Diseases of the Fallopian Tube and Paratubal Region
The Italian physician and anatomist Gabriele Falloppio provided the first detailed and accurate description of the oviducts in humans in 1561 A.D. and designated it the Uteri Tuba (Graham 1951). This organ was eventually named after him. Since that time, a wide variety of nonneoplastic and neoplastic diseases of the fallopian tube has become recognized, but it is only recently that the pathogenesis of fallopian tube carcinoma is beginning to be understood.
The Italian physician and anatomist Gabriele Falloppio provided the first detailed and accurate description of the oviducts in humans in 1561 A.D. and designated it the Uteri Tuba (Graham 1951). This organ was eventually named after him. Since that time, a wide variety of nonneoplastic and neoplastic diseases of the fallopian tube has become recognized, but it is only recently that the pathogenesis of fallopian tube carcinoma is beginning to be understood.
Surgical specimens removed specifically for lesions of the fallopian tube are much less common than specimens from other sites in the gynecologic tract; nonetheless, the fallopian tube is frequently examined by the surgical pathologist because it accompanies specimens which were removed for lesions of other gynecologic organs, and the tube plays an important role in reproduction, including problems related to infertility. The majority of fallopian tube lesions examined by the surgical pathologist are nonneoplastic. Benign and malignant tumors of the fallopian tube are uncommon, but, as discussed below, early carcinomas of the fimbriated end of the fallopian tube are becoming more frequently recognized because of complete examination of all fallopian tube tissue submitted as part of prophylactic bilateral salpingo-oophorectomy specimens or major resections for ovarian carcinoma. Also, intraepithelial carcinomas are detected as incidental findings in a small subset of routine specimens when the fallopian tubes are completely submitted for histologic examination.
This chapter provides a detailed discussion of normal fallopian tube (embryology, gross anatomy, and histology) and gross examination, nonneoplastic lesions, benign and malignant tumors, and gestational trophoblastic disease of the fallopian tube. Paratubal/para-ovarian and pelvic ligament lesions are presented as well.
Normal Fallopian Tube and Gross Examination
The lumen of the fallopian tube is initially oval to round and lined by immature columnar epithelium, but the mucosa forms plicae at week 14. In week 16, the fallopian tube begins an active growth phase and starts to coil. Smooth muscle appears in the walls of the genital canal between 18 and 20 weeks. The fallopian tube muscular wall develops only around the müllerian duct, so that the wolffian duct remnants are external to the true wall of the canal. From the 22nd to 36th weeks, there is an increase in the growth and coiling of the fallopian tube at a rate of approximately 3 mm/week (Hunter 1930). Fimbriae do not develop until the 20th week, at which time only 3–4 are present in each fallopian tube (Sulak et al. 2005). The fimbriae increase in number throughout gestation, and at term, 6–8 are present in each tube. The number continues to increase after birth.
Important genes in the embryologic development of the müllerian duct include the Wnt family, Lim1, Pax2, and Emx2 (Yin and Ma 2005). In addition, the Hox family of genes (Hox in mice, HOX in humans) is particularly essential for development of this anatomic structure (Du and Taylor 2004; Taylor et al. 1997; Yin and Ma 2005). The Hox family represents four clusters of genes (Hoxa through Hoxd) which encode transcription factors that direct embryogenesis. Their main function is to control patterning and positional identity along a developing axis, such as the hindbrain, axial skeleton, and limbs. One of the anatomic sites controlled by the Hoxa cluster during embryogenesis is the müllerian duct, in which each Hoxa gene controls the morphogenesis of different segments along the developing axis of the müllerian duct. Hoxa-9 through Hoxa-13 are sequentially located in tandem with one another in the same region of the chromosome. It has been shown in mice that the physical order of the Hoxa genes on the chromosome corresponds to the same spatial order of the different segments of the developing müllerian duct (i.e., Hoxa-9 is expressed in the fallopian tube, Hoxa-10 and Hoxa-11 in the uterine corpus, Hoxa-11 in the uterine cervix, and Hoxa-13 in the upper vagina). This same spatial organization of Hoxa genes with their respective derivatives of the different segments of the müllerian duct is also maintained in humans (Taylor et al. 1997). Thus, interaction between HOXA-9 and presumably several other non-HOX genes determines the proper development of the human fallopian tube.
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.
The secretory cell also is columnar and approximately the same height as the ciliated cell but often narrower with scant eosinophilic cytoplasm. Its nucleus is columnar, and it is thinner and slightly darker than the nucleus of the ciliated cell. Immunohistochemically, the normal mucosal epithelium of the fallopian tube frequently and diffusely expresses WT-1, ER, and PR. The Ki-67 labeling index is typically <10% (George et al. 2012; Kuhn et al. 2012a), but it is higher in the proliferative compared with secretory phase of the menstrual cycle (George et al. 2012). The secretory cell exhibits the immunophenotype HMFG2(+)/PAX8(+)/p73(-), while the opposite pattern is characteristic of ciliated cells (Bowen et al. 2007; Lee et al. 2007; Roh et al. 2009).
The morphologic characteristics of the tubal epithelium change during life. Ciliated cells appear during early fetal development and persist until the postmenopausal years. At this time, as circulating estrogen levels drop, the cilia are gradually lost. Estrogen therapy in postmenopausal women, however, restores both the cilia and the ability to transport particulate matter. The presence of estrogen receptor in the fallopian tube also supports that estrogen is involved with ciliogenesis. The characteristics of the tubal epithelium change during the course of the menstrual cycle (Donnez et al. 1985). Early in the cycle, the cells are of low height, and the secretory cells appear relatively inactive. As ovulation approaches, probably under the influence of an increasing amount of estrogen, the secretory cells become prominent and actually project above the luminal border of the ciliated cells. In association with the effects of estrogen and progesterone, changes in cilial maturity and repeated ciliation and deciliation occur during the menstrual cycle, including maximal ciliation around the time of ovulation (Donnez et al. 1985; Verhage et al. 1979). Additional details of fallopian tube physiology are available elsewhere (Jansen 1984).
In addition to the three epithelial cell types described above, scattered lymphocytes may be seen located basally above the basement membrane. Immunohistological analysis of these lymphocytes indicates a preponderance of the T-cytotoxic/suppressor subtype, consistent with formation of mucosal-associated lymphoid tissue (MALT) (Morris et al. 1986). In addition, the inflammatory component of normal tubal mucosa includes macrophages and dendritic cells (Ardighieri et al. 2014).
Salpingectomy for Benign Disease, with or Without Hysterectomy
In hysterectomies with benign disease, both fallopian tubes should be measured in the longitudinal and transverse dimensions. The serosa should be examined for gross lesions. The patency of the fimbriated end can be determined with a blunt probe. If a lesion is present, it should be measured, its location (corneal/intramural, isthmic, ampullary, infundibular, or fimbriated end) noted, and its relationship to the lumen and serosa described. The entire length of the tube should be transversely cut (“bread loafed”) to identify lesions within the lumen. Grossly visible lesions should be sampled. For grossly unremarkable tubes, standard sections include ≥1 block from each side, but submission of the fimbriated end is recommended.
Hysterectomy and/or Oophorectomy with Salpingectomy for Non-fallopian Tube Malignant Disease
In hysterectomies for malignant disease, attention should be given to identifying involvement of the fallopian tubes, especially since focal disease may upstage the patient. The tubes should be examined, measured, and cut as described above. In cases of ovarian, peritoneal, or endometrial serous carcinomas, it is advisable to submit all tissue from both fallopian tubes for histologic examination to identify serous tubal intraepithelial carcinoma (STIC), especially in the fimbriated end (see “Carcinoma” section below). A number of studies have shown the clinical and diagnostic value of submitting all tubal tissue in this setting (Koc et al. 2018; Lengyel et al. 2013; Singh et al. 2015).
Total or Partial Salpingectomy for Tubal Ectopic Pregnancy
The external appearance of the specimen should be carefully examined, and blood distending the lumen should be sought and sampled. If the tubal pregnancy is apparent, its site and location should be noted as described previously and sampled. A rupture site if present should be described and sampled. If the ectopic pregnancy is not obvious, extensive sampling may be necessary. Even a tubal abortion leaves foci of trophoblast at the implantation site. Blood clot in the tube or as a separate specimen should be sampled for microscopic examination to identify trophoblastic cells or chorionic villi.
Bilateral Partial Salpingectomy for Tubal Sterilization
The most important goal in this setting is to document that the tube has been completely transected. This requires complete cross sectioning of the entire tube and submitting the entire specimen for histologic examination. For instances where a complete transection cannot be demonstrated on the original H&E slides, it may be necessary to have the tissue reoriented in the paraffin block and then cut multiple deeper H&E levels exhausting the entire paraffin block.
Prophylactic Bilateral Salpingo-Oophorectomy
Although there is no standard in terms of how many H&E slides need to be prepared from each block, our routine practice is 1 H&E slide per block; however, it has been recognized that in anecdotal cases, additional deeper H&E levels may identify a small tubal intraepithelial carcinoma not present on the initial H&E level. Nonetheless, based on the findings in one study, it has been proposed that routine performance of multiple deeper H&E levels for risk-reducing specimens is not necessary (Rabban et al. 2009b).
Salpingectomy for Tubal Neoplasms, with or Without Hysterectomy and/or Oophorectomy
A protocol for gross examination of a tube with carcinoma has been developed by the Association of Directors of Anatomic and Surgical Pathology (Longacre et al. 2007). That protocol also lists the essential clinical, gross, and histologic information which should be included in the pathology report. Similarly, the International Collaboration on Cancer Reporting has also published their recommendations for which elements should be provided in a pathology report for tubal carcinoma (McCluggage et al. 2015a).
The size of the specimen and tumor should be recorded, as should the exact location of the tumor within the tube. The external surface should be examined for visible disease, and any lesions should be sampled. It is important to note whether the fimbriated end is open or closed, the latter being determined by having a hydrosalpinx-like, hematosalpinx-like, or pyosalpinx-like gross appearance. At least three sections from the tumor should be obtained. Sections should show the relationship of the tumor with mucosa, depth of invasion, and serosa.
Nonneoplastic Lesions of Fallopian Tube
Metaplasia, Hyperplasia, and Other Epithelial Changes
Psammoma bodies (“salpingoliths”) are an occasional finding. They are often nonspecific and can be seen with normal-appearing epithelium or in various miscellaneous settings, such as chronic salpingitis associated with IgG antibodies to Chlamydia, ovarian serous tumors, papillary tubal hyperplasia (Fig. 13; see above), or otherwise normal epithelium (Martin et al. 1995; Seidman et al. 2002).
Endometriosis and Endosalpingiosis
Normally, endometrial tissue can be found within the mucosa of the intramural and isthmic portions of the fallopian tube. The presence of endometrial tissue within the lumen has been referred to as “endometrial colonization”; however, it is unclear whether this is a variant of normal as opposed to true endometriosis. Endometriosis of the tube can be found within the lumen or myosalpinx or on the serosa. In occasional cases, the configuration of endometriosis may produce a mass clinically or grossly simulating a tumor (“polypoid endometriosis”) (Parker et al. 2004). A form of endometriosis designated “post-salpingectomy endometriosis” occurs in the tip of the proximal stump of the fallopian tube years after tubal ligation (Clement 2007). This form is apparently common. Endosalpingiosis is ectopic tubal-type epithelium involving the serosal surface of the tube. Both endometriosis and endosalpingiosis are discussed in detail in the chapter on “Diseases of the Peritoneum”.
