular epithelial mucin is present, as might be found in a tumor of müllerian origin. Immunohistochemically, tumors express mesothelial markers (WT-1, calretinin, CK5/6, D2-40) and are usually negative for epithelial-specific markers (Ber-EP4, B72.3, MOC-31, ER, PR) (Sangoi et al. 2009; Wachter et al. 2011). Electron microscopic studies also support a mesothelial origin for these lesions. Clinically, they are asymptomatic, and recurrences after adequate excision are rare.

The most important lesion to be considered in the differential diagnosis, particularly at the time of frozen section, is metastatic signet ring cell carcinoma. Clinical data such as prior history of a carcinoma (some primary tumors may be occult, and such a history will not be known), extra-fallopian tube tumor seen intraoperatively (especially if multifocal), bilaterality, and histologic presence of a combination of glands, papillae, and solid sheets of tumor help favor a diagnosis of carcinoma. Nuclear atypia and mitotic activity should raise suspicion for carcinoma, but some signet ring cell carcinomas may lack these features. A source of confusion may be the presence of the alcian blue-positive, hyaluronidase-digestible material within the lumens of the tubules in adenomatoid tumor. At the time of intraoperative consultation, this material resembles epithelial-type mucin on H&E frozen section slides; however, it is lost during routine processing and, as a result, is not present in permanent H&E sections. After frozen section analysis, immunohistochemical stains specific for mesothelial and epithelial markers will help aid distinction.

Epithelial Tumors

Papilloma is rare (Gisser 1986). It is composed of an intraluminal mass with an “adenomatous” and very complex papillary proliferation. At low-power, the proliferation resembles an exaggerated pattern of tubal mucosa with fine stromal fibrovascular cores, and the quantity of papillae is much greater than in the normal fallopian tube (Fig. 33). On higher power, the epithelium resembles normal fallopian tube mucosa, including the presence of ciliated and secretory cells. The nuclei are bland, and mitotic activity is not seen. In our anecdotal experience, fallopian tube papilloma diffusely expresses ER and WT-1, and the Ki-67 proliferation index is low. Because of the complex papillary proliferation, this tumor may be confused with atypical proliferative (borderline) serous tumor, low-grade serous carcinoma, or a villoglandular variant of endometrioid carcinoma. Although very complex, the orderly degree of papillary branching of papilloma is in contrast to a greater degree of complexity and hierarchical papillary branching with cellular stratification and tufting of atypical proliferative (borderline) serous tumor. The fine micropapillary tufting, associated psammoma bodies, and stromal invasion of low-grade serous carcinoma are not seen in papilloma. At low-power, papilloma can resemble a villoglandular endometrioid carcinoma, but closer examination at high-power shows endosalpingeal cell types and an absence of endometrioid differentiation. Furthermore, squamous metaplasia, endometriosis, and foci with solid growth would favor endometrioid carcinoma.
Fig. 33

Fallopian tube papilloma. Abundant papillae with complex branching resemble the plicae of normal fallopian tube. Closer magnification will show the same type of epithelium seen in normal fallopian tube

Metaplastic papillary tumor is rare and found as an incidental finding in the lumen of the fallopian tube during the postpartum period (Bartnik et al. 1989; Keeney and Thrasher 1988; Saffos et al. 1980). It is of microscopic size and composed of broad papillae lined by stratified and tufted epithelium with cells showing abundant eosinophilic cytoplasm (Fig. 34). The nuclei do not exhibit malignant features. It is not clear whether this lesion is a papillary metaplastic proliferation or small atypical proliferative (borderline) serous tumor associated with pregnancy. Regardless, the behavior appears benign.
Fig. 34

Metaplastic papillary tumor. The tumor is small and characteristically located within the lumen of the fallopian tube. It contains a limited number of medium-sized papillae. Closer magnification will show papillae lined by columnar to cuboidal cells that have abundant, dense, and eosinophilic cytoplasm with nuclei which are bland or have, at most, mild atypia. Only a limited degree of stratification is present

Cystadenomas have been reported but are rare. Although the topic of whether or not atypical proliferative (borderline) tumors are benign has been debated in the literature, these tumors are included in the benign neoplasm section of this chapter for simplicity. Rare atypical proliferative (borderline) serous, endometrioid, and clear cell tumors of the fallopian tube have been reported. The literature is too limited to predict their outcome; however, behavior similar to their ovarian counterparts would be anticipated. Atypical proliferative (borderline) mucinous tumors have been described, but such cases should be rigorously evaluated to exclude the likely possibility that they represent secondary involvement of the fallopian tubes from a non-ovarian site.

Leiomyoma and Adenomyoma

Leiomyoma is the most common mesenchymal tumor of the fallopian tube; however, these are much less common than uterine leiomyomas. They are usually small and grossly and microscopically similar to those found in the uterus and other gynecologic sites, and they can undergo similar degenerative changes. Rarely, benign glands and smooth muscle may be so intimately involved in a tumor that a diagnosis of adenomyoma may be warranted; however, these may arguably represent endometriosis with smooth muscle metaplasia (“endomyometriosis”) or the so-called uterine-like mass.

Other Benign Mesenchymal and Mixed Epithelial–Mesenchymal Tumors

Although adenofibromas producing clinical masses are uncommon, those of microscopic size are not infrequent. In one consecutive series of fallopian tubes unassociated with tubo-ovarian malignancy or inflammatory disorders, and in which all tubal tissue was submitted for histologic examination, adenofibromas were found in 30% of cases (Bossuyt et al. 2008). In that study, the majority were < 0.3 cm in size, and only a small subset were > 1 cm. All arose in the fimbria. Some may be synchronously associated with an ovarian adenofibroma. Histologically, fallopian tube adenofibromas resemble their ovarian counterparts, with admixed epithelial and mesenchymal components (Fig. 35). The epithelial component may contain papillary clefting and is frequently cystic or composed of small round tubules. Most tumors are of serous histologic type, but a minority are of endometrioid type (Alvarado-Cabrero et al. 1997). The mesenchymal component is hypercellular, densely fibrotic, or hyalinized. In lesions <0.1 cm in size, an epithelial component may be absent, and the diagnosis of an early adenofibroma may be suggested because of a patch of cellular spindled stroma with a subepithelial arrangement.
Fig. 35

Adenofibroma. Note the biphasic architecture with cellular fibromatous stroma and round glands lined by a single layer of bland cuboidal epithelium. Other cases may be predominantly composed of round and blunted papillae with cleft-like architecture or have an abundant component of tubules

Cystadenofibroma, hemangioma, lipoma, chondroma, angiomyofibroblastoma, angiomyolipoma, and neural tumors are rare but have been reported. Their microscopic appearances are similar to their counterparts elsewhere in the body.

Teratoma

Tubal teratomas are rare. Clinically, a patient with a tubal teratoma usually is nulliparous and in the fourth decade. Grossly, the tumors are located most frequently in the lumen, often attached by a pedicle to the inner tubal wall. They may, however, be intramural or attached to the serosa. On section, they are more often cystic than solid and may be small (1–2 cm in diameter) or large (10–20 cm in diameter). As with their ovarian counterparts, ectodermal, mesodermal, and endodermal tissues are represented by mature elements. Most are in the form of a dermoid cyst. Rare teratomas consisting entirely of mature thyroid tissue have been described in the tube of women without clinical hyperthyroidism. Only rare cases of immature teratoma of the fallopian tube have been reported, including a mixed germ cell tumor in which one of the components was an immature teratoma (Li et al. 1999). Although ovarian teratomas appear to originate from abnormally developing ova, the pathogenesis of fallopian tube teratomas is unclear.

Malignant Neoplasms

Carcinoma

The history of the discovery and evolution about knowledge of carcinoma of the fallopian tube during the nineteenth and twentieth centuries has been reviewed elsewhere (Young 2007) and will not be repeated here. In the recent past, “carcinoma in situ” of the fallopian tube was considered uncommon since the majority of patients with fallopian tube carcinoma presented with advanced stage disease. Therefore, at the time of presentation, most tumors were of bulky size, and patients had symptomatic disease. Over the last several years, early tubal carcinomas (i.e., those which are commonly of microscopic size and clinically occult) have become diagnosed more frequently due to complete histologic examination of all fallopian tube tissue from prophylactic bilateral salpingo-oophorectomy specimens, and they have been also detected as incidental findings in routine specimens.

Clinical Features

Historically, primary adenocarcinoma of the tube was thought to be uncommon, and it has been estimated to account for 0.7–1.5% of invasive malignancies of the gynecologic tract (Benoit and Hannigan 2006; Platz and Benda 1995). However, the true frequency is difficult to determine because a substantial number of cases traditionally classified as “ovarian” are likely tubal in origin (see below). The incidence of fallopian tube carcinoma is 0.41 per 100,000 women in the United States (Stewart et al. 2007).

Tumors with “carcinoma in situ”/intraepithelial carcinoma and small tumors with microscopic invasion are usually asymptomatic and more commonly seen as occult findings in prophylactic bilateral salpingo-oophorectomy specimens or rarely seen as occult findings in routine specimens (see “Occult Disease in Prophylactic Bilateral Salpingo-Oophorectomy Specimens” and “Occult Disease in Routine Specimens in Women Without Known Genetic Risk (Presumably Sporadic Cases)” sections below for additional details regarding clinical presentation). They may be occasionally detected when tumor cells exfoliate into the fallopian tube lumen and are then found in endometrial or endocervical biopsies/curettages or Pap smears (Bagby et al. 2013). In such instances, a fallopian tube origin may not be clinically evident at first (and sometimes not even grossly evident at the time of hysterectomy), and further clinical evaluation is needed to eventually identify the true origin in the tube. Likewise, in rare cases, occult invasive tubal carcinoma may present as a distant metastasis (e.g., malignant pleural effusion or metastatic carcinoma of unknown primary site in a supraclavicular lymph node).

Most women with symptomatic tumors are between 50 and 80 years of age, with the mean age in large studies ranging from 56 to 64 years (Alvarado-Cabrero et al. 1999, 2013, Hellstrom et al. 1994; Rosen et al. 1999; Stewart et al. 2007). Tubal malignancies in women younger than age 40 years are very uncommon. A substantial proportion of women are nulliparous or have a previous history of infertility or pelvic inflammatory disease. Some patients have had a previous malignancy, usually breast carcinoma. A small percentage of patients have a synchronous tumor in another gynecologic site. The most common symptoms and signs are abnormal uterine bleeding/vaginal discharge, abdominal/pelvic mass, abdominal distention, and abdominal pain; however, a small subset of cases will be detected as an incidental finding as part of another gynecologic disorder (Alvarado-Cabrero et al. 1999; Baekelandt et al. 2000; Peters et al. 1988). Between 5% and 14% of women have ascites at the time of presentation (Baekelandt et al. 2000; Eddy et al. 1984). The classic symptom complex hydrops tubae profluens (intermittent colicky abdominal pain relieved by sudden discharge of watery fluid per vagina) is only present in a very small percentage of patients. Serum CA-125 is elevated in most but not all patients. Some patients have an elevated serum β–hCG level, which has been attributed to ectopic production. A subset of patients have tumor in endometrial biopsies/curettages or Pap smears. Because of the rarity of fallopian tube carcinoma (prior classifications), as well as the clinical presentation which simulates an ovarian tumor, a correct preoperative diagnosis of fallopian tube carcinoma is uncommon (although the vast majority of extrauterine high-grade serous carcinomas are likely of tubal origin). Rare patients can have an associated paraneoplastic syndrome (Matsushita et al. 1998; Seeber et al. 2008).

