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Diseases of the Fallopian Tube and Paratubal Region

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” [88]. This organ was eventually named after him. Since that time, a wide variety of non-neoplastic 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.

Keywords

Fallopian Tube Ectopic Pregnancy Ciliated Cell Serous Carcinoma Endometrioid Carcinoma 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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” [88]. This organ was eventually named after him. Since that time, a wide variety of non-neoplastic 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 that 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 non-neoplastic. 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.

This chapter provides a detailed discussion of normal fallopian tube (embryology, gross anatomy, and histology) and gross examination, non-neoplastic 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 [171, 172, 199]. At the cranial end of the urogenital ridge, the peritoneum gives rise to a population of epithelial cells, which segregate from the peritoneal layer [91]. This new population proliferates and forms the longitudinally oriented müllerian ducts [91, 175]. 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. 11.1 and 11.2 ). 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 that 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. 11.2 ). This pelvic fold forms the broad ligament to which the fallopian tube is attached.
Fig. 11.1

(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:Figs. 15–22. Printed with permission from Lippincott Williams & Wilkins)

Fig. 11.2

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:Figs. 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 week, there is an increase in the growth and coiling of the fallopian tube at a rate of approximately 3 mm/week [108]. Fimbriae do not develop until the 20th week, at which time only three to four are present in each fallopian tube [226]. The fimbriae increase in number throughout gestation, and at term, six to eight 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 [243]. In addition, the Hox family of genes (Hox in mice, HOX in humans) is particularly essential for development of this anatomic structure [65, 228, 243]. 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 -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 [228]. 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. 11.3 ). 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. 11.3

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. 11.4 ), and decidua may be seen in 80% of tubes removed for ectopic pregnancy [89]. 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. 11.5 ). In the ampulla, the plicae are frond-like and delicate, and both secondary and tertiary branches may be appreciated (Fig. 11.6 ). 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.
Fig. 11.4

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. 11.5

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. 11.6

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. 11.7 ). 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 [94]. The reader is referred elsewhere for additional details regarding the structure and physiology of fallopian tube cilia [147].
Fig. 11.7

Mucosa 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, and the Ki-67 labeling index is typically <5%. The secretory cell exhibits the immunophenotype HMFG2(+)/PAX8(+)/p73(−) [28, 140, 201].

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 [61]. 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 [61, 235]. Additional details of fallopian tube physiology are available elsewhere [112].

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) [163].

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. Beneath the mesothelium lies a small amount of connective tissue containing a few collagen fibers and blood vessels.

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. 11.8 ).
Fig. 11.8

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.

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 tubal intraepithelial carcinoma (TIC), especially in the fimbriated end (see Carcinoma section below).

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 thing 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.

Prophylactic Bilateral Salpingo-Oophorectomy

Measurements should be made as specified above. 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. 11.9 ). 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. Although there is no standard in terms of how many H&E slides need to be prepared from each block, our routine practice is one 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.
Fig. 11.9

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)

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 [146]. This protocol also lists the essential clinical, gross, and histologic information which should be included in the pathology report. 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.

Non-neoplastic Lesions of Fallopian Tube

Metaplasia, Hyperplasia, and Other Epithelial/Non-Epithelial Changes

The tubal epithelium may undergo various metaplastic changes, including squamous, transitional, mucinous, or oncocytic type (Fig. 11.10 ) [68, 193, 214]. 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 [162, 200, 241, 242]. 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 [107]. In some cases, particularly those associated with marked salpingitis, the degree of hyperplasia (including cribriform architecture) can simulate carcinoma (Fig. 11.11 ) [43, 64]. This differential diagnosis is diagnosed below in the section on carcinoma. Severe epithelial changes that mimic early adenocarcinoma may be produced by thermal artifact (Fig. 11.12 ).
Fig. 11.10

Squamotransitional cell metaplasia. he 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. 11.11

Epithelial 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. 11.12

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 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, or otherwise normal epithelium [152, 216].

Nests of cells morphologically similar to ovarian hilus cells have been described in the mid-portion of the tube. 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. 11.13 ) can rarely occur.
Fig. 11.13

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. 11.14 ). The cells have nuclei that 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. 11.14

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”) [180]. A form of endometriosis designated “post-salpingectomy endometriosis” occurs in the tip of the proximal stump of the fallopian tube years after tubal ligation [44]. 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  Chap. 13, 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. 11.15 ). 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 [132]. 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. 11.15

Salpingitis isthmica nodosa. Glands infiltrate 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. An important complication of SIN is infertility, and there is a strong association with ectopic tubal pregnancy [89, 104, 149, 183, 206]. 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 [29]. Hepatic, diaphragmatic, and splenic pregnancies are extremely rare [56].

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 [89]. Ultrastructural studies have demonstrated that the mucosa of fallopian tubes in women with ectopic pregnancies have lower numbers of ciliated cells compared with women who have intrauterine pregnancies [234]. 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 intrauterine contraceptive device (IUD) use [27].

Clinical Features

Currently, ectopic pregnancy accounts for 1–2% of clinically known pregnancies [3, 70, 232]. 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 [92, 150]. 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 [29, 30]. 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, respectively [70, 79]. 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 [39, 63].