Salpingitis Isthmica Nodosa
Salpingitis isthmica nodosa (SIN) is a pseudoinfiltrative lesion consisting of diverticula of tubal epithelium in the isthmus. It occurs in women between the ages of 25 and 60 years (average, 30 years). SIN is often bilateral. The external gross appearance is that of one or more nodularities in the isthmus, ranging up to 1–2 cm in diameter. The serosa is smooth. Grossly, the tissue is firm, and careful inspection may disclose some of the dilated diverticula.
The etiology is unknown, but post-inflammatory distortion and an adenomyosis-like process are possibilities (Bolaji et al. 2015). An important complication of SIN is infertility, and there is a strong association with ectopic tubal pregnancy (Green and Kott 1989; Homm et al. 1987; Majmudar et al. 1983; Persaud 1970; Saracoglu et al. 1992). A rare complication that we have seen is rupture of a deep diverticulum through the serosa, with subsequent mild intra-abdominal bleeding and pelvic pain.
An ectopic pregnancy occurs when the developing blastocyst implants at a site other than the endometrium of the fundus or lower uterine segment. Because more than 95% of ectopic pregnancies occur in the fallopian tube, the terms ectopic pregnancy and tubal pregnancy are nearly synonymous. However, implantation on both tubal fimbriae and ovary or in the interstitial segment of the fallopian tube (intramural pregnancy) or cornu, abdominal cavity, cervix, or retroperitoneum also may occur, in descending order of frequency (Breen 1970). Hepatic, diaphragmatic, and splenic pregnancies are extremely rare (Delabrousse et al. 1999).
The mechanisms responsible for ectopic pregnancy are largely unknown, but any disease process that alters the normal tubal anatomy seems to increase the frequency. Although delay in entering the uterine cavity may predispose the blastocyst to tubal nidation, experimentally delayed conceptuses in rabbit, guinea pig, and mouse oviducts degenerate and fail to implant. However, ectopic pregnancy is reported uncommonly in nonhuman primates. As many as 88% and 43% of carefully studied tubes with an ectopic pregnancy will show chronic salpingitis and salpingitis isthmica nodosa, respectively (Green and Kott 1989). Ultrastructural studies have demonstrated that the mucosa of fallopian tubes in women with ectopic pregnancies have lower numbers of ciliated cells compared with women that have intrauterine pregnancies (Vasquez et al. 1983). Risk factors for ectopic pregnancy are (in descending order of magnitude): prior ectopic pregnancy, prior tubal surgery, smoking (>20 cigarettes/day), pelvic inflammatory disease, multiple spontaneous abortions (≥3), increasing age (>40 years), prior medically induced abortion, infertility (>1 year), multiple sexual partners (>5), and previous IUD use (Bouyer et al. 2003).
Currently, ectopic pregnancy accounts for 1–2% of clinically known pregnancies (ACOG 2008; Farquhar 2005; Van Den Eeden et al. 2005). Simultaneous ectopic and intrauterine implantations (heterotopic pregnancy) used to occur in 1 in 30,000 pregnancies decades ago; however, the frequency now can be as high as 0.75–1% of pregnancies after undergoing assisted reproductive technology (Habana et al. 2000; Marcus et al. 1995). The classic presentation of ectopic pregnancy includes amenorrhea with subsequent vaginal bleeding and/or abdominal pain. Tubal rupture is associated with intra-abdominal hemorrhage. The frequency of left- versus right-sided ectopic tubal pregnancies is similar, but they are slightly more common on the right (Breen 1970; Brenner et al. 1980). Rare cases are bilateral.
Serial serum beta-human chorionic gonadotropin (β-hCG) measurements and transvaginal ultrasonography are important parts of the clinical evaluation. Management typically consists of either surgery (salpingectomy or salpingostomy) or medical therapy (methotrexate). Incomplete removal of trophoblastic tissue may result in persistent ectopic pregnancy, which occurs in 2–11% and 4–20% of cases after laparotomy with salpingostomy and laparoscopic salpingostomy (Farquhar 2005; Fylstra 1998). These figures are similar to the frequency of failure with systemic methotrexate therapy. In some cases, persistent ectopic pregnancy may be a result of spillage of gestational tissue from disruption/morcellation of the specimen after salpingostomy or salpingectomy. In such instances, the lesional tissue may be found as nodules/implants on pelvic, omental, or uterine serosal surfaces (Cataldo et al. 1990; Doss et al. 1998).
Chronic salpingitis is found in nearly half the patients, with a reported range of 29–88% (Green and Kott 1989). Salpingitis isthmica nodosa may also be present. Arias-Stella reaction can be seen in the fallopian tube mucosa (Milchgrub and Sandstad 1991). Clear cell hyperplasia has been reported (Tziortziotis et al. 1997).
The clinicopathologic features of extratubal ectopic pregnancy vary according to the site (Oliver et al. 2007). Cornual or interstitial pregnancies may expand up to about 12 weeks, when rupture may lacerate one of the uterine arteries as well as the entire side of the uterus. Cervical ectopic pregnancy presents with bleeding similar to an incomplete abortion. Because of the nature of the cervical tissue underlying placental implantation, control of bleeding may be difficult. Ovarian pregnancy is clinically similar to tubal pregnancy, including frequent preoperative rupture. More than half the patients in one series had a history of previous reproductive tract disease or infertility (Grimes et al. 1983). Macroscopic examination typically reveals a hemorrhagic mass replacing the ovary. Pathologic criteria for ovarian pregnancy have been proposed: (1) the tube must be intact and separate from the ovary; (2) the gestational sac must occupy the normal position of the ovary; (3) the gestational sac must be connected to the uterus by the utero-ovarian ligament; and (4) ovarian tissue must be demonstrated within the wall of the sac (Grimes et al. 1983). Pathologic documentation of ovarian tissue within the pregnancy may be difficult or impossible if treatment consists of conservative resection or if the pregnancy has extensively replaced the ovarian tissue.
The natural history of tubal ectopic pregnancy includes spontaneous expulsion from the fimbriated end (tubal abortion), as well as embryonal death and involution of the conceptus. Typically, however, continued growth of the trophoblast leads to increasing dilatation and weakening of the muscularis, with rupture at about the eighth week. About 25% of tubal pregnancies have ruptured by the time of diagnosis (Falcone et al. 1998). Hemorrhage due to rupture may be massive, and ectopic pregnancy is a major cause of maternal mortality during pregnancy. Rare ectopic pregnancies have proceeded to term with fetal viability.
In grossly normal fallopian tubes, chorionic villi or placental site nodules may be found, indicative of a prior unsuspected ectopic pregnancy (Jacques et al. 1997; Nayar et al. 1996). A subset of tubal pregnancies forms a mass that, with involution of trophoblast and reestablishment of the menstrual cycle, may present problems in differential diagnosis. This convoluted, blood-filled tube (including organization, variable inflammation, and adhesions), often with involved ipsilateral ovary, may simulate a tumor or an endometrioma. Most, but not all, patients will have detectable serum β-hCG. Extensive microscopic sampling of this so-called chronic ectopic pregnancy may be required to demonstrate trophoblastic tissue, which may consist of nonviable chorionic villi (Ugur et al. 1996). In more advanced pregnancy, death of the fetus with retention in the extrauterine location may be followed by calcification of the fetus (lithopedion) or both membranes and fetus (lithokelyphopedion).
Polyps of the fallopian tube have been classified as tumors in other textbooks on gynecologic pathology; however, they are included in the nonneoplastic section of this chapter for conceptual purposes. They are found in approximately 1–3% of women undergoing hysterosalpingography for infertility and may cause proximal tubal occlusion (David et al. 1981; Fernstrom and Lagerlof 1964). Their causality of and relationship with infertility has been debated in the literature. They are typically small and preferentially occur in the intramural segment of the fallopian tube, particularly at the tubal ostium. Polyps are frequently bilateral. Although they are removed for microscopic examination only rarely, histologically they are of endometrioid type and resemble endometrial polyps (Lisa et al. 1954). Given that endometriosis of the tubal mucosa is found in some patients, it is possible that tubal polyps might represent a microscopic form of polypoid endometriosis.
Most of the diseases discussed in this chapter may result in sufficient anatomic distortion to cause tubal infertility. In contrast, purely physiologic tubal dysfunction is not well defined but may be illustrated by the immotile cilia of Kartagener’s syndrome that can lead to reduced fertility – only 3 of 12 women in one series succeeded in becoming pregnant (Afzelius and Eliasson 1983). Paratubal or fimbrial adhesions secondary to endometriosis, prior pelvic inflammatory disease, or appendicitis may interfere with normal tubal motility and ovum pick-up. For a detailed discussion of the pathophysiology of fallopian tube cilia in various diseases in relation to infertility, the reader is referred elsewhere (Lyons et al. 2006). Obliterative fibrosis (possibly secondary to inflammation within the uterus) or polyps at the uterine tubal ostium may lead to obstruction at the uterotubal junction (Fortier and Haney 1985; Lee et al. 1997).
Issues Related to Sterilization Procedures
Sterilization by interference with tubal function involves procedures designed to damage or obstruct the mucosa or lumen of the fallopian tube by surgical removal of a segment of the tube (bilateral partial salpingectomy), rings/clamps, electrocoagulation, intratubal chemical methods (e.g., silicone plugs and methylcyanoacrylate), or intratubal mechanical devices (e.g., Essure System) (Clark et al. 2017; Donnez et al. 1979; Stock 1983). Tubal resection should be confirmed by histologic demonstration of a cross section of the fallopian tube including the entire lumen. On occasion, histologic sections may only show fibromuscular/fibrovascular tissue without fallopian tube mucosa. Such cases may represent pelvic ligaments or vessels which were clinically mistaken for a fallopian tube. In order to completely evaluate those cases, it may be necessary to cut deeper levels from the paraffin block, including the possibility of reorienting and reembedding the tissue in the block so as to entirely cut through it and find a fallopian tube lumen. The above protocol also applies to cases in which a fallopian tube is definitely present histologically but for which a complete cross section of the lumen is not seen on the H&E slide.
In women that were initially treated by surgical resection, spontaneous reanastomosis or fistula formation, which may lead to fertilization and ectopic or intrauterine pregnancy, are common mechanisms of sterilization failure (Soderstrom 1985). To identify the cause of failure of tubal sterilization procedures, careful gross examination of the specimen, occasionally specimen salpingography, longitudinal orientation of the tubal segment in the paraffin block, and meticulous sectioning techniques may be necessary.
Salpingitis 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 is a purulent inflammatory process usually secondary to the passage of bacteria from the cervix and uterine cavity into the tubal lumen (Lareau and Beigi 2008; McCormack 1994). It is the pathologic correlate of the clinical entity, pelvic inflammatory disease. It typically occurs in young, sexually active, and reproductive-age women. Important risk factors include patterns of sexual behavior and contraceptive use.
It is not clear if organisms are carried upward by sperm or trichomonads as vectors or whether some form of passive transport is in effect (Keith et al. 1984). The bacteria implicated in acute salpingitis appear to be from two sources: sexual transmission and lower genital tract flora. Although Neisseria gonorrhoeae and Chlamydia trachomatis have been considered the most common causative organisms, meticulous bacteriologic studies indicate that most cases are polymicrobial and that anaerobic bacteria, especially Bacteroides species and peptostreptococci, frequently are present, as well as aerobes such as Escherichia coli. The presence of serum antibodies against gonococcal pili in some of these women, however, suggests that gonococci may initiate the process, only to be supplanted by anaerobes. The role of mycoplasmas in acute salpingitis is controversial, and viruses do not appear to be etiologic. However, Herpes simplex virus infection involving the mucosa of a prolapsed tube with mixed acute and chronic inflammation has been reported (Lefrancq et al. 1999).