In symptomatic cases, women with BRCA-associated tumors present at an age slightly younger than those with sporadic tumors, and both patient groups have similar clinicopathologic features (Cass et al. 2005; Levine et al. 2003). Although, some studies of ovarian/tubal/peritoneal high-grade serous carcinomas suggest that tumors with BRCA mutations may more frequently exhibit the SET (solid, pseudoendometrioid, and transitional cell carcinoma-like) histologic pattern.

FIGO Stage
The staging system for fallopian tube carcinoma is that of the International Federation of Gynecology and Obstetrics (FIGO) [AJCC Cancer Staging Manual, 8th Edition], which is primarily based on surgical pathology findings. Tubal intraepithelial carcinoma represented stage 0 disease prior to the 7th Edition of the AJCC Cancer Staging Manual; however, stage 0 does not exist in the current 8th Edition. Serous tubal intraepithelial carcinoma (STIC) without invasion or extratubal spread should be classified as FIGO stage IA tubal carcinoma (McCluggage et al. 2015a). With stage I invasive tumors, disease is confined to the fallopian tube (Fig. 36). Involvement of other pelvic sites represents stage II, and with stage III, tumor involves the peritoneum outside of the pelvis. Finally, distant metastases are classified as stage IV. Details are listed in Table 2.
Fig. 36

Stage IA fallopian tube carcinoma. Carcinoma invades into the underlying lamina propria

Table 2

2014 FIGO staging system for fallopian tube carcinoma (AJCC Cancer Staging Manual, 8th Edition)

Stage I

Tumor is confined to fallopian tubes

 

IA:

Tumor limited to one fallopian tube (capsule intact); no tumor on fallopian tube surface; no malignant cells in the ascites or peritoneal washings

 

IB:

Tumor limited to both fallopian tubes (capsules intact); no tumor on fallopian tube surface; no malignant cells in the ascites or peritoneal washings

 

IC:

Tumor limited to one or both fallopian tubes, with any of the following:

IC1: Surgical spill

IC2: Capsule ruptured before surgery or tumor on fallopian tube surface

IC3: Malignant cells in the ascites or peritoneal washings

Stage II

Tumor involves one or both fallopian tubes with pelvic extension (below pelvic brim)

 

IIA:

Extension and/or implants on uterus and/or ovaries

 

IB:

Extension to and/or implants on other pelvic intraperitoneal tissues

Stage III

Tumor involves one or both fallopian tubes, with microscopically confirmed spread to the peritoneum outside the pelvis and/or metastasis to the retroperitoneal (pelvic and/or para-aortic) lymph nodes

 

IIIA1:

Positive retroperitoneal lymph nodes only (histologically proven):

IIIA1i: Metastasis up to 1 cm in greatest dimension

IIIA1ii: Metastasis >1 cm in greatest dimension

 

IIIA2:

Microscopic extrapelvic (above the pelvic brim) peritoneal involvement with or without positive retroperitoneal lymph nodes

 

IIIB:

Macroscopic peritoneal metastasis beyond the pelvis up to 2 cm in greatest dimension, with or without metastasis to the retroperitoneal lymph nodes

 

IIIC:

Macroscopic peritoneal metastasis beyond the pelvis >2 cm in greatest dimension, with or without metastasis to the retroperitoneal lymph nodes (includes extension of tumor to capsule of liver and spleen without parenchymal involvement of either organ)

Stage IV

Distant metastasis, including pleural effusion with positive cytology; liver or splenic parenchymal metastasis; metastases to extra-abdominal organs (including inguinal lymph nodes and lymph nodes outside the abdominal cavity); and transmural involvement of intestine

 

IVA:

Pleural effusion with positive cytology

 

IVB:

Liver or splenic parenchymal metastasis; metastases to extra-abdominal organs (including inguinal lymph nodes and lymph nodes outside the abdominal cavity); and transmural involvement of intestine

The staging terminology for cases with STIC and only positive washings is unclear. Some clinicians have considered this scenario FIGO stage 0 (old staging system) while other authors have designated this stage IC. As STIC can be associated with disease on ovarian or peritoneal surfaces (especially since many STICs are located in the fimbriated end of the tube and, therefore, have direct access to the peritoneal cavity), one can speculate whether STICs with only positive washings should be considered greater than stage 0 (old staging system).

It has been suggested that intraluminal masses without invasion qualify as neither stage 0 (old staging system) nor stage IA (Alvarado-Cabrero et al. 1999). Also, because of observed differences in prognosis for stage I fallopian tube carcinomas with different depths of invasion into the wall (similar to other abdominal/pelvic organs with a muscular wall), it has been recommended that the FIGO stage should be modified since such cases are not appropriately represented by the current version of the FIGO staging system. Alvarado-Cabrero et al. have proposed that stage I cases should be divided into substages IA-0 (intraluminal masses without invasion into lamina propria), IA-1 (invasion into lamina propria but not muscularis), and IA-2 (invasion of muscularis) (Alvarado-Cabrero et al. 1999). As it has also been suggested that carcinomas in the fimbriated end without invasion have a worse prognosis than carcinomas invading the wall of the tube because of direct access to the peritoneal cavity, it has been proposed that the FIGO system should be modified since the former are not represented by the current version (Alvarado-Cabrero et al. 1997, 1999). This proposed stage would be designated I(F).

The majority of patients with symptomatic disease have advanced stage disease at presentation (stage >I). In the largest clinicopathologic study using hospital-based cases by Baekelandt et al., the distribution of stage was: stage 0 (6%) [old staging system], stage I (27%), stage II (22%), stage III (35%), and stage IV (12%) (Baekelandt et al. 2000). These results are similar to those of other large hospital-based or population-based studies which have found the percentage of stage I cases to be 30–56% (Heintz et al. 2006; Hellstrom et al. 1994; Rosen et al. 1999; Stewart et al. 2007).

The true stage distribution of all fallopian tube carcinomas in the general population is difficult to determine because of the existence of two patient populations which are usually not included together in the same studies – patients with asymptomatic tumors (i.e., occult tubal carcinomas in prophylactic bilateral salpingo-oophorectomy specimens from women with an increased genetic risk for carcinoma) and those with symptomatic tumors (i.e., women with bulky tumors and advanced stage disease who may not be suspected of having an increased genetic risk for carcinoma).

Intraoperative and Gross Features
Bilaterality is infrequent (3–13% of cases) (Alvarado-Cabrero et al. 1999, 2013, Baekelandt et al. 2000; Hellstrom et al. 1994; Stewart et al. 2007). The average tumor size is 4–5 cm (range, 0.2–10 cm) (Alvarado-Cabrero et al. 1999, 2013). The fallopian tube is dilated in slightly over one-half of cases, which intraoperatively can be mistaken for a hydrosalpinx, hematosalpinx, or pyosalpinx (Alvarado-Cabrero et al. 1999). The tumor can appear as one or more yellow to tan nodules or a mass that fills the lumen (Fig. 37). Hemorrhage or necrosis is frequent. Most tumors are within the tubal portion (usually the distal two-thirds), but a small percentage is located in the fimbriated end.
Fig. 37

Gross features of fallopian tube carcinoma. The cut surface is slightly heterogeneous, nodular, irregular, and yellow-tan. For comparison, the structure at the upper left is the ovary uninvolved by tumor

Histologic Features
Intraepithelial Carcinoma

Noninvasive carcinomas of the fallopian tube have been considered “carcinoma in situ” in the past. With recognition of early carcinomas without invasion of underlying fallopian tube stroma in prophylactic bilateral salpingo-oophorectomy specimens, as well as their detection as incidental findings in routine specimens, the term serous tubal intraepithelial carcinoma (STIC) has emerged over the last several years. Given the ability of STIC to spread beyond the fallopian tube without invasion of underlying stroma (see below), the term carcinoma in situ should be abandoned because it implies that there is no potential for metastasis.

Essentially all intraepithelial carcinomas of the fallopian tube are of high-grade serous type, and the lesional cells of STIC show secretory cell differentiation (Lee et al. 2007). However, rare endometrioid intraepithelial carcinomas have been reported (Jarboe et al. 2008).

Histologically, STIC is the earliest morphologically recognizable form of tubal carcinoma. It is characterized by absence of invasion of underlying fallopian tube stroma and the presence of cytologic abnormalities that result in the fallopian tube epithelium appearing darker than adjacent normal epithelium at low-power magnification (Fig. 38). In cases with invasive carcinoma in the same tube, STIC may be found directly adjacent to invasion. STIC can occur as a single focus or multifocally. It preferentially occurs in the distal or fimbriated end of the fallopian tube, and some investigators have also suggested that STIC frequently occurs at or near the tubo-peritoneal junction (see section on “Normal Histology”) (Seidman 2015). The lesional epithelium is typically flat, but some degree of stratification may be seen. The luminal border may be straight or exhibit variable amounts of irregular contours and hobnail morphology. With increased stratification, small tufts of detached cells can be found within the tubal lumen. At high-power magnification, the lesional cells lack cilia and show variable combinations of nuclear enlargement, increased nuclear-to-cytoplasmic ratios, hyperchromasia or irregular chromatin distribution, loss of polarity, prominent nuclei, and mitotic figures (Fig. 39). Nuclei may be oval or columnar but are frequently round.
Fig. 38

Serous tubal intraepithelial carcinoma (STIC). (a) STIC is composed mostly of a flat proliferation of cells. However, at low-power magnification, STIC is visible because of the thicker and darker epithelium (arrowheads) compared with adjacent normal tubal epithelium (arrow). (b) Abrupt transition between STIC and normal tubal epithelium

Fig. 39

Serous tubal intraepithelial carcinoma (STIC). (a) The lesional cells can be hyperchromatic with high nuclear-to-cytoplasmic ratios, stratification, and loss of polarity (upper half of photograph), or they may show enlarged and round nuclei with vesicular chromatin, nucleoli, and mitotic figures (lower half of photograph). (b) Comparison between normal tubal epithelium (upper half of photograph) and STIC (lower half of photograph)

Before diagnosing an incidental lesion as STIC in a routine specimen, it is necessary to submit all remaining fallopian tube tissue for histologic examination as invasive carcinoma can be of small size.

Invasive Carcinoma

Some otherwise conventional-appearing high-grade serous carcinomas within the lumen of the fallopian tube may be small without enlargement of the fallopian tube and lack invasion of the underlying tubal stroma. Such morphology in occasional cases can overlap with the upper morphologic limit of STIC, especially when the latter shows an increased degree of stratification. In such cases, the diagnostic threshold between STIC vs. a small intraluminal high-grade serous carcinoma without invasion of underlying fallopian tube stroma is subjective and varies between authors (Jarboe et al. 2008; Young 2007). However, some authors have suggested that intraluminal masses without invasion qualify as neither stage 0 (old staging system) nor stage IA (see section “FIGO Stage” above) (Alvarado-Cabrero et al. 1999).