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. 11.16 ). Within the tube, most ectopic pregnancies are found in the ampulla (∼80%), isthmus (12%), and fimbriae (5%) [29].
Fig. 11.16

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 [121]. 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 [33, 211]; however, this appearance is within the range of proliferation that can be encountered in ectopic pregnancies (Fig. 11.17 ). 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 [181]. Another major difference compared with uterine implantation is the failure of tubal trophoblast to differentiate into chorion frondosum and chorion laeve [196], but a gestational sac can be seen [181]. 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. 11.17

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% [89]. Salpingitis isthmica nodosa may also be present. Arias-Stella reaction can be seen in the fallopian tube mucosa [159]. Clear cell hyperplasia has been reported [230].

The clinicopathologic features of extratubal ectopic pregnancy vary according to the site [173]. 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 [90]. Macroscopic examination typically reveals a hemorrhagic mass replacing the ovary. Pathologic criteria for ovarian pregnancy have been proposed as follows: (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 [90]. 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 [69]. 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 [111, 168]. 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 [231]. 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 the WHO Classification of fallopian tube neoplasms and in other textbooks on gynecologic pathology; however, they are included in the non-neoplastic 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 [50, 71]. 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 [145]. 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 [5]. 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 [147]. Obliterative fibrosis (possibly secondary to inflammation within the uterus) or polyps at the uterine tubal ostium may lead to obstruction at the uterotubal junction [76, 139].

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) [62, 223]. 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 that 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 re-orienting and re-embedding 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 who were initially treated by surgical resection, spontaneous re-anastomosis or fistula formation, which may lead to fertilization and ectopic or intrauterine pregnancy, are common mechanisms of sterilization failure [221]. 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 [137, 154]. 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. 11.18 ). 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. 11.19 ). 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. 11.18

Fallopian tube with 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. 11.19

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 [120]. 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 [141].

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 [227]. Elegant in vitro studies by Ward et al. [237] have clarified the likely initial steps in gonococcal infection, and the molecular mechanisms involved have been reviewed elsewhere [67, 147]. 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 [148, 156], and the degree of pathogenicity likely depends on the bacterial as well as the host genome [11]. 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 [131, 151]. 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 [147]. 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 [240]. On occasion, the lymphofollicular response may be so florid as to suggest lymphoma [236].

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 the 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 the tube are attached to one another by adhesions and create a mass in the form of a tubo-ovarian abscess (Fig. 11.20 ). 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 [136]. Typically, these infections are polymicrobial.
Fig. 11.20

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 [184]. Actinomycotic infections of the tube are associated with intrauterine contraceptive devices (IUDs) (see  Chap. 7, Benign Diseases of the Endometrium) [60]. 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 [24, 192].

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. 11.21 ). 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. 11.21

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 [103]. 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. 11.22 ). 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. 11.23 ); 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. 11.24 ). 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. 11.22

Clubbed tube. The fimbriated end is closed because of fimbrial adhesions, creating a blunted end

Fig. 11.23

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

Fig. 11.24

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. 11.25 ). 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. 11.26 ). A few lymphocytes may be found in the wall of the hydrosalpinx but are more commonly absent.
Fig. 11.25

Hydrosalpinx. The fallopian tube is massively dilated, producing a large cystic mass

Fig. 11.26

Hydrosalpinx. Most of the dilated fallopian tube contains a thin wall and atrophic mucosa. Residual small plicae are present. Note the 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. 11.27 ) [45, 78, 101, 164, 215]. 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 [45, 215]. 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 [78]. 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 [78, 133]. A potentially related lesion that has been described in the tube is xanthelasma [41].
Fig. 11.27

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 USA to nearly 40% in India [178]. Twenty percent of women who die of tuberculosis have tubal involvement [208]. 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 [93]. 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 [178]. 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. 11.28 ). 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. 11.28

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, the mycobacterial culture and the histologic finding of endometrial granulomas on curettage are diagnostically useful (see  Chap. 7, 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. 11.29 ), but identification of ova can be obscured by calcification and granulomas.
Fig. 11.29

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 USA. In Africa, the fallopian tube is involved by schistosomiasis in 22% of all infected women [84]. 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 adnexa. Cysticercosis (Taenia solium) also has been described in the tube [2]. Other rare parasites that have been reported in the fallopian tube include Entamoeba histolytica (amebiasis). Liesegang rings should not be mistaken for parasites [46].

Fungal Salpingitis

Other fungi that 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 [25]. 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 [32]. 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) [20]. Foreign body granulomas due to starch and talc, as well as pulse granulomas [197] 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 [124]. 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 [123]. 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 [22]. 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 are enlarged, edematous, and dark and show 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  Chap. 3, Diseases of the Vagina) [195]. 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; 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 [4].

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 who 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 [54]. The mucosa may be absent, or when it is present, the plicae do not develop [199].

Tubal duplication and accessory fallopian tubes are uncommon, but the latter occur more frequently [23, 47, 51, 83]. 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. [167]).

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 [82, 105]. 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 [82, 105].