The gonococcus gains access to the tube most readily at the time of menstruation. This situation corresponds to the typical clinical presentation in which the onset of acute pain occurs a few days after menses. The onset of non-gonococcal, non-chlamydial acute salpingitis is not, however, clearly related to the recent onset of menses (Sweet et al. 1986). Elegant in vitro studies by Ward et al. (1974) have clarified the likely initial steps in gonococcal infection, and the molecular mechanisms involved have been reviewed elsewhere (Edwards and Apicella 2004; Lyons et al. 2006). N. gonorrhoeae perfused through the lumen of cultured whole tubes attach only to non-ciliated cells. Within 3 h, microvilli from the cells appear to embrace the gonococci and adhere to them. The bacteria then penetrate both the cells and intercellular junctions, with cell lysis and sloughing. Adjacent ciliated cells are also destroyed but are not invaded directly. Gonococcal lipopolysaccharide and gonococcal-induced tumor necrosis factor-alpha and various other cytokines cause much of the epithelial damage (Maisey et al. 2003; McGee et al. 1999), and the degree of pathogenicity likely depends on the bacterial as well as the host genome (Arvidson et al. 1999). After cell lysis, the bacteria penetrate the subepithelial connective tissue. In vivo, this process is considerably modified by the host response.
N. gonorrhoeae spreads via the epithelial surface and thus causes mucosal damage. A brisk diapedesis of granulocytes from capillaries into the mucosa and lumen occurs, and there is vascular engorgement and edema of all tubal layers. As the lumen fills with granulocytes and cellular debris, and as the tube distends, pus may be seen dripping from the fimbriated end in patients undergoing laparoscopy. In severe cases, transudation of plasma proteins results in a fibrinous exudate on the serosal surface, which is erythematous because of vascular dilatation. The cell necrosis, distension of the tube, and focal peritonitis account for the symptoms of abdominal and pelvic pain. Over time, repeated infections result in recurrent symptoms as well as the anatomic changes of chronic salpingitis, discussed below.
Chlamydia trachomatis is cultured frequently from the cervix, uterus, and fallopian tubes in women with acute salpingitis (Kristensen et al. 1985; Mardh et al. 1977). It is thought that the damage of the fallopian tube by Chlamydia is due to the 60 kDa chlamydial heat shock protein (hsp60), as well as other various cytokines (Hafner 2015; Lyons et al. 2006). The histologic appearance of tubes removed during the acute or subacute phase of chlamydial salpingitis is virtually identical to that caused by the gonococcus. There is an initial transmural and mucosal infiltration of neutrophils with an intraluminal exudate. Subsequently, there is a lymphoplasmacytic response with variable numbers of residual granulocytes. Chlamydial inclusion bodies have been identified within the epithelial cells (Winkler et al. 1985). On occasion, the lymphofollicular response may be so florid as to suggest lymphoma (Wallace and Hart 1991).
As a result of acute salpingitis (usually in the context of gonococcal or chlamydial disease), fibrinous adhesions develop between the fallopian tube serosa and surrounding peritoneal surfaces. Peritoneal inflammation may be widespread, and thin so-called violin-string adhesions may form between the liver and anterior abdominal wall as part of the Fitz-Hugh-Curtis syndrome.
Another organism that can result in tubo-ovarian abscess is Actinomyces israelii, which is part of the indigenous female genital tract flora (Persson and Holmberg 1984). Actinomycotic infections of the tube are associated with intrauterine contraceptive devices (IUDs) (see chapter on “Benign Diseases of the Endometrium”) (Dische et al. 1974). Anaerobic culture is necessary to permit growth of Actinomyces israelii. Microscopically, fragments of gram-positive filaments and sulfur granules may be recognized within pus. Pseudoactinomycotic radiate granules should not be mistaken for the sulfur granules of actinomycosis (Bhagavan et al. 1982; Pritt et al. 2006).
As a result of acute salpingitis, the proximity of the ovary to the fimbriae allows multiple tubo-ovarian adhesions to form, which may also cause occlusion of the tubal ostium. If the fimbriae close before the ovary is involved as part of a tubo-ovarian abscess, the inflamed and dilated tube can form a pyosalpinx full of acute and chronic inflammatory cells. When acute salpingitis resolves, the acute and most of the chronic inflammatory cells gradually disappear, and the patient is left with either a severely scarred tube in the form of chronic salpingitis or a hydrosalpinx. C. trachomatis DNA has even been detected in fallopian tubes in a subset of cases that contained only chronic salpingitis (Hinton et al. 2000). Thus, the finding of chronic salpingitis may imply previous pelvic inflammatory disease in some patients.
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.
Mycobacterium tuberculosis historically has been the predominant etiologic agent of granulomatous salpingitis. The frequency of tuberculous salpingitis in women studied for tubal causes of infertility ranges from much less than 1% in the United States to nearly 40% in India (Parikh et al. 1997). Twenty percent of women who die of tuberculosis have tubal involvement (Schaefer 1970). Primary infection of the genitalia, as by coitus with a partner with genitourinary tuberculosis, is extremely rare. Secondary spread via a hematogenous route, usually from a primary pulmonary infection, is the usual route of infection. For unclear reasons, the blood-borne organism prefers the tubes rather than other parts of the female genital tract. The primary pulmonary lesion may not be radiologically evident, but extrapulmonary involvement of the peritoneum, kidneys, or other sites may be present. Lymphatic spread from primary intestinal tuberculosis or direct spread from the urinary bladder or gastrointestinal tract may occur. Tubal involvement is usually bilateral. Although the earliest pathologic lesions are microscopic, with advancing disease the tube increases in diameter and may become nodular, mimicking salpingitis isthmica nodosa. In the more common adhesive form of the disease, multiple dense adhesions may form between the tube and ovary, and the fimbriae and ostium may be obliterated (Haines 1958). With the exudative form of disease, progressive distension mimics bacterial pyosalpinx. Hematosalpinx, hydrosalpinx, tubo-ovarian abscesses, or a so-called frozen pelvis may be found late in the disease process (Parikh et al. 1997). In either form, serosal tubercles may be present.
There are several complications of tuberculous salpingitis. Alteration in function is expected, and sterility is almost universal because of the common bilaterality of the disease. Because of repeated seeding of the endometrium from the infected tubes, mycobacterial culture and the histologic finding of endometrial granulomas on curettage are diagnostically useful (see chapter on “Benign Diseases of the Endometrium”).
Although tubal schistosomiasis may be one of the more common causes of granulomatous salpingitis worldwide, it is rare in the United States. In Africa, the fallopian tube is involved by schistosomiasis in 22% of all infected women (Gelfand et al. 1971). The ova of Schistosoma haematobium are most common, but Schistosoma mansoni eggs may be present in some women. Gross findings appear to be related to fibrosis surrounding the ova, producing a nodular or fibrotic tube. Histologically, the inflammatory reaction is typically granulomatous and may contain eosinophils, neutrophils, plasma cells, lymphocytes, and macrophages, including multinucleated giant cells. Some granulomas may be present within the stroma of the plicae and produce plical expansion. Ectopic pregnancy has been reported as occurring synchronously with tubal schistosomiasis in some patients.
Where the condition is common, hydatid disease secondary to Echinococcus granulosus infection may involve the female genital tract, including the adnexae. Cysticercosis (Taenia solium) also has been described in the tube (Abraham et al. 1982). Other rare parasites that have been reported in the fallopian tube include Entamoeba histolytica (amebiasis). Liesegang rings should not be mistaken for parasites (Clement et al. 1989).
Other fungi which rarely can cause tubo-ovarian abscesses or granulomatous salpingitis include Blastomyces dermatitidis, Coccidioides immitis, Candida, and Aspergillus. These may be secondary to hematogenous spread or disseminated disease.
Sarcoidosis of the tube is rare (Boakye et al. 1997). Histologically, noncaseating granulomas may be seen in the mucosa. Culture, histochemical stains, and clinical information are necessary to exclude other granulomatous diseases.
Crohn’s disease of the ileum, colon, or appendix may secondarily involve the tube and ovary to produce a granulomatous salpingitis and tubo-ovarian abscess. Noncaseating granulomas can involve the entire thickness of the tubal muscularis as well as the mucosa. The mucosa may exhibit hyperplasia with reactive atypia (Brooks and Wheeler 1977). Fistulas from bowel to tube also can occur.
Other Types of Granulomatous/Histiocytic Lesions and Foreign Bodies
Malakoplakia has rarely been reported in the fallopian tube. Some vasculitides have a granulomatous pattern (see “Vasculitis” section below) (Bell et al. 1986). Foreign body granulomas due to starch and talc, as well as pulse granulomas (Rhee and Wu 2006), can occur in the tube. In order to detect some foreign bodies, granulomatous or histiocytic reactions should be examined under polarized light. Extruded keratin from endometrioid carcinomas with squamous differentiation of the endometrium or ovary can produce keratin granulomas on the serosa or fimbriated end of the tube, as well as within the tubal lumen (Kim and Scully 1990). It should be noted, however, that not all foreign bodies produce a significant granulomatous or histiocytic response. Gelatin microsphere embolization particles (Embospheres®/EmboGold®) used in uterine artery embolization for treatment of uterine leiomyomas may sometimes be found in the fallopian tubes or ovaries because of the vascular anastomosis between the uterine and ovarian arteries (Kim et al. 2007). In the fallopian tube, these particles are typically found within arterial lumens in the outer wall of the tube or para-tubal locations. They usually elicit only a mild lymphocytic response with rare multinucleated giant cells as opposed to the marked multinucleated giant cell reaction with a granulomatous or histiocytic component seen with other foreign bodies.
Torsion, Prolapse, and Intussusception
Among the various anatomic displacements of the tube, torsion is the most common. The usual predisposing factor is cystic enlargement of the ipsilateral ovary. A benign ovarian cyst or tumor is present in the majority of patients, but in a minority, a malignant ovarian tumor is the cause. Para-ovarian cysts also are associated with torsion. Tubal enlargement secondary to hydrosalpinx or pyosalpinx, or previous gynecologic surgery (especially sterilization), are additional etiologies, but torsion may occur in the absence of apparent adnexal disease (Bernardus et al. 1984). The typical patient is in the reproductive years, occasionally pregnant, and complains of the sudden onset of lower abdominal pain. At operation, the adnexa on one side is twisted, usually once or twice. Venous outflow is compromised early, and the resulting congestion may lead to arterial compression. The adnexa often is enlarged, edematous, and dark and shows hemorrhagic infarction. If surgical intervention is prompt, the tube may be preserved. Asymptomatic or undiagnosed torsion can occur.
Tubal prolapse into the vagina may occur rarely as a complication of vaginal or abdominal hysterectomy (See chapter on “Diseases of the Vagina”) (Ouldamer et al. 2013; Ramin et al. 1999). Clinically, this is characterized by dyspareunia, vaginal bleeding/discharge, or abdominal pain beginning a few days to several years after hysterectomy. However, some women may be asymptomatic. On clinical examination, an excrescence is seen in the vaginal vault, suggestive of granulation tissue or carcinoma. Fimbriae may be apparent grossly. Severe acute and chronic inflammation can be present microscopically, and papillary architecture or pseudogland formation by the tubal epithelium can mimic adenocarcinoma. Due to admixed granulation tissue, it may be difficult to recognize the lesional tissue as a distorted segment of fallopian tube (Song et al. 2005); however, close scrutiny should reveal papillae lined by benign tubal epithelium. Depending on the specific differential diagnosis, immunohistochemical staining for WT-1, ER/PR, CK7, CK20, p16, and/or Ki-67 may be of help.