Some invasive carcinomas may be of small volume. As these may not be clinically evident, and in order to assess the possibility of the fallopian tube being a primary site of occult disease, it is important to submit all remaining fallopian tube tissue from grossly unremarkable tubes for histologic examination in women presenting with metastatic high-grade adenocarcinoma of unknown primary site.

The histologic types and appearances of invasive fallopian tube carcinoma are similar to its ovarian counterparts. In the largest clinicopathologic study using hospital-based cases, the distribution of histologic types was: serous (80%), adenocarcinoma, NOS (10%), endometrioid (7%), clear cell (2%), mucinous (2%), and mixed serous-mucinous (1%) (Baekelandt et al. 2000). Most fallopian tube carcinomas are poorly differentiated, and well-differentiated tumors are very uncommon. Fallopian tube carcinomas are graded in a fashion analogous to those in the ovary (i.e., low- vs. high-grade for serous, FIGO uterine criteria for endometrioid, etc.).

The majority, if not all, tubal serous carcinomas are histologically indistinguishable from high-grade serous carcinomas of the ovary and include broad papillae with epithelial stratification, irregular slit-like spaces with micropapillary tufting, invasion by solid nests of variable size or sheets of tumor cells, necrosis, and psammoma bodies (Fig. 40) (Alvarado-Cabrero et al. 1999). The nuclei are high-grade, characterized by nuclear enlargement, hyperchromasia or irregular chromatin distribution with prominent nucleoli, irregular nuclear membranes, and abundant mitotic figures. STIC may be found adjacent to invasive carcinoma.
Fig. 40

Invasive high-grade serous carcinoma. (a) Complex papillae with stratified epithelium producing irregular slit-like spaces and small epithelial tufts. (b) The nuclei are high-grade with abundant mitotic figures. Note enlarged nuclei with vesicular chromatin and nucleoli. In other cases, the nuclei may be hyperchromatic rather than vesicular

Most endometrioid carcinomas are grade 2 or 3, but some are grade 1 (Navani et al. 1996; Rabczynski and Ziolkowski 1999). They may resemble conventional endometrioid carcinomas as seen in the endometrium, including squamous differentiation and villoglandular architecture, but oxyphilic types, sex cord-like appearances, and spindled epithelial cells may be seen. In some cases, associated endometriosis is present. Benign stromal osseous metaplasia can be seen in a minority of cases. Almost one-half of cases have an appearance resembling female adnexal tumor of wolffian origin (FATWO-like type) (Daya et al. 1992; Navani et al. 1996). Independent primary endometrioid carcinomas can synchronously arise in the fallopian tube and uterus (Culton et al. 2006).

Clear cell and transitional cell carcinomas resemble those seen in the ovary (Alvarado-Cabrero et al. 1999; Koshiyama et al. 1994). Other rare histologic types include undifferentiated, small cell neuroendocrine, lymphoepithelioma-like, mixed serous-transitional cell, squamous cell, adenosquamous, hepatoid, glassy cell, and giant cell carcinomas (Alvarado-Cabrero et al. 1999; Aoyama et al. 1996; Cheung et al. 1994a; Herbold et al. 1988). Mucinous carcinomas with a synchronous endocervical adenocarcinoma have been described, but such cases should be rigorously evaluated to exclude the likely possibility that they represent secondary involvement of the fallopian tubes from the endocervix. Unlike the ovary, low-grade serous carcinomas typically are not seen in the fallopian tube.

Immunohistochemical Features
Although some cases of STIC may be diagnosed solely on histologic features without the need for immunohistochemistry, immunostains are helpful in establishing the diagnosis in problematic cases. STIC diffusely and strongly expresses p53 (Fig. 41) (pattern associated with TP53 missense mutations) in the majority of cases while a minority of cases have complete loss of expression (pattern associated with TP53 null mutations) (Kuhn et al. 2012c). The Ki-67 proliferation index is usually elevated (Fig. 41). In one study, the mean Ki-67 proliferation index was 72% (range: 40–95%) (Jarboe et al. 2008) while in another the mean index and range were 36% and 12–71%, respectively (Kuhn et al. 2012a). Also, p16, which is diffusely and strongly expressed in endometrial serous carcinomas and many ovarian high-grade serous carcinomas, can be expressed with a similar pattern in STIC; however, as this occurs in only a subset of cases, it is not a reliable diagnostic marker for this lesion. Laminin has been reported as being overexpressed in STIC with diffuse and intense cytoplasmic staining (see section on “Pathogenesis, Including Molecular Features” of “Serous Carcinoma”) (Kuhn et al. 2012b).
Fig. 41

Immunohistochemical features of serous tubal intraepithelial carcinoma. (a) H&E. (b) Diffuse expression of p53. (c) Elevated Ki-67 proliferation index. (d) Diffuse expression of p16

Invasive high-grade serous carcinomas usually show diffuse expression of WT-1. It should be noted, however, that expression is not restricted to invasive carcinomas, as normal fallopian tube epithelium and STIC also show WT-1 expression. Expression of ER and PR is variable. p53 expression, similar to STIC, will have an abnormal pattern, either diffuse or null. Immunohistochemical data are limited for endometrioid carcinomas, but in our experience, WT-1 and p53 can be diffusely expressed in some cases.

Diagnostic Criteria and Classification for STIC and Intraepithelial Atypias: Algorithmic Approach Based on Morphology and Immunohistochemistry
Diagnosis of STIC based solely on histologic features has been shown to lack high interobserver agreement and, therefore, not be highly reproducible (Carlson et al. 2010; Vang et al. 2012; Visvanathan et al. 2011). Accordingly, a diagnostic algorithm utilizing a combination of morphology and immunohistochemistry for p53 and Ki-67 (Fig. 42) has been proposed for classifying epithelial atypia of the fallopian tube, which results in a more reproducible diagnosis of STIC (Vang et al. 2012, 2013, Visvanathan et al. 2011). As there has been no standardized criteria for this spectrum of lesions, this algorithm allows for classification of STIC, atypical lesions intermediate between STIC and p53 signature (serous tubal intraepithelial lesion [STIL]), and p53 signature. Also, this type of algorithmic approach facilitates consistency of terminology between practicing pathologists, as well as clinicians, and more uniform classification of lesions among investigators at different academic centers.
Fig. 42

Histologic-immunohistochemical algorithm for classification of serous tubal intraepithelial carcinoma (STIC) and epithelial atypias of the fallopian tube. The diagnosis of STIC is based on the combination of atypia (unequivocal for STIC or suspicious for STIC), abnormal p53 pattern (diffuse expression or null pattern), and high Ki-67 proliferation index (≥10% positive cells in the focus of atypia). See text for details. Also, see Figs. 41a–c. STIL, serous tubal intraepithelial lesion. WT, wild-type (non-aberrant) pattern. ©JHU 2017, The Department of Art as Applied to Medicine, The Johns Hopkins University School of Medicine

According to the algorithm, first the morphology of atypical foci is classified as unequivocal for STIC, suspicious for STIC, or not suspicious for STIC utilizing a variable combination of histologic features described above. Then, p53 expression is scored as abnormal (diffuse or null pattern, with moderate to strong intensity) or normal. Of note, a “wild-type”/normal pattern will have occasional cells with usually mild intensity. In contrast, a “null” pattern demonstrates complete loss of expression provided an adequate positive internal control with a “wild-type”/normal pattern is present. The Ki-67 proliferation index is scored as either low (<10%) or high (≥10%) in only the focus with morphologic atypia. Of note, normal fallopian tube mucosa and STIC usually have Ki-67 proliferation indices that are less than or greater than 10%, respectively (George et al. 2012; Kuhn et al. 2012a), and this distinction of low versus high has been shown to have substantial interobserver reproducibility (Vang et al. 2012; Visvanathan et al. 2011).

Finally, based on the coordinate profile of p53 and Ki-67, the lesion can be classified as either STIC, STIL, p53 signature, or normal/reactive. In order to reproducibly diagnose STIC, morphologic atypia (considered unequivocal for STIC or suspicious for STIC) combined with an abnormal p53 pattern and high Ki-67 index is necessary (Figs. 41a–c and 42). In routine practice, lesions that would be classified as STIL also can be simply diagnosed as “epithelial atypia” with a comment in the pathology report that the lesion does not qualify for a diagnosis of STIC. Tubal dysplasias have been described in the literature, but use of the diagnostic term “dysplasia” is discouraged. Additionally, the term “p53 signature” should not be used in a pathology report, and that terminology is best reserved for academic studies.

Treatment and Prognosis: Invasive Carcinoma

Tumor usually spreads in an intraperitoneal, lymphatic, and hematogenous manner. At presentation, lymph node metastases are frequent, the lymph node groups most frequently involved are those in para-aortic and pelvic sites, and inguinal and supraclavicular lymph nodes can be involved as well; however, lymph node metastases may be present even when it appears that the tumor is limited to the tube (Alvarado-Cabrero et al. 1999; Baekelandt et al. 2000; Deffieux et al. 2005; di Re et al. 1996; Klein et al. 1994, 1999).

In the largest studies of fallopian tube carcinoma, patients have been treated in various fashions, but the most important prognostic factor is stage (Alvarado-Cabrero et al. 1999, 2013; Baekelandt et al. 2000; Hellstrom et al. 1994; Peters et al. 1988; Riska and Leminen 2007; Rosen et al. 1999). The overall 5-year survivals for fallopian tube carcinoma for all stages combined range from 43% to 56% between studies (Alvarado-Cabrero et al. 2013; Baekelandt et al. 2000; Heintz et al. 2006; Rosen et al. 1999). In the largest clinicopathologic study using hospital-based cases, the 5-year survivals were: stage 0 (88%) [old staging system], stage 1 (73%), stage 2 (37%), stage 3 (29%), and stage 4 (12%) (Baekelandt et al. 2000). These 5-year survivals are similar to those of other large studies (Alvarado-Cabrero et al. 2013; Heintz et al. 2006; Hellstrom et al. 1994; Moore et al. 2007; Peters et al. 1988; Rosen et al. 1999). It is also noteworthy that stage 0 disease (old staging system) does not guarantee a cure, as the 5-year survivals for stage 0 (old staging system) ranged from 75% to 91% between studies (Baekelandt et al. 2000; Eddy et al. 1984; Schiller and Silverberg 1971). However, these studies do not provide details specifying whether the entire fallopian tube was submitted for histologic examination in those cases in order to exclude microscopic invasion (i.e., stage IA).

Alvarado-Cabrero et al. showed that subcategorization of stage I cases based on depth of invasion was prognostically significant (Alvarado-Cabrero et al. 1999). In their study, patients with substages IA/B-0 (intraluminal masses without invasion into lamina propria) and IA/B-1 (invasion into lamina propria but not muscularis) had a better disease-free survival than those with substage IA-2 (invasion of muscularis), which was a statistically significant difference. They also demonstrated that patients with stage I(F) (carcinomas in the fimbriated end without invasion) had a poorer survival than those with substages IA/B-0 and IA/B-1, as well as that the survival for stage I(F) was similar to stages IA-2 and IC. These aspects have not been extensively studied in the literature. Two other studies also showed that differences in depth of invasion in the wall of the fallopian tube in stage I cases were prognostically significant while another study demonstrated that it was not (Asmussen et al. 1988; Baekelandt et al. 2000; Peters et al. 1988).