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 11.1 . Most of these are nonspecific histologic types since the same ones can be seen in other gynecologic sites, especially the ovary.
Table 11.1

Histologic classification for neoplasms of the fallopian tube, including gestational trophoblastic disease: Modified 2003 WHO Classification

Epithelial

Benign, including mixed epithelial–mesenchymal tumors

 Papilloma

 Cystadenoma/cystadenofibroma (specify histologic type)

 Metaplastic papillary tumor

 Other

Borderline tumor (atypical proliferative, low malignant potential)

 Serous

 Mucinous

 Endometrioid

 Other histologic types

Malignant

Non-invasive carcinoma

 Tubal intraepithelial carcinoma (specify histologic type when possible)

Invasive carcinoma

 Serous

 Mucinous

 Endometrioid

 Clear cell

 Transitional cell

 Squamous cell

 Undifferentiated

 Other histologic types

Mixed epithelial–mesenchymal

Adenofibroma (specify histologic type)

Adenosarcoma

Malignant müllerian mixed tumor (MMMT; carcinosarcoma)

Soft Tissue

Leiomyoma

Leiomyosarcoma

Mesothelial

Adenomatoid tumor

Germ cell

Teratoma

 Mature

 Immature

Other histologic types

Gestational trophoblastic disease

Placental site nodule

Hydatidiform mole

Choriocarcinoma

Placental site trophoblastic tumor

Other histologic types

Secondary involvement

Gynecologic and non-gynecologic carcinomas

Hematolymphoid

 Lymphoma

 Leukemia

Malignant mesothelioma

Other histologic types

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  Chap. 10, 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. 11.30 ). Foci of chronic inflammation can also be present. 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 line the tubules. Mitotic figures are rare. The tubules may be empty or contain pale fluid. Infarction may occur in adenomatoid tumor. When it 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 non-neoplastic tissue, pseudoinfiltration, solid patterns in viable tumor, and reactive atypia [218].
Fig. 11.30

Adenomatoid tumor. (a) Nodular configuration in the wall of the fallopian tube. (b) Diffuse proliferation of tubules that 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 intraluminal 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). 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 [87]. 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. 11.31 ). At 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. 11.31

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 [19, 119, 203]. It is of microscopic size and composed of broad papillae lined by stratified and tufted epithelium with cells showing abundant eosinophilic cytoplasm (Fig. 11.32 ). 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. 11.32

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 neoplasms 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 tumors 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 [26]. 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. 11.33 ). 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 of the tumors are of endometrioid type [7]. 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. 11.33

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 [144]. 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 [244] 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 that 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.

Clinical Features

Primary adenocarcinoma of the tube is uncommon, and it has been estimated to account for 0.7–1.5% of invasive malignancies of the gynecologic tract [21, 190]. However, the true frequency is difficult to determine, partly because some fallopian tube carcinomas might be misclassified as “ovarian” (see below). The incidence of fallopian tube carcinoma is 0.41 per 100,000 women in the USA [222].

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 (see Occult Disease in Prophylactic Bilateral Salpingo-Oophorectomy Specimens section below for 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. 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 63 years [8, 98, 202, 222]. Tubal malignancies in women younger than age 40 years are very uncommon. Ninety percent of patients are white, non-Hispanic. 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 [8, 17, 185]. Between 5% and 14% of women have ascites at the time of presentation [17, 66]. 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, as well as the clinical presentation that simulates an ovarian tumor, a correct preoperative diagnosis of fallopian tube carcinoma is uncommon. Rare patients can have an associated paraneoplastic syndrome [153, 213].

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; however, information in the literature is too limited to make definitive conclusions regarding prognostic differences [38, 143].

FIGO Stage
The staging system for fallopian tube carcinoma is that of the International Federation of Gynecology and Obstetrics (FIGO), which is primarily based on surgical pathology findings. Tubal intraepithelial carcinoma (TIC) represented stage 0 disease prior to the Seventh Edition of the AJCC Cancer Staging Manual; however, stage 0 no longer exists in the current system. With stage I tumors, disease is confined to the fallopian tube (Fig. 11.34 ). 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 11.2 .
Fig. 11.34

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

Table 11.2

International Federation of Gynecology and Obstetrics (FIGO) staging system for fallopian tube carcinomaa

Stage I

Growth limited to fallopian tubes

IA: Growth limited to one tube with extension into submucosab and/or muscularis but not penetrating serosal surface; no ascites

IB: Growth limited to both tubes with extension into submucosa and/or muscularis but not penetrating serosal surface; no ascites

IC: Tumor either Stage IA or Stage IB with extension through or onto tubal serosa or with positive ascites/peritoneal washings

Stage II

Growth involving one or both fallopian tubes with pelvic extension

IIA: Extension and/or metastases to uterus and/or ovaries

IIB: Extension to other pelvic tissues

IIC: Tumor either Stage IIA or IIB and with positive ascites/peritoneal washings

Stage III

Tumor involving one or both fallopian tubes with peritoneal implants outside pelvis and/or positive retroperitoneal or inguinal lymph nodes. Superficial liver metastasis equals stage III. Tumor appears limited to true pelvis but with histologically proven malignant extension to small bowel or omentum

IIIA: Tumor grossly limited to true pelvis with negative lymph nodes but with histologically confirmed microscopic involvement of abdominal peritoneal surfaces

IIIB: Tumor involving one or both tubes with histologically confirmed implants of abdominal peritoneal surfaces, none exceeding 2 cm in diameter. Lymph nodes are negative

IIIC: Abdominal implants >2 cm in diameter and/or positive retroperitoneal or inguinal lymph nodes

Stage IV

Growth involving one or both fallopian tubes with distant metastases. If pleural effusion is present, tumor cells must be present to be Stage IV. Parenchymal liver metastasis equals Stage IV

From Pettersson with slight modifications [186]

a Stage 0 does not exist in the 7th Edition of the AJCC Cancer Staging Manual

b “Submucosa” is interpreted as meaning lamina propria

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

It has been suggested that intraluminal masses without invasion qualify as neither stage 0 (prior staging system) nor stage IA [8]. 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) [8]. 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 [7, 8]. 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 as follows: stage 0 (6%) (prior staging system), stage I (27%), stage II (22%), stage III (35%), and stage IV (12%) [17]. 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% [96, 98, 202, 222].