Intussusception of the tube is rare. In one case, a para-ovarian cyst was engulfed by the end of the tube, and the fimbriated end was pulled into the ampulla (Adams 1969).
Structural congenital anomalies of the fallopian tube are rare. Diethylstilbestrol (DES) use during pregnancy was discontinued decades ago, but surgical specimens from patients that were born during the DES era may still be examined today. In utero exposure to DES produces shortened, sacculated, and convoluted fallopian tubes. The fimbriae are constricted, and the os is pinpoint (DeCherney et al. 1981). The mucosa may be absent, or when it is present, the plicae do not develop (Robboy et al. 1982).
Tubal duplication and accessory fallopian tubes are uncommon, but the latter occur more frequently (Beyth and Kopolovic 1982; Coddington et al. 1990; Daw 1973; Gardner et al. 1948). Absence of various segments of the fallopian tube (also variably referred to as atresia, hypoplasia, or interruption), absence of the ampullary muscularis, and complete absence of the tube have been described. These may be unilateral or bilateral, and they can occur with or without uterine anomalies, such as unicornuate or bicornuate uterus (reviewed in Nawroth et al. (2006)).
The fallopian tube can be involved by vasculitis as part of localized or systemic disease, and involvement of the tube is less frequent compared with other sites within the gynecologic tract. Vasculitis involving the female genital tract can be of polyarteritis nodosa or giant cell arteritis types, but the former is more common (Ganesan et al. 2000; Hernandez-Rodriguez et al. 2009; Hoppe et al. 2007). Either one or multiple arterioles/small arteries may be involved. Clinical correlation is needed to determine whether or not vasculitis is localized to the gynecologic tract; however, it is uncommon for patients with vasculitis involving the female genital tract to have either a previous diagnosis of systemic disease or subsequent development of systemic disease (Ganesan et al. 2000; Hoppe et al. 2007).
Neoplasms of the Fallopian Tube
2014 WHO classification of tumors of the fallopian tube
Serous tubal intraepithelial carcinoma
Serous borderline tumor/atypical proliferative serous tumor
Low-grade serous carcinoma
High-grade serous carcinoma
Transitional cell carcinoma
Clear cell carcinoma
Carcinosarcoma (malignant müllerian mixed tumor; MMMT)
Lymphoid and myeloid
Adenomatoid tumor (benign mesothelioma) is the most frequent type of benign tubal tumor. Previously reported lymphangiomas probably represent examples of this entity. They are usually only 1–2 cm in diameter, appearing as a nodule beneath the tubal serosa, and are yellow or white-gray on cross section. Rare cases are bilateral. Similar lesions may be found in the uterus, cul-de-sac, or ovary (see chapter on “Mesenchymal Tumors of the Uterus”). Their origin is presumed to be from the cells of the serosal mesothelium. A fortuitous section may demonstrate a connection between serosa and tumor, but usually the serosa covers the lesion.
Histochemical studies have shown alcian blue-positive, hyaluronidase-digestible material in the cells and spaces; however, this material may be absent after routine processing for histologic sections. No significant glycogen or intracellular epithelial mucin is present, as might be found in a tumor of müllerian origin. Immunohistochemically, tumors express mesothelial markers (WT-1, calretinin, CK5/6, D2-40) and are usually negative for epithelial-specific markers (Ber-EP4, B72.3, MOC-31, ER, PR) (Sangoi et al. 2009; Wachter et al. 2011). Electron microscopic studies also support a mesothelial origin for these lesions. Clinically, they are asymptomatic, and recurrences after adequate excision are rare.
The most important lesion to be considered in the differential diagnosis, particularly at the time of frozen section, is metastatic signet ring cell carcinoma. Clinical data such as prior history of a carcinoma (some primary tumors may be occult, and such a history will not be known), extra-fallopian tube tumor seen intraoperatively (especially if multifocal), bilaterality, and histologic presence of a combination of glands, papillae, and solid sheets of tumor help favor a diagnosis of carcinoma. Nuclear atypia and mitotic activity should raise suspicion for carcinoma, but some signet ring cell carcinomas may lack these features. A source of confusion may be the presence of the alcian blue-positive, hyaluronidase-digestible material within the lumens of the tubules in adenomatoid tumor. At the time of intraoperative consultation, this material resembles epithelial-type mucin on H&E frozen section slides; however, it is lost during routine processing and, as a result, is not present in permanent H&E sections. After frozen section analysis, immunohistochemical stains specific for mesothelial and epithelial markers will help aid distinction.
Cystadenomas have been reported but are rare. Although the topic of whether or not atypical proliferative (borderline) tumors are benign has been debated in the literature, these tumors are included in the benign neoplasm section of this chapter for simplicity. Rare atypical proliferative (borderline) serous, endometrioid, and clear cell tumors of the fallopian tube have been reported. The literature is too limited to predict their outcome; however, behavior similar to their ovarian counterparts would be anticipated. Atypical proliferative (borderline) mucinous tumors have been described, but such cases should be rigorously evaluated to exclude the likely possibility that they represent secondary involvement of the fallopian tubes from a non-ovarian site.
Leiomyoma and Adenomyoma
Leiomyoma is the most common mesenchymal tumor of the fallopian tube; however, these are much less common than uterine leiomyomas. They are usually small and grossly and microscopically similar to those found in the uterus and other gynecologic sites, and they can undergo similar degenerative changes. Rarely, benign glands and smooth muscle may be so intimately involved in a tumor that a diagnosis of adenomyoma may be warranted; however, these may arguably represent endometriosis with smooth muscle metaplasia (“endomyometriosis”) or the so-called uterine-like mass.
Other Benign Mesenchymal and Mixed Epithelial–Mesenchymal Tumors
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.
Tubal teratomas are rare. Clinically, a patient with a tubal teratoma usually is nulliparous and in the fourth decade. Grossly, the tumors are located most frequently in the lumen, often attached by a pedicle to the inner tubal wall. They may, however, be intramural or attached to the serosa. On section, they are more often cystic than solid and may be small (1–2 cm in diameter) or large (10–20 cm in diameter). As with their ovarian counterparts, ectodermal, mesodermal, and endodermal tissues are represented by mature elements. Most are in the form of a dermoid cyst. Rare teratomas consisting entirely of mature thyroid tissue have been described in the tube of women without clinical hyperthyroidism. Only rare cases of immature teratoma of the fallopian tube have been reported, including a mixed germ cell tumor in which one of the components was an immature teratoma (Li et al. 1999). Although ovarian teratomas appear to originate from abnormally developing ova, the pathogenesis of fallopian tube teratomas is unclear.
The history of the discovery and evolution about knowledge of carcinoma of the fallopian tube during the nineteenth and twentieth centuries has been reviewed elsewhere (Young 2007) and will not be repeated here. In the recent past, “carcinoma in situ” of the fallopian tube was considered uncommon since the majority of patients with fallopian tube carcinoma presented with advanced stage disease. Therefore, at the time of presentation, most tumors were of bulky size, and patients had symptomatic disease. Over the last several years, early tubal carcinomas (i.e., those which are commonly of microscopic size and clinically occult) have become diagnosed more frequently due to complete histologic examination of all fallopian tube tissue from prophylactic bilateral salpingo-oophorectomy specimens, and they have been also detected as incidental findings in routine specimens.
Historically, primary adenocarcinoma of the tube was thought to be uncommon, and it has been estimated to account for 0.7–1.5% of invasive malignancies of the gynecologic tract (Benoit and Hannigan 2006; Platz and Benda 1995). However, the true frequency is difficult to determine because a substantial number of cases traditionally classified as “ovarian” are likely tubal in origin (see below). The incidence of fallopian tube carcinoma is 0.41 per 100,000 women in the United States (Stewart et al. 2007).
Tumors with “carcinoma in situ”/intraepithelial carcinoma and small tumors with microscopic invasion are usually asymptomatic and more commonly seen as occult findings in prophylactic bilateral salpingo-oophorectomy specimens or rarely seen as occult findings in routine specimens (see “Occult Disease in Prophylactic Bilateral Salpingo-Oophorectomy Specimens” and “Occult Disease in Routine Specimens in Women Without Known Genetic Risk (Presumably Sporadic Cases)” sections below for additional details regarding clinical presentation). They may be occasionally detected when tumor cells exfoliate into the fallopian tube lumen and are then found in endometrial or endocervical biopsies/curettages or Pap smears (Bagby et al. 2013). In such instances, a fallopian tube origin may not be clinically evident at first (and sometimes not even grossly evident at the time of hysterectomy), and further clinical evaluation is needed to eventually identify the true origin in the tube. Likewise, in rare cases, occult invasive tubal carcinoma may present as a distant metastasis (e.g., malignant pleural effusion or metastatic carcinoma of unknown primary site in a supraclavicular lymph node).
Most women with symptomatic tumors are between 50 and 80 years of age, with the mean age in large studies ranging from 56 to 64 years (Alvarado-Cabrero et al. 1999, 2013, Hellstrom et al. 1994; Rosen et al. 1999; Stewart et al. 2007). Tubal malignancies in women younger than age 40 years are very uncommon. A substantial proportion of women are nulliparous or have a previous history of infertility or pelvic inflammatory disease. Some patients have had a previous malignancy, usually breast carcinoma. A small percentage of patients have a synchronous tumor in another gynecologic site. The most common symptoms and signs are abnormal uterine bleeding/vaginal discharge, abdominal/pelvic mass, abdominal distention, and abdominal pain; however, a small subset of cases will be detected as an incidental finding as part of another gynecologic disorder (Alvarado-Cabrero et al. 1999; Baekelandt et al. 2000; Peters et al. 1988). Between 5% and 14% of women have ascites at the time of presentation (Baekelandt et al. 2000; Eddy et al. 1984). The classic symptom complex hydrops tubae profluens (intermittent colicky abdominal pain relieved by sudden discharge of watery fluid per vagina) is only present in a very small percentage of patients. Serum CA-125 is elevated in most but not all patients. Some patients have an elevated serum β–hCG level, which has been attributed to ectopic production. A subset of patients have tumor in endometrial biopsies/curettages or Pap smears. Because of the rarity of fallopian tube carcinoma (prior classifications), as well as the clinical presentation which simulates an ovarian tumor, a correct preoperative diagnosis of fallopian tube carcinoma is uncommon (although the vast majority of extrauterine high-grade serous carcinomas are likely of tubal origin). Rare patients can have an associated paraneoplastic syndrome (Matsushita et al. 1998; Seeber et al. 2008).
In symptomatic cases, women with BRCA-associated tumors present at an age slightly younger than those with sporadic tumors, and both patient groups have similar clinicopathologic features (Cass et al. 2005; Levine et al. 2003). Although, some studies of ovarian/tubal/peritoneal high-grade serous carcinomas suggest that tumors with BRCA mutations may more frequently exhibit the SET (solid, pseudoendometrioid, and transitional cell carcinoma-like) histologic pattern.