Presence/amount of residual disease after surgery is a poor prognostic factor (Baekelandt et al. 2000; Peters et al. 1988; Rosen et al. 1999). Closure of the fimbriated end (hydrosalpinx-like, hematosalpinx-like, or pyosalpinx-like gross appearance) has been shown to be a favorable prognostic factor on univariate but not multivariate analysis (Alvarado-Cabrero et al. 1999; Baekelandt et al. 2000). Disagreement exists between studies regarding whether or not histologic grade, vascular invasion, age, or ascites is prognostically significant (Alvarado-Cabrero et al. 1999; Baekelandt et al. 2000; Hellstrom et al. 1994; Peters et al. 1988; Rosen et al. 1999). Histologic type has not been shown to be of prognostic importance (Alvarado-Cabrero et al. 1999; Baekelandt et al. 2000). In studies combing ovarian, fallopian tube, and peritoneal high-grade serous carcinomas, cases with homologous recombination mutations (including BRCA) demonstrated better progression-free survival (Ritterhouse et al. 2016).

Treatment of fallopian tube carcinoma consists of cytoreductive surgery and combination platinum/taxane chemotherapy, and as response to this chemotherapy regimen is analogous to that in patients with ovarian carcinoma, fallopian tube carcinoma is treated similarly to ovarian carcinoma (Baekelandt et al. 2000; Moore et al. 2007; Papadimitriou et al. 2008; Riska and Leminen 2007). In patients with a pre-chemotherapy elevated serum CA-125 level, this marker can be used to monitor disease for response and progression. In the study by Baekelandt et al., the median progression-free survival for the entire cohort was 32 months (Baekelandt et al. 2000). In that study, patients were not postoperatively treated in a uniform fashion. In a study of patients that received postoperative combination platinum/taxane chemotherapy, carcinoma recurred in 74% of patients with stage III or IV disease by 33 months (Moore et al. 2007). In the study by Baekelandt et al., the pelvis was the most common site of recurrence, followed by upper abdomen, retroperitoneal lymph nodes, liver, pleura, vagina, lungs, supraclavicular lymph nodes, groin lymph nodes, brain, bone, breast, and adrenal gland in descending order (Baekelandt et al. 2000).

Given the association of fallopian tube (and ovarian) carcinoma with germline BRCA mutations, genetic counseling should be considered for all new diagnoses of fallopian tube high-grade serous carcinoma.

Also, see section below “Behavior of STIC (BRCA Germline Mutation-Associated and Sporadic Cases).”

Occult Disease in Prophylactic Bilateral Salpingo-Oophorectomy Specimens

At least 10% of ovarian carcinomas are hereditary rather than sporadic, and approximately 90% of the former have mutations of the BRCA1 or BRCA2 gene. Carriers of germline BRCA1 and BRCA2 mutations have 44% and 17% lifetime risks for ovarian carcinoma, respectively, and the incidence of ovarian cancer increases with age up to 61–70 years (Kuchenbaecker et al. 2017). Women with such mutations are also at risk for peritoneal and fallopian tube carcinoma. The exact proportion of fallopian tube carcinomas that is hereditary is not clear; however, 16–43% of patients with tubal carcinoma has shown BRCA germline mutations (Aziz et al. 2001; Cass et al. 2005; Levine et al. 2003). As these figures are based on older data with relatively small numbers of cases and that the vast majority of ovarian carcinomas is likely of tubal origin (see below), the true frequency of BRCA germline mutations in fallopian tube high-grade serous carcinomas is probably similar to their “ovarian” counterparts (i.e., 17%) (Cancer Genome Atlas Research Network 2011). Given the significant risk of ovarian carcinoma for patients with BRCA mutations, prophylactic salpingo-oophorectomy is recommended by age 35–40 and 40–45 for BRCA1 and BRCA2 mutation carriers, respectively, and such surgical procedures have been shown to significantly reduce the risk of pelvic carcinoma (Kauff and Barakat 2007; Society of Gynecologic Oncology 2017). This risk is not reduced to 0% since a small percentage of patients subsequently develop peritoneal carcinomas.

A portion of the fallopian tube (chiefly, the intramural segment) remains in the uterus after prophylactic bilateral salpingo-oophorectomy. In one study, it was shown that the segment of fallopian tube remaining in the hysterectomy specimen after prophylactic bilateral salpingo-oophorectomy had a median length of 1.2 cm (range: 0.6–1.5 cm) (Gerritzen et al. 2006). In another study, 73% of hysterectomy specimens had a tubal remnant after the fallopian tubes were fulgurated and transected simulating a risk-reducing salpingo-oophorectomy specimen procedure (Cass et al. 2010). In that study, the median length of residual fallopian tube was 0.6 cm. Despite the fact that not all tubal mucosa is removed during the prophylactic procedure, the risk for development of carcinoma in the remaining tube is probably minimal since (A) tubal carcinomas are not frequently found in the intramural segment, (B) follow-up studies of women after prophylactic bilateral salpingo-oophorectomy show a low frequency of subsequent pelvic carcinoma (in one study, the estimated risk of peritoneal carcinoma at 20 years after prophylactic surgery was only 4% (Finch et al. 2006)), and (C) most occult tubal carcinomas arise in the fimbriated end. Details regarding handling of prophylactic bilateral salpingo-oophorectomy specimens are provided in the section on “Gross Examination” above.

Table 3 highlights features of patients with carcinomas detected in prophylactic salpingo-oophorectomy specimens (Callahan et al. 2007; Lamb et al. 2006; Manchanda et al. 2011; Poon et al. 2016; Powell et al. 2011; Reitsma et al. 2013; Ricciardi et al. 2017; Sherman et al. 2014; Zakhour et al. 2016). The mean/median age of patients with carcinoma in these risk reducing salpingo-oophorectomy specimens ranges from 50 to 58 between studies, and the distribution of BRCA1 and BRCA2 mutations among patients with carcinoma is 72% vs. 28%, respectively. The frequency of finding a malignancy involving the ovary, fallopian tube, or peritoneum during surgery or in the surgical specimen varies from 2% to 9% between studies. However, among 2,786 patients from 9 large studies, carcinoma is found in 4% of cases (mean). The majority of carcinomas are primary tumors in the fallopian tube (either isolated STIC or invasive carcinoma +/− STIC) or ovary, but a very small proportion is due to primary peritoneal carcinomas or metastatic breast carcinoma in the ovary. Isolated STIC accounts for 46% of all carcinomas. Of just primary carcinomas in the fallopian tube and ovary, more are found in the tube compared with the ovary (79% vs. 21%, respectively). The invasive carcinomas can be either FIGO stage I or stage >I. Most of these invasive tumors are high-grade serous carcinomas, but a minority are of endometrioid type.
Table 3

Carcinoma detected in risk-reducing salpingo-oophorectomy specimens from selected large studies

Studya

Total patients that underwent surgery (n)

Total patients with Ca, n (%)

Mean/median ageb (years)

Distribution of BRCA germline mutationsb

Patients with STIC-only

Patients with FT Cac (+/− STIC)

Patients with OV Cac (+/− STIC)

Patients with Perit Cac (+/− STIC)

Comments

Callahan, J Clin Oncol 2007 (Callahan et al. 2007)

122

7(6%)

58

4, BRCA1

3, BRCA2

3

4

0

0

 

Lamb, Am J Obstet Gynecol 2006 (Lamb et al. 2006)

113

6(5%)

53

5, BRCA1

1, BRCA2

4

1

0

1

 

Manchandra, BJOG 2011 (Manchanda et al. 2011)

308

14 (5%)

53

7, BRCA1

5, BRCA2

2, mutation status unknown

9

1

3

0

One case with metastatic breast Ca involving ovary

Poon, Int J Gynecol Cancer 2016 (Poon et al. 2016)

138

5 (4%)

55

3, BRCA1

2, BRCA2

3

2

0

0

 

Powell, Int J Gynecol Cancer 2011 (Powell et al. 2011)

111

10 (9%)

50

8, BRCA1

2, BRCA2

4

3

1

0

Two cases with Ca involving ovary and FT

Reitsma, Eur J Cancer 2013 (Reitsma et al. 2013)

360

7(2%)

54

4, BRCA1

2, BRCA2

1, BRCA(−)

3

2

2

0

 

Ricciardi, Anticancer Res 2017 (Ricciardi et al. 2017)

411

13 (3%)

54

9, BRCA1

1, BRCA2

2, BRCA(−)

1, Mutation status unknown

7

2

2

0

Two cases with metastatic breast Ca involving adnexa

Sherman, J Clin Oncol 2014 (Sherman et al. 2014)

966

25 (3%)

54

15, BRCA1

8, BRCA2

2, BRCA(−)

4

6

10

5

 

Zakhour, Gynecol Oncol 2016 (Zakhour et al. 2016)

257

13 (5%)

56

11, BRCA1

2, BRCA2

9

3

1

0

 

Ca Carcinoma, FT Fallopian tube, n Number, OV Ovarian, Perit Peritoneal, + Present, − Absent

aSeries that were apparently reported in more than one publication are listed only once here

bAmong patients with carcinoma

cPrimary site based on designation listed in each study

Also, see section above “Treatment and Prognosis: Invasive Carcinoma” and section below “Behavior of STIC (BRCA Germline Mutation-Associated and Sporadic Cases).”

Occult Disease in Routine Specimens in Women Without Known Genetic Risk (Presumably Sporadic Cases)

Occult fallopian tube carcinomas are not restricted to the setting of risk-reducing salpingo-oophorectomy specimens (women at increased risk for hereditary ovarian carcinoma). On occasion, occult sporadic carcinomas can be detected in specimens performed for other surgical indications, such as uterine leiomyomas (Gilks et al. 2015; Morrison et al. 2015). When occult sporadic carcinoma is found in this scenario, STIC is almost always present, either in isolation or with associated invasive high-grade serous carcinoma. When the latter component is identified, it is usually found in the fallopian tube but sometimes the ovary. The invasive carcinomas are typically small (often ≤1 cm). While cases with invasive carcinoma can be FIGO stage I, staging has revealed advanced disease in some patients.

With regard to the frequency of incidentally finding STIC in routine specimens, a number of large studies have shown that sporadic STIC would be expected to be present in <1% of cases (Meserve et al. 2017b; Rabban et al. 2014; Seidman et al. 2016). Also, see section below “Behavior of STIC (BRCA Germline Mutation-Associated and Sporadic Cases).”