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) [8, 17, 98, 222]. The average tumor size is 5 cm (range, 0.2–10 cm) [8]. The fallopian tube is dilated in slightly over one half of cases, which intraoperatively can be mistaken for a hydrosalpinx, hematosalpinx, or pyosalpinx [8]. The tumor can appear as one or more yellow to tan nodules or a mass that fills the lumen (Fig. 11.35 ). 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. 11.35

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 traditionally been considered “carcinoma in situ.” With recognition of early carcinomas without invasion of underlying fallopian tube stroma in prophylactic bilateral salpingo-oophorectomy specimens, the term tubal intraepithelial carcinoma (TIC) has become popular in recent years. Given the ability of TIC 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.

Histologically, TIC is the earliest morphologically recognizable form of 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. 11.36 ). In cases with invasive carcinoma in the same tube, TIC may be found directly adjacent to invasion. TIC may occur as a single focus or multifocally. 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 nucleoli, and mitotic figures (Fig. 11.37 ). Nuclei may be oval or columnar but are frequently round.
Fig. 11.36

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. 11.37

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)

The lesional cells of TIC show secretory cell differentiation [140]. Also, they cytologically resemble the cells of high-grade serous carcinoma. For these reasons, as well as what is known about the pathogenic relationship between TIC and invasive high-grade serous carcinoma (see below), most TICs should be considered as being of serous histologic type. Therefore, the diagnostic terms “tubal serous intraepithelial carcinoma” and “tubal intraepithelial carcinoma” should usually be considered synonymous. However, rare endometrioid TICs have been reported [113].

Before diagnosing an incidental lesion as TIC 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.

Tubal dysplasias have been described in the literature, and the clinical significance of such lesions is unclear. Furthermore, standardized criteria and terminology, as well as reproducibility studies, have not been published. Accordingly, use of the diagnostic term “dysplasia” is discouraged. For worrisome atypical mucosal lesions of the fallopian tube which do not entirely qualify as TIC based on a combination of histologic and immunohistochemical features (see below), one option for handling such problematic cases is to use a descriptive diagnosis with a comment that the lesion is concerning for but not sufficiently diagnostic of TIC.

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 TIC, especially when the latter shows an increased degree of stratification. In such cases, the diagnostic threshold between TIC versus a small intraluminal high-grade serous carcinoma without invasion of underlying fallopian tube stroma is subjective and varies between authors [113, 244]. However, some authors have suggested that intraluminal masses without invasion qualify as neither stage 0 (prior staging system) nor stage IA (see FIGO Stage above) [8].

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 as follows: serous (80%), adenocarcinoma, not otherwise specified (10%), endometrioid (7%), clear cell (2%), mucinous (2%), and mixed serous-mucinous (1%) [17]. Most fallopian tube carcinomas are poorly differentiated, and well-differentiated tumors are very uncommon. Standardized grading schemes for fallopian tube carcinoma have not been implemented. However, we apply the same grading schemes as used for the ovary (i.e., low- versus 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. 11.38 ) [8]. The nuclei are high grade, characterized by nuclear enlargement, hyperchromasia or irregular chromatin distribution with prominent nucleoli, irregular nuclear membranes, and abundant mitotic figures. TIC may be found adjacent to invasive carcinoma.
Fig. 11.38

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 [166, 194]. 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) [53, 166]. Independent primary endometrioid carcinomas can synchronously arise in the fallopian tube and uterus [49].

Clear cell and transitional cell carcinomas resemble those seen in the ovary [8, 130]. 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 [8, 10, 42, 99]. 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 TIC may be diagnosed solely on histologic features without the need for immunohistochemistry, immunostains are helpful in establishing the diagnosis in problematic cases. TIC diffusely and strongly expresses p53 (Fig. 11.39 ); however, 21% of TICs did not overexpress p53 in one study [217]. The Ki-67 proliferation index is usually markedly elevated (Fig. 11.39 ). In one study, the mean Ki-67 labeling index was 72% (range: 40–95%) [113]. Also, p16, which is diffusely and strongly expressed in endometrial serous carcinomas and many ovarian high-grade serous carcinomas, is occasionally expressed with a strong diffuse pattern in TIC in our experience. Of note, the diffuse patterns of expression of p53 and p16 show nearly all lesional cells being positive as opposed to a patchy pattern of staining in which substantial numbers of both negative and positive cells are present.
Fig. 11.39

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 TIC also show WT-1 expression. Expression of ER and PR is variable. Although most cases overexpress p53, the exact extent of expression has not been adequately detailed in the literature. Immunohistochemical data are limited for endometrioid carcinomas, but in our experience, WT-1 and p53 can be diffusely expressed in some cases.

Treatment and Prognosis

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 [8, 17, 55, 59, 127, 128].