2014 FIGO staging system for fallopian tube carcinoma (AJCC Cancer Staging Manual, 8th Edition)
Tumor is confined to fallopian tubes
Tumor limited to one fallopian tube (capsule intact); no tumor on fallopian tube surface; no malignant cells in the ascites or peritoneal washings
Tumor limited to both fallopian tubes (capsules intact); no tumor on fallopian tube surface; no malignant cells in the ascites or peritoneal washings
Tumor limited to one or both fallopian tubes, with any of the following:
IC1: Surgical spill
IC2: Capsule ruptured before surgery or tumor on fallopian tube surface
IC3: Malignant cells in the ascites or peritoneal washings
Tumor involves one or both fallopian tubes with pelvic extension (below pelvic brim)
Extension and/or implants on uterus and/or ovaries
Extension to and/or implants on other pelvic intraperitoneal tissues
Tumor involves one or both fallopian tubes, with microscopically confirmed spread to the peritoneum outside the pelvis and/or metastasis to the retroperitoneal (pelvic and/or para-aortic) lymph nodes
Positive retroperitoneal lymph nodes only (histologically proven):
IIIA1i: Metastasis up to 1 cm in greatest dimension
IIIA1ii: Metastasis >1 cm in greatest dimension
Microscopic extrapelvic (above the pelvic brim) peritoneal involvement with or without positive retroperitoneal lymph nodes
Macroscopic peritoneal metastasis beyond the pelvis up to 2 cm in greatest dimension, with or without metastasis to the retroperitoneal lymph nodes
Macroscopic peritoneal metastasis beyond the pelvis >2 cm in greatest dimension, with or without metastasis to the retroperitoneal lymph nodes (includes extension of tumor to capsule of liver and spleen without parenchymal involvement of either organ)
Distant metastasis, including pleural effusion with positive cytology; liver or splenic parenchymal metastasis; metastases to extra-abdominal organs (including inguinal lymph nodes and lymph nodes outside the abdominal cavity); and transmural involvement of intestine
Pleural effusion with positive cytology
Liver or splenic parenchymal metastasis; metastases to extra-abdominal organs (including inguinal lymph nodes and lymph nodes outside the abdominal cavity); and transmural involvement of intestine
The staging terminology for cases with STIC and only positive washings is unclear. Some clinicians have considered this scenario FIGO stage 0 (old staging system) while other authors have designated this stage IC. As STIC can be associated with disease on ovarian or peritoneal surfaces (especially since many STICs are located in the fimbriated end of the tube and, therefore, have direct access to the peritoneal cavity), one can speculate whether STICs with only positive washings should be considered greater than stage 0 (old staging system).
It has been suggested that intraluminal masses without invasion qualify as neither stage 0 (old staging system) nor stage IA (Alvarado-Cabrero et al. 1999). Also, because of observed differences in prognosis for stage I fallopian tube carcinomas with different depths of invasion into the wall (similar to other abdominal/pelvic organs with a muscular wall), it has been recommended that the FIGO stage should be modified since such cases are not appropriately represented by the current version of the FIGO staging system. Alvarado-Cabrero et al. have proposed that stage I cases should be divided into substages IA-0 (intraluminal masses without invasion into lamina propria), IA-1 (invasion into lamina propria but not muscularis), and IA-2 (invasion of muscularis) (Alvarado-Cabrero et al. 1999). As it has also been suggested that carcinomas in the fimbriated end without invasion have a worse prognosis than carcinomas invading the wall of the tube because of direct access to the peritoneal cavity, it has been proposed that the FIGO system should be modified since the former are not represented by the current version (Alvarado-Cabrero et al. 1997, 1999). This proposed stage would be designated I(F).
The majority of patients with symptomatic disease have advanced stage disease at presentation (stage >I). In the largest clinicopathologic study using hospital-based cases by Baekelandt et al., the distribution of stage was: stage 0 (6%) [old staging system], stage I (27%), stage II (22%), stage III (35%), and stage IV (12%) (Baekelandt et al. 2000). These results are similar to those of other large hospital-based or population-based studies which have found the percentage of stage I cases to be 30–56% (Heintz et al. 2006; Hellstrom et al. 1994; Rosen et al. 1999; Stewart et al. 2007).
The true stage distribution of all fallopian tube carcinomas in the general population is difficult to determine because of the existence of two patient populations which are usually not included together in the same studies – patients with asymptomatic tumors (i.e., occult tubal carcinomas in prophylactic bilateral salpingo-oophorectomy specimens from women with an increased genetic risk for carcinoma) and those with symptomatic tumors (i.e., women with bulky tumors and advanced stage disease who may not be suspected of having an increased genetic risk for carcinoma).
Intraoperative and Gross Features
Noninvasive carcinomas of the fallopian tube have been considered “carcinoma in situ” in the past. With recognition of early carcinomas without invasion of underlying fallopian tube stroma in prophylactic bilateral salpingo-oophorectomy specimens, as well as their detection as incidental findings in routine specimens, the term serous tubal intraepithelial carcinoma (STIC) has emerged over the last several years. Given the ability of STIC to spread beyond the fallopian tube without invasion of underlying stroma (see below), the term carcinoma in situ should be abandoned because it implies that there is no potential for metastasis.
Essentially all intraepithelial carcinomas of the fallopian tube are of high-grade serous type, and the lesional cells of STIC show secretory cell differentiation (Lee et al. 2007). However, rare endometrioid intraepithelial carcinomas have been reported (Jarboe et al. 2008).
Before diagnosing an incidental lesion as STIC in a routine specimen, it is necessary to submit all remaining fallopian tube tissue for histologic examination as invasive carcinoma can be of small size.
Some otherwise conventional-appearing high-grade serous carcinomas within the lumen of the fallopian tube may be small without enlargement of the fallopian tube and lack invasion of the underlying tubal stroma. Such morphology in occasional cases can overlap with the upper morphologic limit of STIC, especially when the latter shows an increased degree of stratification. In such cases, the diagnostic threshold between STIC vs. a small intraluminal high-grade serous carcinoma without invasion of underlying fallopian tube stroma is subjective and varies between authors (Jarboe et al. 2008; Young 2007). However, some authors have suggested that intraluminal masses without invasion qualify as neither stage 0 (old staging system) nor stage IA (see section “FIGO Stage” above) (Alvarado-Cabrero et al. 1999).
Some invasive carcinomas may be of small volume. As these may not be clinically evident, and in order to assess the possibility of the fallopian tube being a primary site of occult disease, it is important to submit all remaining fallopian tube tissue from grossly unremarkable tubes for histologic examination in women presenting with metastatic high-grade adenocarcinoma of unknown primary site.
The histologic types and appearances of invasive fallopian tube carcinoma are similar to its ovarian counterparts. In the largest clinicopathologic study using hospital-based cases, the distribution of histologic types was: serous (80%), adenocarcinoma, NOS (10%), endometrioid (7%), clear cell (2%), mucinous (2%), and mixed serous-mucinous (1%) (Baekelandt et al. 2000). Most fallopian tube carcinomas are poorly differentiated, and well-differentiated tumors are very uncommon. Fallopian tube carcinomas are graded in a fashion analogous to those in the ovary (i.e., low- vs. high-grade for serous, FIGO uterine criteria for endometrioid, etc.).
Most endometrioid carcinomas are grade 2 or 3, but some are grade 1 (Navani et al. 1996; Rabczynski and Ziolkowski 1999). They may resemble conventional endometrioid carcinomas as seen in the endometrium, including squamous differentiation and villoglandular architecture, but oxyphilic types, sex cord-like appearances, and spindled epithelial cells may be seen. In some cases, associated endometriosis is present. Benign stromal osseous metaplasia can be seen in a minority of cases. Almost one-half of cases have an appearance resembling female adnexal tumor of wolffian origin (FATWO-like type) (Daya et al. 1992; Navani et al. 1996). Independent primary endometrioid carcinomas can synchronously arise in the fallopian tube and uterus (Culton et al. 2006).
Clear cell and transitional cell carcinomas resemble those seen in the ovary (Alvarado-Cabrero et al. 1999; Koshiyama et al. 1994). Other rare histologic types include undifferentiated, small cell neuroendocrine, lymphoepithelioma-like, mixed serous-transitional cell, squamous cell, adenosquamous, hepatoid, glassy cell, and giant cell carcinomas (Alvarado-Cabrero et al. 1999; Aoyama et al. 1996; Cheung et al. 1994a; Herbold et al. 1988). Mucinous carcinomas with a synchronous endocervical adenocarcinoma have been described, but such cases should be rigorously evaluated to exclude the likely possibility that they represent secondary involvement of the fallopian tubes from the endocervix. Unlike the ovary, low-grade serous carcinomas typically are not seen in the fallopian tube.
Invasive high-grade serous carcinomas usually show diffuse expression of WT-1. It should be noted, however, that expression is not restricted to invasive carcinomas, as normal fallopian tube epithelium and STIC also show WT-1 expression. Expression of ER and PR is variable. p53 expression, similar to STIC, will have an abnormal pattern, either diffuse or null. Immunohistochemical data are limited for endometrioid carcinomas, but in our experience, WT-1 and p53 can be diffusely expressed in some cases.
Diagnostic Criteria and Classification for STIC and Intraepithelial Atypias: Algorithmic Approach Based on Morphology and Immunohistochemistry
According to the algorithm, first the morphology of atypical foci is classified as unequivocal for STIC, suspicious for STIC, or not suspicious for STIC utilizing a variable combination of histologic features described above. Then, p53 expression is scored as abnormal (diffuse or null pattern, with moderate to strong intensity) or normal. Of note, a “wild-type”/normal pattern will have occasional cells with usually mild intensity. In contrast, a “null” pattern demonstrates complete loss of expression provided an adequate positive internal control with a “wild-type”/normal pattern is present. The Ki-67 proliferation index is scored as either low (<10%) or high (≥10%) in only the focus with morphologic atypia. Of note, normal fallopian tube mucosa and STIC usually have Ki-67 proliferation indices that are less than or greater than 10%, respectively (George et al. 2012; Kuhn et al. 2012a), and this distinction of low versus high has been shown to have substantial interobserver reproducibility (Vang et al. 2012; Visvanathan et al. 2011).
Finally, based on the coordinate profile of p53 and Ki-67, the lesion can be classified as either STIC, STIL, p53 signature, or normal/reactive. In order to reproducibly diagnose STIC, morphologic atypia (considered unequivocal for STIC or suspicious for STIC) combined with an abnormal p53 pattern and high Ki-67 index is necessary (Figs. 41a–c and 42). In routine practice, lesions that would be classified as STIL also can be simply diagnosed as “epithelial atypia” with a comment in the pathology report that the lesion does not qualify for a diagnosis of STIC. Tubal dysplasias have been described in the literature, but use of the diagnostic term “dysplasia” is discouraged. Additionally, the term “p53 signature” should not be used in a pathology report, and that terminology is best reserved for academic studies.
Treatment and Prognosis: Invasive Carcinoma
Tumor usually spreads in an intraperitoneal, lymphatic, and hematogenous manner. At presentation, lymph node metastases are frequent, the lymph node groups most frequently involved are those in para-aortic and pelvic sites, and inguinal and supraclavicular lymph nodes can be involved as well; however, lymph node metastases may be present even when it appears that the tumor is limited to the tube (Alvarado-Cabrero et al. 1999; Baekelandt et al. 2000; Deffieux et al. 2005; di Re et al. 1996; Klein et al. 1994, 1999).
In the largest studies of fallopian tube carcinoma, patients have been treated in various fashions, but the most important prognostic factor is stage (Alvarado-Cabrero et al. 1999, 2013; Baekelandt et al. 2000; Hellstrom et al. 1994; Peters et al. 1988; Riska and Leminen 2007; Rosen et al. 1999). The overall 5-year survivals for fallopian tube carcinoma for all stages combined range from 43% to 56% between studies (Alvarado-Cabrero et al. 2013; Baekelandt et al. 2000; Heintz et al. 2006; Rosen et al. 1999). In the largest clinicopathologic study using hospital-based cases, the 5-year survivals were: stage 0 (88%) [old staging system], stage 1 (73%), stage 2 (37%), stage 3 (29%), and stage 4 (12%) (Baekelandt et al. 2000). These 5-year survivals are similar to those of other large studies (Alvarado-Cabrero et al. 2013; Heintz et al. 2006; Hellstrom et al. 1994; Moore et al. 2007; Peters et al. 1988; Rosen et al. 1999). It is also noteworthy that stage 0 disease (old staging system) does not guarantee a cure, as the 5-year survivals for stage 0 (old staging system) ranged from 75% to 91% between studies (Baekelandt et al. 2000; Eddy et al. 1984; Schiller and Silverberg 1971). However, these studies do not provide details specifying whether the entire fallopian tube was submitted for histologic examination in those cases in order to exclude microscopic invasion (i.e., stage IA).