Behavior of STIC (BRCA Germline Mutation-Associated and Sporadic Cases)

The outcome of a number of cases of isolated STIC has been reported. In a review of 78 patients with STIC from 15 publications, 5% of cases subsequently developed peritoneal carcinoma from 3.6 to 6.0 years later (Patrono et al. 2015). However, of all the cases in the entire analysis, the vast majority had BRCA germline mutations, and few sporadic cases (women at low/average genetic risk for ovarian carcinoma) with follow-up were reported. Moreover, a substantial number of all cases had either <4 years follow-up or a duration of follow-up that was not reported. Of note, 11% of patients had positive washings, and 16% of patients were treated with chemotherapy. Two of nine (22%) patients with STIC in a series of risk-reducing salpingo-oophorectomies also subsequently developed pelvic serous carcinoma at 2.7 and 3.5 years, respectively, after surgery (Zakhour et al. 2016). Additionally, in a series of 11 sporadic STICs detected at the time of initial surgery (excluding cases ultimately determined to have a BRCA germline mutation), completion staging was performed in five cases, three of which were upstaged to invasive high-grade serous carcinoma (Chay et al. 2016). In the remaining eight cases with STIC-only, one patient was without evidence of serous carcinoma at 7.3 years, three patients were without evidence of serous carcinoma with follow-up of 2.1 years or less, and outcome/follow-up duration was unknown in four patients. In other series with sporadic STICs, too few cases with meaningful follow-up are available (Gilks et al. 2015; Morrison et al. 2015; Rabban et al. 2014; Seidman et al. 2016).

Although the available data on the behavior of isolated STIC suggest low-risk of progression, it should be emphasized that there are a number of limitations to the current understanding of this topic. The total number of cases in the literature is relatively small, and a number of the reported cases have either no follow-up or follow-up of short duration. Interestingly, in a molecular study by Labidi-Galy et al., a mathematical model estimated that the average time from STIC to development of ovarian high-grade serous carcinoma was 6.5 years (Labidi-Galy et al. 2017). Furthermore, also considering that some of the reported cases of STIC have been associated with subsequent development of serous carcinoma a number of years after initial surgery, the length of follow-up necessary to understand the true behavior of STIC may need to be longer than what is provided in the current literature, and it is possible that the available data in the literature may, therefore, underestimate the true risk of progression. Additionally, the predominance of reported STICs is heavily weighted toward cases with BRCA germline mutations/risk-reducing salpingo-oophorectomy procedures, and too few cases and very little follow-up are available for sporadic STICs. Based on the observation that BRCA-mutated ovarian high-grade serous carcinomas have better survival than wild-type cases (Bolton et al. 2012; Cancer Genome Atlas Research Network 2011), there is the theoretical consideration that sporadic STICs could have a higher progression rate than those associated with BRCA germline mutations, but specific data would be needed to address this concern.

Accordingly, in view of the above limitations to the current literature, as well as that (a) some STICs have positive washings; (b) STIC is frequently present in the fimbriated end of the fallopian tube, which is the portion with direct access to the peritoneal cavity; (c) a subset of cases were ultimately discovered to have disease beyond the fallopian tube after the initial detection of STIC (Bijron et al. 2013; Chay et al. 2016; Morrison et al. 2015); and (d) STIC is morphologically and immunohistochemically analogous to serous endometrial intraepithelial carcinoma (another lesion which can have disease at a distant site in a subset of cases), isolated STIC is probably best considered a lesion whose behavior is uncertain until more robust data becomes available in the future. Lastly, completion staging for sporadic STICs should be considered (Chay et al. 2016).

Pathogenesis, Including Molecular Features
Serous Carcinoma

DNA cytometry and molecular genetic studies have shown that fallopian tube carcinomas are aneuploid and have a high degree of chromosomal instability, characterized by multiple gains and losses of genetic material at various loci on all chromosomes (Heselmeyer et al. 1998; Nowee et al. 2007a; Pere et al. 1998; Ritterhouse et al. 2016; Snijders et al. 2003). One study also demonstrated that epithelial atypia/dysplasia of the fallopian tube and STIC in risk-reducing prophylactic specimens contained chromosomal abnormalities, which suggests that chromosomal instability is an early event in the pathogenesis of serous carcinoma (Salvador et al. 2008).

Gene expression profiles of fallopian tube and ovarian serous carcinomas have been shown to be similar, implying that tumorigenesis in both organs shares related molecular pathways (Tone et al. 2008). The results of molecular genetic studies have also suggested multiple potential candidate oncogenes involved in the development of fallopian tube carcinoma (Nowee et al. 2007b; Snijders et al. 2003; Tone et al. 2008). Also, in studies that have combined ovarian, tubal, and peritoneal high-grade serous carcinomas together, the most common mutations are TP53, BRCA1 or BRCA2 (germline or somatic), and ATM (Ritterhouse et al. 2016). Furthermore, TP53 has been identified as an important gene in the development of fallopian tube carcinoma. Mutations have been observed in serous carcinoma, but the frequency differs between studies (Hellstrom et al. 2000; Zheng et al. 1997) although the proportion of cases would be expected to be nearly 100% similar to ovarian high-grade serous carcinoma (Cancer Genome Atlas Research Network 2011; Vang et al. 2016). TP53 mutations have even been detected in early stage carcinoma and > 90% of STICs, suggesting that mutation of this gene is an early event in carcinogenesis (Kuhn et al. 2012c; Lee et al. 2007; Zheng et al. 1997).

An important molecular event involved in the development of hereditary fallopian tube carcinoma is germline mutation of BRCA1 or BRCA2. These tumor suppressor genes are located on chromosomes 17 and 13, respectively. They are normally involved in transcriptional regulation of gene expression, cell cycle control, and recognition/repair of DNA damage. BRCA-associated carcinomas appear to follow the “2-hit model” of tumorigenesis, as seen in other organs (i.e., patients inherit a germline BRCA mutation [first hit], and with somatic loss of the wild-type allele [second hit], carcinoma develops).

The small number of samples of histologically normal fallopian tube epithelium from women with BRCA mutations that were analyzed in one study showed that the gene expression profile during the luteal phase of the menstrual cycle more closely resembled that of serous carcinoma compared with histologically normal samples from the follicular phase (Tone et al. 2008). These findings suggest that the hormonal milieu during the menstrual cycle might play a role in carcinogenesis for women with BRCA mutations. Some evidence also suggests that epigenetic reprogramming within normal fimbrial mucosa is an early event of carcinogenesis in women with BRCA mutations (Bartlett et al. 2016).

Other early molecular events identified as occurring in STIC include CCNE1/cyclin E copy number gain/amplification/overexpression, telomere shortening, and upregulation/overexpression of laminin (see section on “Immunohistochemical Features of Carcinoma”), Rsf-1, and fatty acid synthase (Chene et al. 2013; Karst et al. 2014; Kuhn et al. 2010, 2012b, 2016; Sehdev et al. 2010).

The pathogenesis of invasive high-grade serous carcinoma of the fallopian tube appears to begin with STIC as the first histologically identifiable lesion in this pathway. However, a precursor lesion of STIC has been proposed – the p53 signature (Jarboe et al. 2008; Lee et al. 2007). This lesion is composed of histologically normal mucosal epithelium and characterized by immunohistochemical overexpression of p53, which has been defined as a linear extent of ≥12 consecutive secretory cells showing strong expression (according to this definition, intervening p53-negative ciliated cells are allowed) (Fig. 43). In one study, 57% of p53 signatures contained a TP53 mutation (Lee et al. 2007). p53 signatures, however, have a low Ki-67 proliferation index. The mean Ki-67 proliferation index in one study was 3% (range: 0–30%) (Jarboe et al. 2008). They show evidence of DNA damage, as manifested by immunohistochemical expression of γ-H2AX (Jarboe et al. 2008; Lee et al. 2007). When present, p53 signatures are usually located in the fimbriated end of the tube, and their frequency in women with BRCA mutations is similar to that of controls (10–71% vs. 17–50%, respectively); however, p53 signatures are more frequent and multifocal in tubes with STIC (Folkins et al. 2008; Lee et al. 2007; Mehra et al. 2011b; Shaw et al. 2009).
Fig. 43

p53 signature. (a) The tubal mucosa lacks morphologic features of intraepithelial carcinoma. (b) p53 expression is diffuse in three small segments of the mucosa (arrows), corresponding to (a). (c) The Ki-67 proliferation index is low in the three segments of diffuse p53 expression shown in (b). If these foci of diffuse p53 expression represented intraepithelial carcinoma, then the Ki-67 proliferation index would have been much higher (compare with Fig. 41c)

A model has been suggested linking the p53 signature with STIC in which the p53 signature is the earliest step in the pathogenesis of fallopian tube carcinoma (Jarboe et al. 2008; Meserve et al. 2017a). This is supported by the following: (1) p53 signatures are more common in tubes with STIC; (2) the p53 signature preferentially occurs in the same portion of the tube as STIC (fimbriated end); (3) both the p53 signature and STIC are thought to arise from the secretory cell (and transformation of secretory cells into carcinoma has been demonstrated in mouse models (Karst et al. 2011; Perets et al. 2013)); (4) the p53 signature, like STIC, shows p53 overexpression, TP53 mutations, and evidence of DNA damage; (5) direct continuity of the p53 signature with STIC has been reported (including an identical TP53 mutation in both components in one case (Lee et al. 2007)); (6) lesions histologically and immunohistochemically (Ki-67) intermediate between the p53 signature and STIC have been described; (7) identical TP53 mutations in a p53 signature and peritoneal serous carcinoma in one case have been reported (Carlson et al. 2008); and (8) molecular studies constructing evolutionary trees in patients with p53 signature, STIC, and invasive high-grade serous carcinoma involving the fallopian tube, ovary, and metastases have suggested p53 signature as the earliest event in some cases (Labidi-Galy et al. 2017).

In this model, the fallopian tube mucosa in the fimbriated end undergoes injury, and as a result, the secretory cell experiences DNA damage with overaccumulation of p53 protein (p53 signature). With the development of a TP53 mutation, along with further cell proliferation and malignant transformation in a very small subset of women, the p53 signature then evolves into STIC. Although the p53 signature would be a common lesion in the general population regardless of BRCA status, it would, therefore, be in this setting that further molecular alterations would allow for the possible development of a malignant clone with the potential to transform into STIC. Women without BRCA mutations can have a p53 signature, but it is possible that germline mutations of BRCA act as a promoter for the development of STIC (Folkins et al. 2008). It should also be noted that STIC and invasive carcinoma can arise independently of a BRCA mutation. In one study, the frequency of STIC in women with a BRCA mutation was not significantly different from that of controls (8% vs. 3%, respectively) (Shaw et al. 2009). At this stage of growth, the STIC is of microscopic size, but with continued cell proliferation and growth of the tumor, malignant tumor cells eventually exfoliate into the peritoneal cavity (or proximally along the lumen of the tube) or infiltrate underlying tubal stroma in the form of invasive high-grade serous carcinoma. Progressive tumor growth eventually results in increasing tumor stage and volume of disease, peritoneal spread, and metastases, including involvement of lymph nodes.