In the largest studies of fallopian tube carcinoma, patients have been treated in various fashions, but the most important prognostic factor is stage [8, 17, 98, 185, 198, 202]. The overall 5-year survivals for fallopian tube carcinoma for all stages combined range from 43% to 56% between studies [17, 96, 202]. In the largest clinicopathologic study using hospital-based cases, the 5-year survivals were as follows: stage 0 (88%) (prior staging system), stage I (73%), stage II (37%), stage III (29%), and stage IV (12%) [17]. These 5-year survivals are similar to those of other large studies [96, 98, 161, 185, 202]. It is also noteworthy that stage 0 disease (prior staging system) does not guarantee a cure, as the 5-year survivals for stage 0 (prior staging system) range from 75% to 91% between studies [17, 66, 209]. 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). For details regarding behavior of stage 0 cases (prior staging system) in the context of prophylactic bilateral salpingo-oophorectomy specimens, see the respective section below.

Alvarado-Cabrero et al. showed that subcategorization of stage I cases based on depth of invasion was prognostically significant [8]. 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 [14, 17, 185].

Presence/amount of residual disease after surgery is a poor prognostic factor [17, 185, 202]. 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 [8, 17]. Disagreement exists between studies regarding whether or not histologic grade, vascular invasion, age, or ascites is prognostically significant [8, 17, 98, 185, 202]. Histologic type has not been shown to be of prognostic importance [8, 17].

Treatment of fallopian tube carcinoma should consist 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 should be treated similarly to ovarian carcinoma [17, 161, 177, 198]. 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 [17]. In that study, patients were not postoperatively treated in a uniform fashion. In a study of patients who received postoperative combination platinum/taxane chemotherapy, carcinoma recurred in 74% of patients with stage III or IV disease by 33 months [161]. 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 [17].

Given the association of fallopian tube carcinoma with germline BRCA mutations, genetic counseling should be considered for all new diagnoses of fallopian tube carcinoma. For treatment and prognosis of occult fallopian tube carcinoma in prophylactic bilateral salpingo-oophorectomy specimens, see the respective section below.

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 39–62% and 11–27% lifetime risks for ovarian carcinoma, respectively, and those risks (cumulative risk) increase over time from ages 40 to 80 years [9, 72, 75, 126]. 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 have shown BRCA germline mutations [16, 38, 143]. Given the significant risk of ovarian carcinoma for patients with BRCA mutations, prophylactic salpingo-oophorectomy is recommended by age 40 years, and such surgical procedures have been shown to significantly reduce the risk of pelvic carcinoma [1, 117]. This risk is not reduced to 0% since a small percentage of patients subsequently develop peritoneal carcinomas.

Table 11.3 highlights important features of patients with carcinomas detected in prophylactic salpingo-oophorectomy specimens. The frequency of finding a malignancy of the ovary, fallopian tube, or peritoneum during surgery or in the surgical specimen varies from 0% to 14% between studies. However, among 1,662 patients from 13 studies, carcinoma is found in 4% of cases (mean). The majority of carcinomas are primary tumors in the fallopian tube or ovary, but a very small proportion is due to primary peritoneal carcinomas or metastatic breast carcinoma in the ovary. Comparing just carcinomas in the fallopian tube and ovary, more are found in the tube compared with the ovary (64% versus 36%, respectively). The percentage of carcinomas in the tube is even greater when considering only studies that submitted all tubal tissue (81% fallopian tube versus 19% ovary). Some of the earliest studies on occult carcinoma in prophylactic specimens did not remove the fallopian tube, and data from those studies are not presented here.
Table 11.3

Occult carcinoma in prophylactic bilateral salpingo-oophorectomy specimens:a Clinical features, pathologic sampling, and frequency

Referenceb,c

n

Mean age (years) of patients who had surgery

Mean age (years) of patients with FT Ca

BRCA distribution of patients who had surgery

BRCA distribution of patients with FT Ca

All FT tissue submitted for histology

Total with Ca

Site distribution

[72]

490

48

56

374, BRCA 1

113, BRCA 2

3, BRCA 1+2

1, BRCA 1

2, BRCA 2

NR

11

(2%)

7, ovary

3, FT

1, malignant cytology without definitive primary

[73]

159

48

50

94, BRCA 1

65, BRCA 2

4, BRCA 1

7

(4%)

2, ovary

4, FT

1, primary peritoneal

[158]

133

45

51

NR

1, BRCA 1

NRd

2

(2%)

1, FT

1, metastatic breast Ca in ovary

[34]

122

47

58

60, BRCA 1

60, BRCA 2

4, BRCA 1

3, BRCA 2

+

7

(6%)

7, FT

[135]

113

47

54

40, BRCA 1

22, BRCA 2

4, BRCA 1

1, BRCA 2

+

6

(5%)

5, FT

1, primary peritoneal

[80]

101

NR

N/A

NR

N/A

+

0

(0%)

N/A

[118]

98

48

NR

56, BRCA 1

42, BRCA 2

NR

NR

3

(3%)

2, ovary

1, FT

[174]

90

46

41

58, BRCA 1

6, BRCA 2

2, BRCA 1

NR

5

(6%)

2, ovary

2, FT

1, ovary vs. FT indeterminate

[134]

89

49

50

56, BRCA 1

33, BRCA 2

2, BRCA 1

+

4

(4%)

1, ovary

2, FT

1, ovary vs. FT indeterminate

[100]

85

48

NR

NR

NR

NR

3

(4%)

3, FT

[191]

67

47

52

43, BRCA 1

24, BRCA 2

1, BRCA 1

2, BRCA 2

+

6

(9%)

3, ovary

3, FT

[210]

65

46

N/A

37, BRCA 1

28, BRCA 2

N/A

NR

2

(3%)