Alvarado-Cabrero et al. showed that subcategorization of stage I cases based on depth of invasion was prognostically significant (Alvarado-Cabrero et al. 1999). In their study, patients with substages IA/B-0 (intraluminal masses without invasion into lamina propria) and IA/B-1 (invasion into lamina propria but not muscularis) had a better disease-free survival than those with substage IA-2 (invasion of muscularis), which was a statistically significant difference. They also demonstrated that patients with stage I(F) (carcinomas in the fimbriated end without invasion) had a poorer survival than those with substages IA/B-0 and IA/B-1, as well as that the survival for stage I(F) was similar to stages IA-2 and IC. These aspects have not been extensively studied in the literature. Two other studies also showed that differences in depth of invasion in the wall of the fallopian tube in stage I cases were prognostically significant while another study demonstrated that it was not (Asmussen et al. 1988; Baekelandt et al. 2000; Peters et al. 1988).
Presence/amount of residual disease after surgery is a poor prognostic factor (Baekelandt et al. 2000; Peters et al. 1988; Rosen et al. 1999). Closure of the fimbriated end (hydrosalpinx-like, hematosalpinx-like, or pyosalpinx-like gross appearance) has been shown to be a favorable prognostic factor on univariate but not multivariate analysis (Alvarado-Cabrero et al. 1999; Baekelandt et al. 2000). Disagreement exists between studies regarding whether or not histologic grade, vascular invasion, age, or ascites is prognostically significant (Alvarado-Cabrero et al. 1999; Baekelandt et al. 2000; Hellstrom et al. 1994; Peters et al. 1988; Rosen et al. 1999). Histologic type has not been shown to be of prognostic importance (Alvarado-Cabrero et al. 1999; Baekelandt et al. 2000). In studies combing ovarian, fallopian tube, and peritoneal high-grade serous carcinomas, cases with homologous recombination mutations (including BRCA) demonstrated better progression-free survival (Ritterhouse et al. 2016).
Treatment of fallopian tube carcinoma consists of cytoreductive surgery and combination platinum/taxane chemotherapy, and as response to this chemotherapy regimen is analogous to that in patients with ovarian carcinoma, fallopian tube carcinoma is treated similarly to ovarian carcinoma (Baekelandt et al. 2000; Moore et al. 2007; Papadimitriou et al. 2008; Riska and Leminen 2007). In patients with a pre-chemotherapy elevated serum CA-125 level, this marker can be used to monitor disease for response and progression. In the study by Baekelandt et al., the median progression-free survival for the entire cohort was 32 months (Baekelandt et al. 2000). In that study, patients were not postoperatively treated in a uniform fashion. In a study of patients that received postoperative combination platinum/taxane chemotherapy, carcinoma recurred in 74% of patients with stage III or IV disease by 33 months (Moore et al. 2007). In the study by Baekelandt et al., the pelvis was the most common site of recurrence, followed by upper abdomen, retroperitoneal lymph nodes, liver, pleura, vagina, lungs, supraclavicular lymph nodes, groin lymph nodes, brain, bone, breast, and adrenal gland in descending order (Baekelandt et al. 2000).
Given the association of fallopian tube (and ovarian) carcinoma with germline BRCA mutations, genetic counseling should be considered for all new diagnoses of fallopian tube high-grade serous carcinoma.
Also, see section below “Behavior of STIC (BRCA Germline Mutation-Associated and Sporadic Cases).”
Occult Disease in Prophylactic Bilateral Salpingo-Oophorectomy Specimens
At least 10% of ovarian carcinomas are hereditary rather than sporadic, and approximately 90% of the former have mutations of the BRCA1 or BRCA2 gene. Carriers of germline BRCA1 and BRCA2 mutations have 44% and 17% lifetime risks for ovarian carcinoma, respectively, and the incidence of ovarian cancer increases with age up to 61–70 years (Kuchenbaecker et al. 2017). Women with such mutations are also at risk for peritoneal and fallopian tube carcinoma. The exact proportion of fallopian tube carcinomas that is hereditary is not clear; however, 16–43% of patients with tubal carcinoma has shown BRCA germline mutations (Aziz et al. 2001; Cass et al. 2005; Levine et al. 2003). As these figures are based on older data with relatively small numbers of cases and that the vast majority of ovarian carcinomas is likely of tubal origin (see below), the true frequency of BRCA germline mutations in fallopian tube high-grade serous carcinomas is probably similar to their “ovarian” counterparts (i.e., 17%) (Cancer Genome Atlas Research Network 2011). Given the significant risk of ovarian carcinoma for patients with BRCA mutations, prophylactic salpingo-oophorectomy is recommended by age 35–40 and 40–45 for BRCA1 and BRCA2 mutation carriers, respectively, and such surgical procedures have been shown to significantly reduce the risk of pelvic carcinoma (Kauff and Barakat 2007; Society of Gynecologic Oncology 2017). This risk is not reduced to 0% since a small percentage of patients subsequently develop peritoneal carcinomas.
A portion of the fallopian tube (chiefly, the intramural segment) remains in the uterus after prophylactic bilateral salpingo-oophorectomy. In one study, it was shown that the segment of fallopian tube remaining in the hysterectomy specimen after prophylactic bilateral salpingo-oophorectomy had a median length of 1.2 cm (range: 0.6–1.5 cm) (Gerritzen et al. 2006). In another study, 73% of hysterectomy specimens had a tubal remnant after the fallopian tubes were fulgurated and transected simulating a risk-reducing salpingo-oophorectomy specimen procedure (Cass et al. 2010). In that study, the median length of residual fallopian tube was 0.6 cm. Despite the fact that not all tubal mucosa is removed during the prophylactic procedure, the risk for development of carcinoma in the remaining tube is probably minimal since (A) tubal carcinomas are not frequently found in the intramural segment, (B) follow-up studies of women after prophylactic bilateral salpingo-oophorectomy show a low frequency of subsequent pelvic carcinoma (in one study, the estimated risk of peritoneal carcinoma at 20 years after prophylactic surgery was only 4% (Finch et al. 2006)), and (C) most occult tubal carcinomas arise in the fimbriated end. Details regarding handling of prophylactic bilateral salpingo-oophorectomy specimens are provided in the section on “Gross Examination” above.
Carcinoma detected in risk-reducing salpingo-oophorectomy specimens from selected large studies
Total patients that underwent surgery (n)
Total patients with Ca, n (%)
Mean/median ageb (years)
Distribution of BRCA germline mutationsb
Patients with STIC-only
Patients with FT Cac (+/− STIC)
Patients with OV Cac (+/− STIC)
Patients with Perit Cac (+/− STIC)
Callahan, J Clin Oncol 2007 (Callahan et al. 2007)
Lamb, Am J Obstet Gynecol 2006 (Lamb et al. 2006)
Manchandra, BJOG 2011 (Manchanda et al. 2011)
2, mutation status unknown
One case with metastatic breast Ca involving ovary
Poon, Int J Gynecol Cancer 2016 (Poon et al. 2016)
Powell, Int J Gynecol Cancer 2011 (Powell et al. 2011)
Two cases with Ca involving ovary and FT
Reitsma, Eur J Cancer 2013 (Reitsma et al. 2013)
Ricciardi, Anticancer Res 2017 (Ricciardi et al. 2017)
1, Mutation status unknown
Two cases with metastatic breast Ca involving adnexa
Sherman, J Clin Oncol 2014 (Sherman et al. 2014)
Zakhour, Gynecol Oncol 2016 (Zakhour et al. 2016)
Also, see section above “Treatment and Prognosis: Invasive Carcinoma” and section below “Behavior of STIC (BRCA Germline Mutation-Associated and Sporadic Cases).”
Occult Disease in Routine Specimens in Women Without Known Genetic Risk (Presumably Sporadic Cases)
Occult fallopian tube carcinomas are not restricted to the setting of risk-reducing salpingo-oophorectomy specimens (women at increased risk for hereditary ovarian carcinoma). On occasion, occult sporadic carcinomas can be detected in specimens performed for other surgical indications, such as uterine leiomyomas (Gilks et al. 2015; Morrison et al. 2015). When occult sporadic carcinoma is found in this scenario, STIC is almost always present, either in isolation or with associated invasive high-grade serous carcinoma. When the latter component is identified, it is usually found in the fallopian tube but sometimes the ovary. The invasive carcinomas are typically small (often ≤1 cm). While cases with invasive carcinoma can be FIGO stage I, staging has revealed advanced disease in some patients.
With regard to the frequency of incidentally finding STIC in routine specimens, a number of large studies have shown that sporadic STIC would be expected to be present in <1% of cases (Meserve et al. 2017b; Rabban et al. 2014; Seidman et al. 2016). Also, see section below “Behavior of STIC (BRCA Germline Mutation-Associated and Sporadic Cases).”
Behavior of STIC (BRCA Germline Mutation-Associated and Sporadic Cases)
The outcome of a number of cases of isolated STIC has been reported. In a review of 78 patients with STIC from 15 publications, 5% of cases subsequently developed peritoneal carcinoma from 3.6 to 6.0 years later (Patrono et al. 2015). However, of all the cases in the entire analysis, the vast majority had BRCA germline mutations, and few sporadic cases (women at low/average genetic risk for ovarian carcinoma) with follow-up were reported. Moreover, a substantial number of all cases had either <4 years follow-up or a duration of follow-up that was not reported. Of note, 11% of patients had positive washings, and 16% of patients were treated with chemotherapy. Two of nine (22%) patients with STIC in a series of risk-reducing salpingo-oophorectomies also subsequently developed pelvic serous carcinoma at 2.7 and 3.5 years, respectively, after surgery (Zakhour et al. 2016). Additionally, in a series of 11 sporadic STICs detected at the time of initial surgery (excluding cases ultimately determined to have a BRCA germline mutation), completion staging was performed in five cases, three of which were upstaged to invasive high-grade serous carcinoma (Chay et al. 2016). In the remaining eight cases with STIC-only, one patient was without evidence of serous carcinoma at 7.3 years, three patients were without evidence of serous carcinoma with follow-up of 2.1 years or less, and outcome/follow-up duration was unknown in four patients. In other series with sporadic STICs, too few cases with meaningful follow-up are available (Gilks et al. 2015; Morrison et al. 2015; Rabban et al. 2014; Seidman et al. 2016).
Although the available data on the behavior of isolated STIC suggest low-risk of progression, it should be emphasized that there are a number of limitations to the current understanding of this topic. The total number of cases in the literature is relatively small, and a number of the reported cases have either no follow-up or follow-up of short duration. Interestingly, in a molecular study by Labidi-Galy et al., a mathematical model estimated that the average time from STIC to development of ovarian high-grade serous carcinoma was 6.5 years (Labidi-Galy et al. 2017). Furthermore, also considering that some of the reported cases of STIC have been associated with subsequent development of serous carcinoma a number of years after initial surgery, the length of follow-up necessary to understand the true behavior of STIC may need to be longer than what is provided in the current literature, and it is possible that the available data in the literature may, therefore, underestimate the true risk of progression. Additionally, the predominance of reported STICs is heavily weighted toward cases with BRCA germline mutations/risk-reducing salpingo-oophorectomy procedures, and too few cases and very little follow-up are available for sporadic STICs. Based on the observation that BRCA-mutated ovarian high-grade serous carcinomas have better survival than wild-type cases (Bolton et al. 2012; Cancer Genome Atlas Research Network 2011), there is the theoretical consideration that sporadic STICs could have a higher progression rate than those associated with BRCA germline mutations, but specific data would be needed to address this concern.