A lesion designated secretory cell outgrowth (SCOUT) has been proposed as a possible precursor to p53 signature and STIC (Chen et al. 2010; Mehra et al. 2011a; Ning et al. 2014; Quick et al. 2012). SCOUTs are characterized by discrete linear segments of tubal epithelium that predominantly consist of secretory cells, but papillary forms and SCOUTs with a component of ciliated cells have been described (Laury et al. 2011; Meserve et al. 2017a; Ning et al. 2014). Conceptually, p53 signatures are a subset of SCOUTs which exhibits diffuse p53 expression (i.e., p53[+] SCOUTs). However, unlike p53 signatures, p53-negative SCOUTs do not show evidence of DNA damage based on γ-H2AX immunohistochemical staining. Also, in contrast with p53 signature and STIC, SCOUTs are not predominantly restricted to the fimbriated end of the fallopian tube, and they may commonly occur throughout the length of the tube, including the proximal portion. SCOUTs share common features with p53 signature and high-grade serous carcinoma, such as altered gene expression, including reduced PAX2 expression (a marker expressed in secretory cells of normal fallopian tube mucosa). Also, SCOUTs are more frequently present in women that have high-grade serous carcinoma compared with controls, and they are associated with increasing age. The exact mechanism of transformation of SCOUTs into p53 signature and STIC remains to be clarified.

From a diagnostic perspective, SCOUTs can create concern for STIC when viewed at low-power magnification because they appear as a possibly hyperchromatic focus (due to the secretory cell-rich population) distinct from adjacent tubal mucosa (Fig. 44). However, when examined at closer magnification, SCOUTs lack significant atypia, p53 should not be overexpressed, and the Ki-67 proliferation index would not be expected to be increased.
Fig. 44

Secretory cell outgrowth (SCOUT). SCOUT consists of predominantly secretory cells without ciliated cells. The lower-power magnification appearance can suggest the possibility of focal STIC (center) (a), but the high-power magnification image shows no significant atypia (b). Compare with usual-type mucosa in lower left and upper right

Some evidence suggests that chronic salpingitis could be an etiology and that serous carcinomas may develop on a background of atrophy (Demopoulos et al. 2001). Unlike the ovary, serous carcinomas of the fallopian tube usually do not follow a dualistic model as proposed for the ovary. Thus, a low-grade pathway, in which serous adenofibroma/cystadenofibroma evolves into atypical proliferative (borderline) serous tumor/noninvasive micropapillary (low-grade) serous carcinoma and then invasive low-grade serous carcinoma, typically does not occur in the fallopian tube although these types of low-grade serous tumors rarely arise in the fallopian tube.

Endometrioid Carcinoma

As endometrioid carcinoma can evolve from endometriosis and atypical proliferative (borderline) endometrioid tumors in the ovary, these pathways are plausible in the fallopian tube. In one study of 26 endometrioid carcinomas of the fallopian tube, 23% of cases were associated with adjacent endometriosis (Navani et al. 1996). In that study, direct continuity between carcinoma and endometriosis was not observed, but that does not exclude the possibility that carcinoma arose from endometriosis and obliterated any direct connection between the two. Although the fallopian tube is not an uncommon location for endometriosis, atypical (proliferative) borderline tumors occur only rarely in this anatomic site (Alvarado-Cabrero et al. 1997).

Differential Diagnosis
Nonneoplastic Lesions

Pseudocarcinomatous hyperplasia can histologically simulate carcinoma because of cribriform architecture, pseudoinvasion of the muscularis, papillae within lymphatics, and subserosal mesothelial hyperplasia (Fig. 12) (Cheung et al. 1994b). Patients with hyperplasia are usually premenopausal while those with carcinoma are typically postmenopausal. The tube can be enlarged in hyperplasia but does not show a mass on cross section unlike most cases of carcinoma; thus, the epithelial proliferation in hyperplasia is a microscopic finding. In contrast with carcinoma, hyperplasia usually exhibits a low mitotic index, absence of solid architecture, and a substantially lesser degree of nuclear atypia and nucleolar prominence. Acute or chronic salpingitis is usually present in hyperplasia, but some carcinomas can have an inflammatory component.

Determination of Site of Origin of Serous Carcinoma: Distinction from Ovarian/Peritoneal Primary Origin

Traditionally, when carcinoma involves both the fallopian tube and ovary, the ovary has been considered the primary site given the much more frequent occurrence of presumed primary ovarian carcinomas compared with fallopian tube primaries. Similarly, in the context of what would be conventionally considered a primary peritoneal carcinoma, involvement of the fallopian tube would generally be thought to represent secondary disease. In the past, criteria were proposed for determining fallopian tube origin for tumors synchronously involving the tube and ovary. These criteria of Hu et al. (and subsequently modified by Sedlis) are: (1) tumor arises from the endosalpinx, (2) histology of the tumor resembles tubal mucosa, (3) transition from benign to malignant epithelium, and (4) size of the fallopian tube tumor is larger than the ovarian tumor (Hu et al. 1950; Sedlis 1978). As will be seen below, these criteria are nonspecific and unreliable.

It has been suggested that the vast majority of cases which appear to represent a primary ovarian or peritoneal high-grade serous carcinoma may actually be fallopian tube in origin. The finding of a synchronous STIC, in the setting of a ovarian or peritoneal high-grade serous carcinoma, has been proposed as indicating a fallopian tube origin (Jarboe et al. 2008; Kindelberger et al. 2007). Lines of evidence supporting a tubal include: (1) the fimbriated end of the tube is the preferred site of STIC, which is the portion of the fallopian tube in close proximity to the ovarian surface/peritoneal cavity; (2) STIC is frequently present in patients with high-grade serous carcinomas in the ovary or peritoneum; (3) STIC is restricted to high-grade serous histologic type and not associated with other histologic types of ovarian/peritoneal carcinoma; (4) intraepithelial carcinoma in the ovary or peritoneum is a rare finding or nonexistent; (5) early/occult serous carcinomas in prophylactic bilateral salpingo-oophorectomy specimens from women with BRCA mutations (i.e., women who are at an increased risk for “ovarian” carcinoma) are commonly found in the fallopian tube (especially the fimbriated end and in the form of STIC) without disease in the ovary; (6) early/occult sporadic serous carcinomas in routine specimens (i.e., women who are at low/average risk for “ovarian” carcinoma) are commonly found in the fallopian tube (especially the fimbriated end and in the form of STIC) without disease in the ovary (Gilks et al. 2015; Morrison et al. 2015); (7) identical TP53 mutations have been reported in STIC and synchronous ovarian/peritoneal high-grade serous carcinomas (Carlson et al. 2008; Kindelberger et al. 2007; Kuhn et al. 2012c); (8) identical TP53 mutations in a p53 signature (see “Pathogenesis, Including Molecular Features” section above) and peritoneal serous carcinoma in one case have been reported (Carlson et al. 2008); (9) in STICs associated with high-grade serous carcinomas in the ovary/peritoneum, the STICs frequently have shorter telomere lengths than their associated carcinomas in the ovary/peritoneum, consistent with a precursor lesion (Chene et al. 2013; Kuhn et al. 2010); high-grade serous carcinomas in the ovary have molecular profiles more similar to fallopian tube epithelium than ovarian surface epithelium (Klinkebiel et al. 2016; Marquez et al. 2005); and (10) molecular studies comparing the signature patterns in STICs, high-grade serous carcinomas in the ovary, and metastases have demonstrated evidence of tubal origin with STIC being a precursor (Eckert et al. 2016; Labidi-Galy et al. 2017). However, it should be noted that some investigators have proposed that the STIC pathway may be only one pathway leading to the development of ovarian high-grade serous carcinoma, in which STIC leads to the formation of classic high-grade serous carcinoma whereas high-grade serous carcinomas with the SET (solid, pseudoendometrioid, and transitional cell carcinoma-like) pattern might be unrelated to STIC (Ritterhouse et al. 2016). For additional information on pathogenesis of ovarian carcinoma, see the chapter on “Ovarian Epithelial Tumors”.

The proportion of primary “ovarian” and “peritoneal” high-grade serous carcinomas associated with synchronous STIC ranges from 19% to 61% and 29% to 61%, respectively (Carlson et al. 2008; Kindelberger et al. 2007; Przybycin et al. 2010; Schneider et al. 2017; Seidman et al. 2011; Tang et al. 2012). However, there are a number of potential explanations for a “STIC-negative” ovarian or peritoneal high-grade serous carcinoma.

It is possible that a small fallopian tube carcinoma can exfoliate cells onto the ovary or peritoneum, and preferential tumor growth in these secondary sites may overgrow the fallopian tube/STIC and obliterate any clues to a true fallopian tube origin in cases that do not initially appear as having arisen from the fallopian tube. Similarly, in carcinomas at other primary sites (e.g., breast, colon, endometrium, cervix), the precursor lesion is not always present in the resection specimen presumably due to tumor overgrowth. Interestingly, cases with a dominant mass in the ovary have a low frequency of STIC (11%) whereas STIC is much more common (45%) in cases in which involvement of the ovary did not create a dominant mass (Roh et al. 2009).

Also, STICs may not be present on the initial H&E level but can be discovered upon deeper leveling into the paraffin block (Mahe et al. 2013; Przybycin et al. 2010). Some STICs may be minute, attenuated, and subtle and possibly not identified if only examining H&E sections at low-power magnification. Although STIC may still persist in patients that have received neoadjuvant chemotherapy (Colon and Carlson 2014), the frequency of STIC is lower in such patients (Mahe et al. 2013). Accordingly, in patients treated with neoadjuvant therapy, the latter may have eradicated a preexisting STIC in some cases.

It has been recognized that a subset of risk-reducing salpingo-oophorectomy specimens can have a portion of fimbrial mucosa adherent to the ovarian surface (Ayres et al. 2017; Gan et al. 2017). In such cases, or in other patients (non-risk-reducing salpingo-oophorectomy procedures) where there may have been prior tubo-ovarian adhesions, if a STIC arose in a portion of fimbrial mucosa adherent to the ovarian surface (but which is detached from the fallopian tube proper) and eventually developed into invasive high-grade serous carcinoma creating a mass in the ovary, a fallopian tube completely submitted for histologic examination would appear to not contain any evidence of STIC whatsoever.

Lastly, the concept of “precursor escape” has been proposed, in which nonmalignant epithelial cells with a TP53 mutation spread beyond the fallopian tube and subsequently develop into a high-grade serous carcinoma in the pelvis (Meserve et al. 2017a).

Thus, the true frequency of “ovarian” carcinomas that really originated in the tube may be underestimated.

Although it has been debated regarding the exact origin of ovarian carcinoma as well as the exact proportion of “ovarian” high-grade serous carcinomas that truly originate from the fallopian tube, a survey of members of several national and international gynecologic pathology and clinical cancer societies revealed that 86% of pathologists and 92% of clinicians accept the fallopian tube origin for high-grade serous carcinoma (McCluggage et al. 2017).

Three possibilities may exist for cases with high-grade serous carcinoma in the ovary/peritoneum and STIC: (1) the fallopian tube is the primary lesion with secondary involvement of the ovary/peritoneum; (2) the ovary/peritoneum is the primary site with secondary involvement of the fallopian tube in the form of intraepithelial spread; and (3) both sites may be independent primaries. While the evidence discussed above supports that the majority of cases are of tubal origin, some clinicopathologic, immunohistochemical, and molecular evidence suggests that STIC-like lesions in some cases may actually represent non-fallopian tube gynecologic carcinomas that have metastasized to the fallopian tube (Eckert et al. 2016; Kommoss et al. 2017; McDaniel et al. 2015; Rabban et al. 2015).