1, ovary

1, malignant cytology without definitive primary

[35]

50

50

NR

37, BRCA 1

13, BRCA 2

4, BRCA 1

7

(14%)

2, ovary

4, FT

1, metastatic breast Ca in ovary

Total

(13 studies)

1,662

47

53

855, BRCA 1

406, BRCA 2

23, BRCA 1

8, BRCA 2

30% of all patients e

Mean, 4%

Range, 0–14%

Ovary-to-FT ratio = 36%:64% f

(19%:81%) g

Ca, Carcinoma

FT, Fallopian tube

n, Number of patients who underwent prophylactic surgery

N/A, Not applicable

NR, Not reported

+, Yes

–, No

a Patients with BRCA mutations or other increased risk for ovarian carcinoma

b When possible, cases that were apparently reported in more than one publication are listed only once here

c Series in which only ovaries were removed as part of the prophylactic surgery (or if it was not stated that fallopian tubes were removed) are not listed in this table

d Fallopian tubes not removed in all patients

e Percentage of all patients in table who definitively had all fallopian tube tissue submitted for histologic examination

f All series

g Only series that definitively had all fallopian tube tissue submitted for histologic examination

The mean age of patients with fallopian tube carcinoma is 53 years, which is slightly older than that of the entire cohort undergoing prophylactic surgery (mean, 47 years). The mean age of BRCA2 mutation-positive patients with fallopian tube carcinoma (59 years) is slightly older than that of BRCA1 mutation-positive patients (50 years) [34, 72, 73, 95, 134, 135, 155, 158, 174, 176, 187, 191]. The proportion of patients with BRCA1 mutations who undergo surgery is essentially twice that of those with mutations of BRCA2. Three percent and 2% of patients with BRCA1 and BRCA2 mutations, respectively, had carcinoma of the fallopian tube in the surgical specimen.

The vast majority of these carcinomas are occult, being of microscopic size and not seen intraoperatively. Most are either “carcinoma in situ”/intraepithelial carcinoma or invasive high-grade serous carcinoma, and in some cases TIC is found adjacent to the invasive carcinoma. Frequently, the carcinoma is located in the fimbriated end [6, 35, 73, 95, 157, 176, 187, 217]. A small proportion of carcinomas are of endometrioid histologic type. Clear cell carcinoma has been reported but is rare [95].

The invasive fallopian tube carcinomas are of variable stage but frequently stage I. Issues of interest are the behavior for cases with only TIC (+/− positive washings) and whether such patients should be treated with chemotherapy. Table 11.4 lists features of patients with TIC in prophylactic bilateral salpingo-oophorectomy specimens. Only a limited number of such cases have been reported, and the available follow-up in many is short. Of the reported cases in the literature, some have been treated with chemotherapy, including those in which the peritoneal washings were negative for tumor. Based on the few cases with available follow-up, these do not appear to behave aggressively, but more cases with longer follow-up are needed.
Table 11.4

Fallopian tube “carcinoma in situ”/intraepithelial carcinoma in prophylactic bilateral salpingo-oophorectomy specimens:a pathologic features, treatment, and outcome

Referenceb

Located in fimbriated endc

Peritoneal washingsd

Chemotherapyc

Follow-up

[6]

Case 4

+

No evidence of disease at 2.5 years

[34]

Case 1

+

+

+

NR

Case 2

+

NR

Case 4

+

+

NR

[35]

Case 4

NR

NR

Alive and well at 7.3 years

Case 5

NR

Alive and well at 3.2 years

Case 6

NR

Alive and well at 7 months

[48]

Case 48

+

NR

NR

Alive and well, <12 months

[135]

Case 2

NR

+

+

No evidence of disease at 4 years (follow-up from [6])

Case 4

NR

+

No evidence of disease at 3 years (follow-up from [6])

Case 6

NR

No evidence of disease (follow-up interval NR)

Case 7

NR

No evidence of disease (follow-up interval NR)

NR, not reported

a Patients with BRCA mutations or other increased risk for ovarian carcinoma

b When possible, cases that were apparently reported in more than one publication are listed only once here

c Yes (+) or no (−)

d Positive (+) or negative (–) for malignant cells

Since many of the invasive fallopian tube carcinomas are occult and of small volume, an important question is whether the behavior of such cases is similar to symptomatically detected carcinomas that have bulky disease. The behavior of carcinomas (other than “carcinoma in situ”/intraepithelial carcinoma) in prophylactic bilateral salpingo-oophorectomy specimens is listed in Table 11.5 . Stage IA tumors in prophylactic specimens with available follow-up in the literature have not shown aggressive behavior; however, too few cases have been reported, and the available follow-up is short. Advanced-stage tumors in prophylactic specimens show potential for aggressive behavior.
Table 11.5

Behavior of fallopian tube carcinomas (other than “carcinoma in situ”/intraepithelial carcinoma) in prophylactic bilateral salpingo-oophorectomy specimens with available follow-upa

Referenceb

Histologic typec

Stage

Chemotherapy

Follow-up

[35]

Case 3

High-grade serous carcinoma

IIB

+

Recurrence at 1.6 years; Alive with disease at 1.7 years

[72]

Case 5

NR

IA

NR

Alive at 1 year

Case 8

NR

IA

NR

Alive at 6 years

Case 9

NR

IIIC

NR

Alive at 2 years

[134]

Case 1

“Adenocarcinoma”