Accordingly, in view of the above limitations to the current literature, as well as that (a) some STICs have positive washings; (b) STIC is frequently present in the fimbriated end of the fallopian tube, which is the portion with direct access to the peritoneal cavity; (c) a subset of cases were ultimately discovered to have disease beyond the fallopian tube after the initial detection of STIC (Bijron et al. 2013; Chay et al. 2016; Morrison et al. 2015); and (d) STIC is morphologically and immunohistochemically analogous to serous endometrial intraepithelial carcinoma (another lesion which can have disease at a distant site in a subset of cases), isolated STIC is probably best considered a lesion whose behavior is uncertain until more robust data becomes available in the future. Lastly, completion staging for sporadic STICs should be considered (Chay et al. 2016).
Pathogenesis, Including Molecular Features
DNA cytometry and molecular genetic studies have shown that fallopian tube carcinomas are aneuploid and have a high degree of chromosomal instability, characterized by multiple gains and losses of genetic material at various loci on all chromosomes (Heselmeyer et al. 1998; Nowee et al. 2007a; Pere et al. 1998; Ritterhouse et al. 2016; Snijders et al. 2003). One study also demonstrated that epithelial atypia/dysplasia of the fallopian tube and STIC in risk-reducing prophylactic specimens contained chromosomal abnormalities, which suggests that chromosomal instability is an early event in the pathogenesis of serous carcinoma (Salvador et al. 2008).
Gene expression profiles of fallopian tube and ovarian serous carcinomas have been shown to be similar, implying that tumorigenesis in both organs shares related molecular pathways (Tone et al. 2008). The results of molecular genetic studies have also suggested multiple potential candidate oncogenes involved in the development of fallopian tube carcinoma (Nowee et al. 2007b; Snijders et al. 2003; Tone et al. 2008). Also, in studies that have combined ovarian, tubal, and peritoneal high-grade serous carcinomas together, the most common mutations are TP53, BRCA1 or BRCA2 (germline or somatic), and ATM (Ritterhouse et al. 2016). Furthermore, TP53 has been identified as an important gene in the development of fallopian tube carcinoma. Mutations have been observed in serous carcinoma, but the frequency differs between studies (Hellstrom et al. 2000; Zheng et al. 1997) although the proportion of cases would be expected to be nearly 100% similar to ovarian high-grade serous carcinoma (Cancer Genome Atlas Research Network 2011; Vang et al. 2016). TP53 mutations have even been detected in early stage carcinoma and > 90% of STICs, suggesting that mutation of this gene is an early event in carcinogenesis (Kuhn et al. 2012c; Lee et al. 2007; Zheng et al. 1997).
An important molecular event involved in the development of hereditary fallopian tube carcinoma is germline mutation of BRCA1 or BRCA2. These tumor suppressor genes are located on chromosomes 17 and 13, respectively. They are normally involved in transcriptional regulation of gene expression, cell cycle control, and recognition/repair of DNA damage. BRCA-associated carcinomas appear to follow the “2-hit model” of tumorigenesis, as seen in other organs (i.e., patients inherit a germline BRCA mutation [first hit], and with somatic loss of the wild-type allele [second hit], carcinoma develops).
The small number of samples of histologically normal fallopian tube epithelium from women with BRCA mutations that were analyzed in one study showed that the gene expression profile during the luteal phase of the menstrual cycle more closely resembled that of serous carcinoma compared with histologically normal samples from the follicular phase (Tone et al. 2008). These findings suggest that the hormonal milieu during the menstrual cycle might play a role in carcinogenesis for women with BRCA mutations. Some evidence also suggests that epigenetic reprogramming within normal fimbrial mucosa is an early event of carcinogenesis in women with BRCA mutations (Bartlett et al. 2016).
Other early molecular events identified as occurring in STIC include CCNE1/cyclin E copy number gain/amplification/overexpression, telomere shortening, and upregulation/overexpression of laminin (see section on “Immunohistochemical Features of Carcinoma”), Rsf-1, and fatty acid synthase (Chene et al. 2013; Karst et al. 2014; Kuhn et al. 2010, 2012b, 2016; Sehdev et al. 2010).
A model has been suggested linking the p53 signature with STIC in which the p53 signature is the earliest step in the pathogenesis of fallopian tube carcinoma (Jarboe et al. 2008; Meserve et al. 2017a). This is supported by the following: (1) p53 signatures are more common in tubes with STIC; (2) the p53 signature preferentially occurs in the same portion of the tube as STIC (fimbriated end); (3) both the p53 signature and STIC are thought to arise from the secretory cell (and transformation of secretory cells into carcinoma has been demonstrated in mouse models (Karst et al. 2011; Perets et al. 2013)); (4) the p53 signature, like STIC, shows p53 overexpression, TP53 mutations, and evidence of DNA damage; (5) direct continuity of the p53 signature with STIC has been reported (including an identical TP53 mutation in both components in one case (Lee et al. 2007)); (6) lesions histologically and immunohistochemically (Ki-67) intermediate between the p53 signature and STIC have been described; (7) identical TP53 mutations in a p53 signature and peritoneal serous carcinoma in one case have been reported (Carlson et al. 2008); and (8) molecular studies constructing evolutionary trees in patients with p53 signature, STIC, and invasive high-grade serous carcinoma involving the fallopian tube, ovary, and metastases have suggested p53 signature as the earliest event in some cases (Labidi-Galy et al. 2017).
In this model, the fallopian tube mucosa in the fimbriated end undergoes injury, and as a result, the secretory cell experiences DNA damage with overaccumulation of p53 protein (p53 signature). With the development of a TP53 mutation, along with further cell proliferation and malignant transformation in a very small subset of women, the p53 signature then evolves into STIC. Although the p53 signature would be a common lesion in the general population regardless of BRCA status, it would, therefore, be in this setting that further molecular alterations would allow for the possible development of a malignant clone with the potential to transform into STIC. Women without BRCA mutations can have a p53 signature, but it is possible that germline mutations of BRCA act as a promoter for the development of STIC (Folkins et al. 2008). It should also be noted that STIC and invasive carcinoma can arise independently of a BRCA mutation. In one study, the frequency of STIC in women with a BRCA mutation was not significantly different from that of controls (8% vs. 3%, respectively) (Shaw et al. 2009). At this stage of growth, the STIC is of microscopic size, but with continued cell proliferation and growth of the tumor, malignant tumor cells eventually exfoliate into the peritoneal cavity (or proximally along the lumen of the tube) or infiltrate underlying tubal stroma in the form of invasive high-grade serous carcinoma. Progressive tumor growth eventually results in increasing tumor stage and volume of disease, peritoneal spread, and metastases, including involvement of lymph nodes.
A lesion designated secretory cell outgrowth (SCOUT) has been proposed as a possible precursor to p53 signature and STIC (Chen et al. 2010; Mehra et al. 2011a; Ning et al. 2014; Quick et al. 2012). SCOUTs are characterized by discrete linear segments of tubal epithelium that predominantly consist of secretory cells, but papillary forms and SCOUTs with a component of ciliated cells have been described (Laury et al. 2011; Meserve et al. 2017a; Ning et al. 2014). Conceptually, p53 signatures are a subset of SCOUTs which exhibits diffuse p53 expression (i.e., p53[+] SCOUTs). However, unlike p53 signatures, p53-negative SCOUTs do not show evidence of DNA damage based on γ-H2AX immunohistochemical staining. Also, in contrast with p53 signature and STIC, SCOUTs are not predominantly restricted to the fimbriated end of the fallopian tube, and they may commonly occur throughout the length of the tube, including the proximal portion. SCOUTs share common features with p53 signature and high-grade serous carcinoma, such as altered gene expression, including reduced PAX2 expression (a marker expressed in secretory cells of normal fallopian tube mucosa). Also, SCOUTs are more frequently present in women that have high-grade serous carcinoma compared with controls, and they are associated with increasing age. The exact mechanism of transformation of SCOUTs into p53 signature and STIC remains to be clarified.
Some evidence suggests that chronic salpingitis could be an etiology and that serous carcinomas may develop on a background of atrophy (Demopoulos et al. 2001). Unlike the ovary, serous carcinomas of the fallopian tube usually do not follow a dualistic model as proposed for the ovary. Thus, a low-grade pathway, in which serous adenofibroma/cystadenofibroma evolves into atypical proliferative (borderline) serous tumor/noninvasive micropapillary (low-grade) serous carcinoma and then invasive low-grade serous carcinoma, typically does not occur in the fallopian tube although these types of low-grade serous tumors rarely arise in the fallopian tube.
As endometrioid carcinoma can evolve from endometriosis and atypical proliferative (borderline) endometrioid tumors in the ovary, these pathways are plausible in the fallopian tube. In one study of 26 endometrioid carcinomas of the fallopian tube, 23% of cases were associated with adjacent endometriosis (Navani et al. 1996). In that study, direct continuity between carcinoma and endometriosis was not observed, but that does not exclude the possibility that carcinoma arose from endometriosis and obliterated any direct connection between the two. Although the fallopian tube is not an uncommon location for endometriosis, atypical (proliferative) borderline tumors occur only rarely in this anatomic site (Alvarado-Cabrero et al. 1997).
Pseudocarcinomatous hyperplasia can histologically simulate carcinoma because of cribriform architecture, pseudoinvasion of the muscularis, papillae within lymphatics, and subserosal mesothelial hyperplasia (Fig. 12) (Cheung et al. 1994b). Patients with hyperplasia are usually premenopausal while those with carcinoma are typically postmenopausal. The tube can be enlarged in hyperplasia but does not show a mass on cross section unlike most cases of carcinoma; thus, the epithelial proliferation in hyperplasia is a microscopic finding. In contrast with carcinoma, hyperplasia usually exhibits a low mitotic index, absence of solid architecture, and a substantially lesser degree of nuclear atypia and nucleolar prominence. Acute or chronic salpingitis is usually present in hyperplasia, but some carcinomas can have an inflammatory component.
Determination of Site of Origin of Serous Carcinoma: Distinction from Ovarian/Peritoneal Primary Origin
Traditionally, when carcinoma involves both the fallopian tube and ovary, the ovary has been considered the primary site given the much more frequent occurrence of presumed primary ovarian carcinomas compared with fallopian tube primaries. Similarly, in the context of what would be conventionally considered a primary peritoneal carcinoma, involvement of the fallopian tube would generally be thought to represent secondary disease. In the past, criteria were proposed for determining fallopian tube origin for tumors synchronously involving the tube and ovary. These criteria of Hu et al. (and subsequently modified by Sedlis) are: (1) tumor arises from the endosalpinx, (2) histology of the tumor resembles tubal mucosa, (3) transition from benign to malignant epithelium, and (4) size of the fallopian tube tumor is larger than the ovarian tumor (Hu et al. 1950; Sedlis 1978). As will be seen below, these criteria are nonspecific and unreliable.