In cases in which the primary site cannot be determined, this distinction usually will not be critical since most cases will typically be high-stage, and the treatment and prognosis for a high-grade serous carcinoma simultaneously involving these sites will be similar regardless of which site is designated the primary origin (Baekelandt et al. 2000; Moore et al. 2007).

Although the 8th Edition of the AJCC Cancer Staging Manual states that ovarian high-grade serous carcinoma with only STIC should be classified as stage IA ovarian carcinoma, the International Collaboration on Cancer Reporting has suggested that for instances with high-grade serous carcinoma involving multiple sites, tumors should be assigned tubal primary origin if any of the following are present: STIC, invasive carcinoma involving tubal mucosa, or no tubal fimbria identified (McCluggage et al. 2015a).

Determination of Site of Origin of Serous Carcinoma: Distinction from Endometrial Primary Origin

Endometrial serous intraepithelial carcinoma has been observed in association with STIC (Jarboe et al. 2009). We have encountered cases of synchronous STIC and uterine malignant müllerian mixed tumor with a component of serous carcinoma. In these situations, the relationship between the fallopian tube and uterine tumors is not clear. Three possibilities may also exist, similar to that mentioned above: (1) the fallopian tube is the primary lesion with secondary involvement of the uterus; (2) the uterus is the primary site with secondary involvement of the fallopian tube (Kommoss et al. 2017); and (3) both sites may be independent primaries.

Other Fallopian Tube and Paratubal Neoplasms

Because of the admixture of spindle cells in the epithelial component in some endometrioid carcinomas, the differential diagnosis can include malignant müllerian mixed tumor (MMMT). In general, the epithelial and mesenchymal components of MMMT, while admixed, do not show a histologic transition as opposed to the gradual transition between endometrioid glands and spindle cells in endometrioid carcinoma, and the latter has more of an orderly growth than MMMT. The degree of nuclear atypia and mitotic activity is greater in MMMT. The presence of malignant heterologous tissues would favor MMMT.

Endometrioid carcinomas with a female adnexal tumor of wolffian origin-like (FATWO-like) growth pattern can be confused with FATWO. Location within the lumen of the fallopian tube typically favors carcinoma since FATWO is usually in a paratubal location, but rare FATWOs can arise within the wall of the tube (see section on “Wolffian Adnexal Tumor (“Female Adnexal Tumor of Probable Wolffian Origin”; FATWO” below); however, the latter is predominantly within the muscularis as opposed to mostly occupying the lumen as in an endometrioid carcinoma. Villoglandular architecture, squamous differentiation, and endometriosis would favor carcinoma. Also, carcinoma contains larger, more conventional-appearing endometrioid glands. The degree of glandular confluence and nuclear atypia are usually greater in carcinoma than FATWO. The latter typically has more of an admixture of patterns, including open or closed tubules and sieve-like, solid, and spindled architecture; however, these features can be seen in FATWO-like endometrioid carcinomas. Calretinin is often positive in FATWO but occasionally may be negative; however, most carcinomas are negative. Carcinomas would be expected to express CK7, EMA, ER, and PR and be negative for inhibin. FATWO occasionally expresses CK7 and inhibin. ER, PR, and EMA are frequently negative in FATWO, but expression may occasionally be seen.

Sarcomas and Mixed Epithelial-Mesenchymal Tumors

Pure sarcomas of the tube may occur, and the mesenchymal component of mixed epithelial-mesenchymal tumors can be sarcomatous. Mixed epithelial-mesenchymal neoplasms in which the mesenchymal component is malignant and the epithelial component is benign are designated adenosarcoma whereas those in which both components are malignant are classified as malignant müllerian mixed tumor (MMMT; carcinosarcoma).

Pure sarcomas may be histologically subtyped if sufficient differentiation is present. Leiomyosarcomas are perhaps the most common type and may arise from the tube or broad ligament (Jacoby et al. 1993). However, some may actually represent gastrointestinal stromal tumors arising outside of the gastrointestinal tract (Foster et al. 2006). Other gynecologic-specific sarcomas, such as primary endometrioid stromal sarcoma arising in the tube, are rare (Chang et al. 1993). Chondrosarcoma, malignant fibrous histiocytoma, and embryonal rhabdomyosarcoma have been described.

There are only a small number of tubal MMMTs in the literature, most of which are individual case reports (Carlson et al. 1993; Foster et al. 2006; Imachi et al. 1992). Nearly all women are postmenopausal. They may have watery or bloody vaginal discharge and abdominal pain with signs of peritoneal spread. Grossly, the tumors distend the tube, and by the time of discovery, the majority of women have a pelvic mass with spread to adjacent pelvic and abdominal structures. The ovary must be identified clearly to rule out an origin in that organ. The grossly dilated tube when opened reveals an irregular mucosal surface with areas of necrosis and hemorrhage. Microscopically, distinct carcinoma and sarcoma components areas should be identifiable and intimately admixed with one another. The histologic appearance (Fig. 45) is essentially identical to MMMTs of the uterus and ovary. Malignant glandular or squamous foci (or both) lie in an atypical mitotically active spindle or round cell background of sarcoma. In about half the cases, the sarcoma component may consist only of malignant elements homologous to the tube, such as smooth muscle or stromal cells, but commonly there are foci of malignant cartilage, osteosarcoma, or rhabdomyosarcoma. Areas of STIC may be present adjacent to the main tumor mass, especially in the fimbriated end (Carlson et al. 1993; Gagner and Mittal 2005). The histology of metastases from MMMTs may be composed of carcinoma, sarcoma, or a mixture of both. The main tumor in the differential diagnosis of MMMT is a poorly differentiated endometrioid carcinoma with spindle cell features (see above section “Differential Diagnosis of Carcinoma”). MMMT of the fallopian tube behaves aggressively, but prognosis is dependent on stage. Given that the experience is limited with tubal MMMT and that patients have been treated variably in the literature, standardized current treatment recommendations are not available. Other biphasic malignant tumors, such as adenosarcoma, are rare.
Fig. 45

Malignant müllerian mixed tumor (MMMT; carcinosarcoma). Intimate admixture of malignant epithelial and mesenchymal components

Metastatic Tumors/Secondary Involvement

Traditionally, secondary involvement of the fallopian tube by carcinoma has been considered much more common than primary tubal carcinoma, and metastatic carcinomas involving the tube are usually of ovarian or endometrial origin; however, metastases from the endocervix occur as well. Metastatic gynecologic or non-gynecologic carcinomas involving the pelvis typically involve the tubal serosal surface. Secondary involvement of the serosa in the form of implants from an ovarian atypical proliferative (borderline) serous tumor or by disseminated peritoneal adenomucinosis in the clinical syndrome of pseudomyxoma peritonei can occur too. However, some metastases from non-fallopian tube gynecologic and non-gynecologic carcinomas can have a component of intraepithelial spread mimicking STIC (Fig. 46) (Na and Kim 2017; Rabban et al. 2015; Stewart et al. 2012).
Fig. 46

Metastatic endocervical adenocarcinoma (usual type/HPV-related) mimicking serous tubal intraepithelial carcinoma (STIC)

Lymphatic metastases may involve the mucosa or muscularis. Low-grade endometrial stromal sarcoma may involve the tubes by the extension of worm-like tongues of tumor along tubal lymphatics. Hematogenous metastases from breast carcinomas or other extra-pelvic tumors also may occur. Rarely, displaced benign endometrial tissue can be seen in the veins of the fallopian tube and should not be mistaken for metastatic carcinoma. On occasion, squamous carcinoma of the uterine cervix may spread in an in situ manner to involve the endometrial cavity, tubes, and even the ovarian surface (Pins et al. 1997).

The presence of tumor in the lumen of the fallopian tube in cases of endometrial serous carcinoma with metastases in the peritoneum (without myoinvasion or lymph-vascular space invasion in the uterus) suggests that the tubal lumen serves as a conduit for tumor spread (Snyder et al. 2006). However, fragments of endometrial endometrioid carcinoma within the tubal lumen without adherence to tubal mucosa is considered artifactual displacement and does not qualify for upstaging an endometrial carcinoma (Delair et al. 2013; Stewart et al. 2013). In primary ovarian carcinoma, luminal groups of tumor cells may implant onto endosalpingeal surfaces and simulate STIC or early invasive primary tubal carcinoma. The distinction of fallopian tube vs. ovarian origin for serous carcinoma is discussed in the above section “Determination of Site of Origin of Serous Carcinoma.”

Lymphoma

Primary tubal lymphoma is rare and is associated almost invariably with simultaneous involvement of the ipsilateral ovary (Vang et al. 2001). Undifferentiated carcinoma and other small round blue cell tumors must be ruled out with appropriate immunohistochemical stains. For details, see chapter on “Hematolymphoid Neoplasms”.

Gestational Trophoblastic Disease of the Fallopian Tube

Trophoblastic tubal lesions are exceedingly uncommon. Patients have risk factors for ectopic pregnancy such as prior salpingitis and tubal occlusion (Muto et al. 1991). The clinical presentation of a tubal hydatidiform mole or choriocarcinoma is similar to that of a tubal ectopic pregnancy; thus, rarely, an apparent ectopic pregnancy will prove to be a mole or choriocarcinoma. Hydatidiform moles usually occur as isolated growths but may be associated with intrauterine pregnancy. The histologic appearance resembles complete or partial moles as seen in the uterus. However, tubal moles are frequently overdiagnosed because ectopic pregnancies in the fallopian tube commonly have an exuberant extra-villous trophoblastic proliferation (Burton et al. 2001; Sebire et al. 2005). Intraoperatively, the appearance of a tubal choriocarcinoma may be that of a large, hemorrhagic, and fleshy mass mostly destroying the tube. Histologically, the malignant trophoblastic proliferation resembles uterine choriocarcinoma. Response to modern chemotherapy in general has been excellent. Lesions of intermediate trophoblast, including placental site nodule, placental site trophoblastic tumor, and epithelioid trophoblastic tumor, are rare (see chapter on “Gestational Trophoblastic Disease and Related Lesions”) (Baergen et al. 2003; Jacques et al. 1997; Nayar et al. 1996; Parker et al. 2003; Su et al. 1999).