IA

NR

Dead from breast carcinoma 1 year after bilateral salpingo-oophorectomy

Case 3

“Adenocarcinoma”

IA

NR

Alive without evidence of disease at 3.2 years

[135]

Case 3

High-grade serous carcinoma

NR

+

Recurrence at 1.4 years; alive with disease at 5.8 years (follow-up from [6])

[155]

Case report

NR

IA

Alive without evidence of disease at 3 months

[174]

Case 1

Grade 2 endometrioid carcinoma

IA

NR

Alive without evidence of disease at 3.8 years

Case 2

High-grade serous carcinoma

IIIB

+

Recurrence at 1.7 years

NR, not reported

+, Yes

−, No

a Patients with BRCA mutations or other increased risk for ovarian carcinoma

b When possible, cases that were apparently reported in more than one publication are listed only once here

c Histologic type modified based on available details in cited reference

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) [85]. 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 (1) tubal carcinomas are not frequently found in the intramural segment, (2) 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% [72]), and (3) 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.

Pathogenesis, Including Molecular Features
Serous Carcinoma

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 [229]. p53 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 [97, 245]. p53 mutations have been detected in early stage carcinoma and TIC, suggesting that mutation of this gene is an early event in carcinogenesis [140, 245].

Opinions regarding the role of HER-2/neu in the pathogenesis of fallopian tube carcinoma vary. One study did not detect amplification in any cases and concluded that this gene does not play a role in pathogenesis [224]. However, overexpression has been shown in other studies. One study in particular demonstrated a correlation between overexpression and advanced stage, suggesting that HER-2/neu may be involved in tumor progression [169]. K-ras mutations are frequent [160]. This finding is of interest, as mutations of K-ras are infrequent in ovarian high-grade serous carcinoma; therefore, further study is warranted.

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 [102, 170, 182, 219]. One study demonstrated that epithelial atypia/dysplasia of the fallopian tube and TIC in risk-reducing prophylactic specimens contained chromosomal abnormalities, which implies that chromosomal instability is an early event in the pathogenesis of serous carcinoma [204]. The results of molecular genetic studies have also suggested multiple potential candidate oncogenes involved in the development of fallopian tube carcinoma [170, 219, 229].

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).

In one report of two patients with a BRCA1 germline mutation and serous carcinoma of the fallopian tube, both patients showed loss of the wild-type BRCA1 allele in the tumors [246]. In another report, a patient with a BRCA1 germline mutation and dysplasia of the fallopian tube exhibited loss of the wild-type BRCA1 allele [188]. Two patients in a third report had BRCA1 germline mutations and serous carcinoma of the fallopian tube, and loss of heterozygosity at multiple loci was observed on chromosome 13q, indicating that this chromosomal arm may contain tumor suppressor genes involved in the evolution of hereditary fallopian tube carcinoma [115]. Furthermore, 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 [229]. These findings suggest that the hormonal milieu during the menstrual cycle might play a role in carcinogenesis for women with BRCA mutations.

The pathogenesis of invasive high-grade serous carcinoma of the fallopian tube appears to begin with TIC as the first histologically identifiable lesion in this pathway. However, a precursor lesion of TIC has recently been proposed – the p53 signature [113, 140]. 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. 11.40 ). In one study, 57% of p53 signatures contained a p53 mutation [140]. p53 signatures, however, have a low Ki-67 proliferation index. The mean Ki-67 proliferation index in one study was 3% (range: 0–30%) [113]. They show evidence of DNA damage, as manifested by immunohistochemical expression of γ-H2AX [113, 140]. 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 (10–38% versus 17–33%, respectively); however, p53 signatures are more frequent and multifocal in tubes with TIC [74, 140, 217].
Fig. 11.40

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. 11.39 c)

A model has been suggested linking the p53 signature with TIC in which the p53 signature is the earliest step in the pathogenesis of fallopian tube carcinoma [113]. This is supported by the following: (1) p53 signatures are more common in tubes with TIC; (2) the p53 signature preferentially occurs in the same portion of the tube as TIC (fimbriated end); (3) both the p53 signature and TIC are thought to arise from the secretory cell; (4) the p53 signature, like TIC, shows p53 overexpression, p53 mutations, and evidence of DNA damage; (5) direct continuity of the p53 signature with TIC has been reported (including an identical p53 mutation in both components in one case [140]); (6) lesions histologically and immunohistochemically (Ki-67) intermediate between the p53 signature and TIC have been described; and (7) identical p53 mutations in a p53 signature and peritoneal serous carcinoma in one case have been reported [37]. 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 p53 mutation, along with further cell proliferation and malignant transformation in a very small subset of women, the p53 signature then evolves into TIC. 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 TIC. 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 TIC [74]. It should also be noted that TIC and invasive carcinoma may arise independently of a BRCA mutation. In one study, the frequency of TIC in women with a BRCA mutation was not statistically different from that of controls (8% versus 3%, respectively) [217]. At this stage of growth, the TIC 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.

Some evidence suggests that chronic salpingitis could be an etiology and that serous carcinomas may develop on a background of atrophy [57]. Unlike the ovary, serous carcinomas of the fallopian tube do not appear to 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 is not seen 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 [166]. 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 [7].

Differential Diagnosis
Non-neoplastic Lesions

Pseudocarcinomatous hyperplasia can histologically simulate carcinoma because of cribriform architecture, pseudoinvasion of the muscularis, papillae within lymphatics, and subserosal mesothelial hyperplasia (Fig. 11.11 ) [43]. 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 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. Previously, criteria have been 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 as follows: (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 [106, 212]. As will be seen below, these criteria are nonspecific and unreliable.

It has been suggested that a subset 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 TIC, in the setting of a synchronous ovarian or peritoneal high-grade serous carcinoma, has been proposed as indicating a fallopian tube origin [113, 125]. Lines of evidence supporting this include the following: (1) the fimbriated end of the tube is the preferred site of TIC; (2) the fimbriated end of the tube is in close proximity to the ovarian surface/peritoneal cavity; (3) intraepithelial carcinoma in the ovary or peritoneum is a rare finding; (4) early 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) without disease in the ovary; (5) identical p53 mutations have been reported in TIC and synchronous ovarian/peritoneal high-grade serous carcinomas; and (6) identical p53 mutations in a p53 signature (see Pathogenesis, Including Molecular Features section above) and peritoneal serous carcinoma in one case have been reported [37].

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 and obliterate any clues to a true fallopian tube origin in cases that do not initially appear as having arisen from the fallopian tube. Thus, the true frequency of “ovarian” carcinomas that really originated in the tube may be underestimated. In one study of consecutively accessioned pelvic serous carcinomas by Kindelberger et al. in which all fallopian tube tissue was submitted for histologic examination, 48% of cases initially interpreted as ovarian in origin contained a TIC, suggesting that a significant proportion of “ovarian” carcinomas could be of fallopian tube origin [125]. In that study, identical p53 mutations were identified in the TIC and corresponding ovarian carcinoma in five of five cases tested. Interestingly, cases with a dominant mass in the ovary have a low frequency of TIC (11%) whereas TIC is much more common (45%) in cases in which involvement of the ovary did not create a dominant mass [201]. In a study by Carlson et al., nearly half of cases that would have originally been classified as primary peritoneal serous carcinoma contained a TIC [37]. In that study, identical p53 mutations were identified in the TIC and corresponding peritoneal carcinoma in four of four cases tested.

Three possibilities may exist for cases with high-grade serous carcinoma in the ovary/peritoneum and TIC: (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. In cases where 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 [17, 161].

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

Endometrial serous intraepithelial carcinoma (EIC) has been observed in association with TIC [114]. We have encountered cases of synchronous TIC and uterine malignant müllerian mixed tumor (MMMT) 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; 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 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 [110]. However, some may actually represent gastrointestinal stromal tumors arising outside of the gastrointestinal tract [77]. Other gynecologic-specific sarcomas, such as primary endometrioid stromal sarcoma arising in the tube, are rare [40]. 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 [36, 77, 109]. 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 should be identifiable and intimately admixed with one another. The histologic appearance (Fig. 11.41 ) 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 TIC may be present adjacent to the main tumor mass, especially in the fimbriated end [36, 81]. 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 on 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. 11.41

Malignant müllerian mixed tumor. Intimate admixture of malignant epithelial and mesenchymal components

Metastatic Tumors/Secondary Involvement

Secondary involvement of the fallopian tube by carcinoma is 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. In addition, 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 [189]. 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 [220]. In primary ovarian carcinoma, luminal groups of tumor cells may implant onto endosalpingeal surfaces and simulate TIC or early invasive primary tubal carcinoma. The distinction of fallopian tube versus ovarian origin for serous carcinoma is discussed in the above section on differential diagnosis of carcinoma.

Lymphoma

Primary tubal lymphoma is rare and is associated almost invariably with simultaneous involvement of the ipsilateral ovary [233]. Undifferentiated carcinoma and other small round blue cell tumors must be ruled out with appropriate immunohistochemical stains. For details, see  Chap. 21, Hematologic 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 [165]. 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 [33, 211]. 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  Chap. 20, Gestational Trophoblastic Tumors and Related Tumor-Like Lesions) [18, 111, 168, 179, 225].

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. 11.42 ). This accessory tissue may hypertrophy secondary to adrenal destruction or may, rarely, give rise to a functional or nonfunctional cortical adenoma [207, 239].
Fig. 11.42

Adrenal rests. They typically show similar cortical architecture and cells 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 of the cysts were mesonephric [205]. The hydatid of Morgagni is by far the most common paramesonephric cyst. Grossly, it is attached to one of the fimbriae (Fig. 11.3 ). 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. 11.43 ). 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 the specific histologic features of mesonephric cysts are.
Fig. 11.43

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  Chap. 17, Nonspecific Tumors of the Ovary Including Mesenchymal Tumors) [58, 116]. However, rare tumors can arise within the wall of the fallopian tube without growth in the lumen (Fig. 11.44 ). 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. 11.44

Female adnexal tumor of wolffian origin (FATWO) in non-classic 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. 11.45 ). 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. CK20 is typically negative.
Fig. 11.45

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

Fig. 11.46

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 [15]. In contrast with the latter, papillary cystadenoma diffusely expresses CK7 and is negative for RCC marker. CD10 is usually negative, but expression can be seen in some cases.

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 [12]. 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 [13]. 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 [122, 138]. It should be noted that criteria have been suggested for classifying smooth muscle tumors in the ovary [142]. For additional details regarding extra-uterine smooth muscle tumors, see  Chap. 22, Soft Tissue Lesions Involving the Female Reproductive Organs. 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 [138]. 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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Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

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

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