Paratubal Lesions

Adrenal Rests

If a careful search is made, adrenal cortical rests may be found in the broad ligament in more than 20% of women. They lie adjacent to the ovarian vein and just beneath the peritoneum. Grossly, they appear as yellow nodules, but they may be obscured by fat. Medullary tissue is absent, but microscopically all three cortical layers are recognizable (Fig. 47). This accessory tissue may hypertrophy secondary to adrenal destruction or may, rarely, give rise to a functional or nonfunctional cortical adenoma (Sasano et al. 1997; Wild et al. 1988).
Fig. 47

Adrenal rest. It typically shows similar cortical architecture and cell types as seen in the adrenal gland

Paratubal Cysts

Paratubal cysts can be small or large. They have been classified based on their presumed origin: paramesonephric (müllerian), mesothelial, or mesonephric (wolffian). Differentiation may be difficult because of compression and atrophy of the lining cells. Those of paramesonephric type are the most common. In one study of paratubal cysts, 76% were paramesonephric, 24% were mesothelial, and none were mesonephric (Samaha and Woodruff 1985). The hydatid of Morgagni is by far the most common paramesonephric cyst. Grossly, it is attached to one of the fimbriae (Fig. 3). It is ovoid or round, 2–10 mm in diameter, and contains clear serous fluid surrounded by a thin translucent wall. Microscopically, it is lined by epithelium resembling fallopian tube mucosa (including ciliated and non-ciliated cells), may have small epithelial-covered plicae projecting into the lumen, and may contain a thin smooth muscle wall (Fig. 48). However, the cells lining the cyst can be flattened. Mesothelial cysts typically are lined by cuboidal or flattened cells and have a thin wall containing fibrous stroma. They lack the ciliated cells and thin plicae seen in paramesonephric cysts. Based on the available literature, it is not entirely clear what are the specific histologic features of mesonephric cysts.
Fig. 48

Paratubal cyst. The cyst is thin and lined by bland tubal epithelium as seen in normal fallopian tubes. Focal residual plicae may be present

Common differential diagnostic problems, which are usually of no clinical importance, are distinguishing a hydatid cyst of Morgagni from a serous cystadenoma and hydrosalpinx. In some cases, distinction from a serous cystadenoma may not be possible; however, hydatid cysts frequently contain a smooth muscle wall, while the wall of a serous cystadenoma contains more fibromatous stroma than is typically seen in a hydatid cyst. Thin fallopian tube-like plicae, if present, favor a hydatid cyst rather than cystadenoma. In cases where the fallopian tube cannot be clearly discerned, distinction of a hydatid cyst from hydrosalpinx in which the fallopian tube is markedly distorted might be impossible since both can contain a thin smooth muscle wall and thin plicae lined by epithelium resembling that of the fallopian tube.

Wolffian Adnexal Tumor (“Female Adnexal Tumor of Probable Wolffian Origin”; FATWO)

This small group of distinctive tumors is described as located either within the leaves of the broad ligament, the mesosalpinx, or in the ovarian hilus (these tumors are also discussed in chapter on “Nonspecific and Mesenchymal Tumors of the Ovary”) (Devouassoux-Shisheboran et al. 1999; Goyal et al. 2016; Howitt et al. 2015; Kariminejad and Scully 1973). However, rare tumors can arise within the wall of the fallopian tube without growth in the lumen (Fig. 49). Patients range in age from 19 to 83 years (mean ranges from 42 to 45 years between studies). Either they have abdominal pain and a palpable mass or the tumor is discovered as an incidental finding. The tumor is typically unilateral and localized without disseminated disease. The lesions measure from 0.8 to 20 cm in greatest dimension (mean, 6 cm) and are solid and lobulated with gross encapsulation. The cut surface is gray-yellow or tan, and the consistency may be firm, rubbery, or friable. Cysts or calcification may be present.
Fig. 49

Female adnexal tumor of wolffian origin (FATWO) in nonclassic location. (a) The tumor is located within the wall of the fallopian tube rather than in a paratubal site but is not intraluminal. (b) The tumor exhibits the same architectural patterns seen in paratubal locations

The microscopic appearance is variable. The tumors usually show a combination of growth patterns, including tubular (open or solid tubules), cystic, diffuse/solid, lobulated, sieve-like/retiform, and adenomatoid (Fig. 50). The tubal lumens and sieve-like spaces frequently contain eosinophilic, colloid-like material. The cells are cuboidal, flat, and/or spindled and have scant cytoplasm. The nuclei are typically bland, and the mitotic index is usually low. The stroma is either fibrous or hyalinized. FATWO typically expresses pan-cytokeratin and CD10. Calretinin, low molecular weight cytokeratin (CAM5.2), and androgen receptor are often positive but occasionally may be negative. Expression of calretinin is usually diffuse. Tumors occasionally express CK7 and inhibin. Expression of CK7 is typically focal while the pattern with inhibin is variable, but the latter can be focal too. ER, PR, and EMA are frequently negative but expression may be seen on occasion. Available data suggest PAX8 is negative and also that most FATWOs are negative, but experience is limited. CK20 is typically negative.
Fig. 50

Female adnexal tumor of wolffian origin (FATWO). (a) Open tubules. (b) Closed elongated tubules (note focally hyaline stroma). (c) Sieve-like pattern

Patients have been treated surgically, usually with a benign outcome. Malignant behavior is uncommon and includes multiple local recurrences and fatal metastases (Brescia et al. 1985; Daya 1994). It is difficult to predict which cases will exhibit malignant behavior. The tumors that demonstrate malignant behavior generally have nuclear atypia and mitotic activity; however, bland histology has been noted in some FATWOs that exhibit malignant behavior.

The differential diagnosis includes the FATWO-like variant of tubal endometrioid carcinoma (see above section “Differential Diagnosis of Carcinoma”). Many of the histologic and immunohistochemical features of FATWO overlap with those of Sertoli cell tumor; however, the admixture of multiple growth patterns (particularly cystic architecture with a sieve-like pattern) and cell types in FATWO is generally greater than is typically seen in Sertoli cell tumor, and sex cord-stromal tumors are rare in extra-ovarian sites.

Papillary Cystadenoma Associated with Von Hippel-Lindau Disease

These epithelial tumors are rare and characteristically arise in the broad ligament (Aydin et al. 2005; Brady et al. 2012; Gersell and King 1988; Korn et al. 1990; Nogales et al. 2012; Werness and Guccion 1997). Most are thought to be of mesonephric origin, but a müllerian origin has been suggested in one case (Werness and Guccion 1997). In some cases, patients have a known history of the autosomal dominant disorder, von Hippel-Lindau disease; however, in other cases, the tumor in the broad ligament may be the first manifestation of the disease. It should be noted that rare cases do not have an association with this genetic disease. Patients range in age from the third to fifth decades of life. Tumors may be unilateral or bilateral. They vary in size and are composed of cysts that contain a complex papillary proliferation (Fig. 51). The papillae are generally short and blunted. The stroma of the papillae varies in cellularity and may be hyalinized or fibrous. The papillae are usually lined by a single layer of low-cuboidal, non-ciliated cells which have eosinophilic or clear cytoplasm, but ciliated cells have been reported in one case (Werness and Guccion 1997). The nuclei are bland, and the tumors are mitotically inactive. These tumors typically lack epithelial stratification and psammoma bodies. They are thought to be benign.
Fig. 51

Papillary cystadenoma associated with von Hippel-Lindau disease. Cysts contain a complex papillary proliferation. The papillae are short and blunted. Closer magnification will show papillae lined by a single layer of cuboidal, non-ciliated cells with bland nuclei and clear to eosinophilic cytoplasm

The importance of diagnosing this tumor (or suggesting it as a diagnostic possibility in ambiguous cases) is because of the association with von Hippel-Lindau disease (and, hence, various tumors of other organs, including renal cell carcinoma) and to not confuse it with other histologically similar neoplasms that do not have this association. The differential diagnosis includes cystadenofibromas of müllerian type with prominent papillary architecture that are not associated with von Hippel-Lindau disease. Those generally contain papillae which are much larger and less complex and contain cilia. They should also have areas which appear more conventionally adenofibromatous, including distinctive cleft-like architecture. Histologic overlap can also occur with atypical proliferative (borderline) serous tumor, but this tumor exhibits a hierarchical degree of papillae branching with epithelial stratification (including cellular tufts), ciliated cells, and psammoma bodies. Papillary cystadenomas associated with von Hippel-Lindau disease that are predominantly of clear cell type can mimic metastatic renal cell carcinoma (Aydin et al. 2005). In contrast with the latter, papillary cystadenoma diffusely expresses CK7 and is negative for RCC marker. CD10 can be positive or negative. Other positive markers that have been described include WT-1, PAX2, and PAX8. ER/PR have been reported as negative, but experience is limited. Specifically, it is not clear cell renal cell carcinoma that papillary cystadenoma resembles as the latter is more histologically and immunohistochemically similar to clear cell papillary renal cell carcinoma (Cox et al. 2014).

Other Paratubal/Para-ovarian and Pelvic Ligament Lesions

Atypical proliferative (borderline) tumor occurs more commonly in the broad ligament and paratubal/para-ovarian locations compared with carcinoma. Most of the atypical proliferative (borderline) tumors are of serous type (Aslani et al. 1988). These patients range in age from 19 to 67 years (mean, 32 years). The tumors are typically unilateral, and they range in size from 1 to 13 cm. They are usually confined to the broad ligament and histologically similar to their ovarian counterparts. The behavior appears to be favorable. Primary carcinoma of the broad ligament is rare (Aslani and Scully 1989). Many of the patients are relatively young, and the tumors are usually unilateral. Some are associated with pelvic endometriosis. In most cases, disease is limited to the broad ligament. Various histologic types have been described, including endometrioid and clear cell.

Most mesenchymal tumors in paratubal/para-ovarian locations and pelvic ligaments are leiomyomas. Criteria for classification of benign, atypical, and malignant smooth muscle tumors in paratubal/para-ovarian locations have not been developed; however, some authors have advocated using the same criteria as used for uterine locations (Kempson et al. 2001; Lax et al. 2003). It should be noted that criteria have been suggested for classifying smooth muscle tumors in the ovary (Lerwill et al. 2004). For additional details regarding extrauterine smooth muscle tumors, see the chapter on Soft Tissue Tumors. Sarcomas (leiomyosarcoma being the most common one) are rare.

Other primary lesions, some of which are rare, that may occur in paratubal/para-ovarian locations and pelvic ligaments include endometriosis, uterus-like mass, ectopic hilus cell nests, benign epithelial tumors (including serous cystadenoma and Brenner tumor; cystadenofibromas are occasional, usually incidental findings), adenomyoma, benign mesenchymal tumors (including lipoma, benign mesenchymoma, neurofibroma, and schwannoma), sex cord-stromal tumors (including fibroma, thecoma, and steroid cell tumor), ependymoma, teratoma, pheochromocytoma, carcinoid, perivascular epithelioid cell tumor (PEComa), malignant mesenchymal tumors (including extra-skeletal Ewing’s sarcoma/PNET, adenosarcoma, endometrioid stromal sarcoma, rhabdomyosarcoma, “mixed mesenchymal sarcoma,” liposarcoma, and alveolar soft part sarcoma), yolk sac tumor, and choriocarcinoma (Lax et al. 2003). Various gynecologic and non-gynecologic tumors may secondarily involve paratubal/para-ovarian locations and pelvic ligaments. Such mesenchymal gynecologic tumors in particular include intravenous leiomyomatosis, diffuse uterine leiomyomatosis, cotyledenoid dissecting leiomyoma (“Sternberg tumor”), uterine leiomyosarcoma, and endometrial stromal sarcoma.

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Pathology, Division of Gynecologic PathologyThe Johns Hopkins Medical InstitutionsBaltimoreUSA

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