It has been suggested that the vast majority of cases which appear to represent a primary ovarian or peritoneal high-grade serous carcinoma may actually be fallopian tube in origin. The finding of a synchronous STIC, in the setting of a ovarian or peritoneal high-grade serous carcinoma, has been proposed as indicating a fallopian tube origin (Jarboe et al. 2008; Kindelberger et al. 2007). Lines of evidence supporting a tubal include: (1) the fimbriated end of the tube is the preferred site of STIC, which is the portion of the fallopian tube in close proximity to the ovarian surface/peritoneal cavity; (2) STIC is frequently present in patients with high-grade serous carcinomas in the ovary or peritoneum; (3) STIC is restricted to high-grade serous histologic type and not associated with other histologic types of ovarian/peritoneal carcinoma; (4) intraepithelial carcinoma in the ovary or peritoneum is a rare finding or nonexistent; (5) early/occult serous carcinomas in prophylactic bilateral salpingo-oophorectomy specimens from women with BRCA mutations (i.e., women who are at an increased risk for “ovarian” carcinoma) are commonly found in the fallopian tube (especially the fimbriated end and in the form of STIC) without disease in the ovary; (6) early/occult sporadic serous carcinomas in routine specimens (i.e., women who are at low/average risk for “ovarian” carcinoma) are commonly found in the fallopian tube (especially the fimbriated end and in the form of STIC) without disease in the ovary (Gilks et al. 2015; Morrison et al. 2015); (7) identical TP53 mutations have been reported in STIC and synchronous ovarian/peritoneal high-grade serous carcinomas (Carlson et al. 2008; Kindelberger et al. 2007; Kuhn et al. 2012c); (8) identical TP53 mutations in a p53 signature (see “Pathogenesis, Including Molecular Features” section above) and peritoneal serous carcinoma in one case have been reported (Carlson et al. 2008); (9) in STICs associated with high-grade serous carcinomas in the ovary/peritoneum, the STICs frequently have shorter telomere lengths than their associated carcinomas in the ovary/peritoneum, consistent with a precursor lesion (Chene et al. 2013; Kuhn et al. 2010); high-grade serous carcinomas in the ovary have molecular profiles more similar to fallopian tube epithelium than ovarian surface epithelium (Klinkebiel et al. 2016; Marquez et al. 2005); and (10) molecular studies comparing the signature patterns in STICs, high-grade serous carcinomas in the ovary, and metastases have demonstrated evidence of tubal origin with STIC being a precursor (Eckert et al. 2016; Labidi-Galy et al. 2017). However, it should be noted that some investigators have proposed that the STIC pathway may be only one pathway leading to the development of ovarian high-grade serous carcinoma, in which STIC leads to the formation of classic high-grade serous carcinoma whereas high-grade serous carcinomas with the SET (solid, pseudoendometrioid, and transitional cell carcinoma-like) pattern might be unrelated to STIC (Ritterhouse et al. 2016). For additional information on pathogenesis of ovarian carcinoma, see the chapter on “Ovarian Epithelial Tumors”.
The proportion of primary “ovarian” and “peritoneal” high-grade serous carcinomas associated with synchronous STIC ranges from 19% to 61% and 29% to 61%, respectively (Carlson et al. 2008; Kindelberger et al. 2007; Przybycin et al. 2010; Schneider et al. 2017; Seidman et al. 2011; Tang et al. 2012). However, there are a number of potential explanations for a “STIC-negative” ovarian or peritoneal high-grade serous carcinoma.
It is possible that a small fallopian tube carcinoma can exfoliate cells onto the ovary or peritoneum, and preferential tumor growth in these secondary sites may overgrow the fallopian tube/STIC and obliterate any clues to a true fallopian tube origin in cases that do not initially appear as having arisen from the fallopian tube. Similarly, in carcinomas at other primary sites (e.g., breast, colon, endometrium, cervix), the precursor lesion is not always present in the resection specimen presumably due to tumor overgrowth. Interestingly, cases with a dominant mass in the ovary have a low frequency of STIC (11%) whereas STIC is much more common (45%) in cases in which involvement of the ovary did not create a dominant mass (Roh et al. 2009).
Also, STICs may not be present on the initial H&E level but can be discovered upon deeper leveling into the paraffin block (Mahe et al. 2013; Przybycin et al. 2010). Some STICs may be minute, attenuated, and subtle and possibly not identified if only examining H&E sections at low-power magnification. Although STIC may still persist in patients that have received neoadjuvant chemotherapy (Colon and Carlson 2014), the frequency of STIC is lower in such patients (Mahe et al. 2013). Accordingly, in patients treated with neoadjuvant therapy, the latter may have eradicated a preexisting STIC in some cases.
It has been recognized that a subset of risk-reducing salpingo-oophorectomy specimens can have a portion of fimbrial mucosa adherent to the ovarian surface (Ayres et al. 2017; Gan et al. 2017). In such cases, or in other patients (non-risk-reducing salpingo-oophorectomy procedures) where there may have been prior tubo-ovarian adhesions, if a STIC arose in a portion of fimbrial mucosa adherent to the ovarian surface (but which is detached from the fallopian tube proper) and eventually developed into invasive high-grade serous carcinoma creating a mass in the ovary, a fallopian tube completely submitted for histologic examination would appear to not contain any evidence of STIC whatsoever.
Lastly, the concept of “precursor escape” has been proposed, in which nonmalignant epithelial cells with a TP53 mutation spread beyond the fallopian tube and subsequently develop into a high-grade serous carcinoma in the pelvis (Meserve et al. 2017a).
Thus, the true frequency of “ovarian” carcinomas that really originated in the tube may be underestimated.
Although it has been debated regarding the exact origin of ovarian carcinoma as well as the exact proportion of “ovarian” high-grade serous carcinomas that truly originate from the fallopian tube, a survey of members of several national and international gynecologic pathology and clinical cancer societies revealed that 86% of pathologists and 92% of clinicians accept the fallopian tube origin for high-grade serous carcinoma (McCluggage et al. 2017).
Three possibilities may exist for cases with high-grade serous carcinoma in the ovary/peritoneum and STIC: (1) the fallopian tube is the primary lesion with secondary involvement of the ovary/peritoneum; (2) the ovary/peritoneum is the primary site with secondary involvement of the fallopian tube in the form of intraepithelial spread; and (3) both sites may be independent primaries. While the evidence discussed above supports that the majority of cases are of tubal origin, some clinicopathologic, immunohistochemical, and molecular evidence suggests that STIC-like lesions in some cases may actually represent non-fallopian tube gynecologic carcinomas that have metastasized to the fallopian tube (Eckert et al. 2016; Kommoss et al. 2017; McDaniel et al. 2015; Rabban et al. 2015).
In cases in which the primary site cannot be determined, this distinction usually will not be critical since most cases will typically be high-stage, and the treatment and prognosis for a high-grade serous carcinoma simultaneously involving these sites will be similar regardless of which site is designated the primary origin (Baekelandt et al. 2000; Moore et al. 2007).
Although the 8th Edition of the AJCC Cancer Staging Manual states that ovarian high-grade serous carcinoma with only STIC should be classified as stage IA ovarian carcinoma, the International Collaboration on Cancer Reporting has suggested that for instances with high-grade serous carcinoma involving multiple sites, tumors should be assigned tubal primary origin if any of the following are present: STIC, invasive carcinoma involving tubal mucosa, or no tubal fimbria identified (McCluggage et al. 2015a).
Determination of Site of Origin of Serous Carcinoma: Distinction from Endometrial Primary Origin
Endometrial serous intraepithelial carcinoma has been observed in association with STIC (Jarboe et al. 2009). We have encountered cases of synchronous STIC and uterine malignant müllerian mixed tumor with a component of serous carcinoma. In these situations, the relationship between the fallopian tube and uterine tumors is not clear. Three possibilities may also exist, similar to that mentioned above: (1) the fallopian tube is the primary lesion with secondary involvement of the uterus; (2) the uterus is the primary site with secondary involvement of the fallopian tube (Kommoss et al. 2017); and (3) both sites may be independent primaries.
Other Fallopian Tube and Paratubal Neoplasms
Because of the admixture of spindle cells in the epithelial component in some endometrioid carcinomas, the differential diagnosis can include malignant müllerian mixed tumor (MMMT). In general, the epithelial and mesenchymal components of MMMT, while admixed, do not show a histologic transition as opposed to the gradual transition between endometrioid glands and spindle cells in endometrioid carcinoma, and the latter has more of an orderly growth than MMMT. The degree of nuclear atypia and mitotic activity is greater in MMMT. The presence of malignant heterologous tissues would favor MMMT.
Endometrioid carcinomas with a female adnexal tumor of wolffian origin-like (FATWO-like) growth pattern can be confused with FATWO. Location within the lumen of the fallopian tube typically favors carcinoma since FATWO is usually in a paratubal location, but rare FATWOs can arise within the wall of the tube (see section on “Wolffian Adnexal Tumor (“Female Adnexal Tumor of Probable Wolffian Origin”; FATWO” below); however, the latter is predominantly within the muscularis as opposed to mostly occupying the lumen as in an endometrioid carcinoma. Villoglandular architecture, squamous differentiation, and endometriosis would favor carcinoma. Also, carcinoma contains larger, more conventional-appearing endometrioid glands. The degree of glandular confluence and nuclear atypia are usually greater in carcinoma than FATWO. The latter typically has more of an admixture of patterns, including open or closed tubules and sieve-like, solid, and spindled architecture; however, these features can be seen in FATWO-like endometrioid carcinomas. Calretinin is often positive in FATWO but occasionally may be negative; however, most carcinomas are negative. Carcinomas would be expected to express CK7, EMA, ER, and PR and be negative for inhibin. FATWO occasionally expresses CK7 and inhibin. ER, PR, and EMA are frequently negative in FATWO, but expression may occasionally be seen.
Sarcomas and Mixed Epithelial-Mesenchymal Tumors
Pure sarcomas of the tube may occur, and the mesenchymal component of mixed epithelial-mesenchymal tumors can be sarcomatous. Mixed epithelial-mesenchymal neoplasms in which the mesenchymal component is malignant and the epithelial component is benign are designated adenosarcoma whereas those in which both components are malignant are classified as malignant müllerian mixed tumor (MMMT; carcinosarcoma).
Pure sarcomas may be histologically subtyped if sufficient differentiation is present. Leiomyosarcomas are perhaps the most common type and may arise from the tube or broad ligament (Jacoby et al. 1993). However, some may actually represent gastrointestinal stromal tumors arising outside of the gastrointestinal tract (Foster et al. 2006). Other gynecologic-specific sarcomas, such as primary endometrioid stromal sarcoma arising in the tube, are rare (Chang et al. 1993). Chondrosarcoma, malignant fibrous histiocytoma, and embryonal rhabdomyosarcoma have been described.
Metastatic Tumors/Secondary Involvement
Lymphatic metastases may involve the mucosa or muscularis. Low-grade endometrial stromal sarcoma may involve the tubes by the extension of worm-like tongues of tumor along tubal lymphatics. Hematogenous metastases from breast carcinomas or other extra-pelvic tumors also may occur. Rarely, displaced benign endometrial tissue can be seen in the veins of the fallopian tube and should not be mistaken for metastatic carcinoma. On occasion, squamous carcinoma of the uterine cervix may spread in an in situ manner to involve the endometrial cavity, tubes, and even the ovarian surface (Pins et al. 1997).
The presence of tumor in the lumen of the fallopian tube in cases of endometrial serous carcinoma with metastases in the peritoneum (without myoinvasion or lymph-vascular space invasion in the uterus) suggests that the tubal lumen serves as a conduit for tumor spread (Snyder et al. 2006). However, fragments of endometrial endometrioid carcinoma within the tubal lumen without adherence to tubal mucosa is considered artifactual displacement and does not qualify for upstaging an endometrial carcinoma (Delair et al. 2013; Stewart et al. 2013). In primary ovarian carcinoma, luminal groups of tumor cells may implant onto endosalpingeal surfaces and simulate STIC or early invasive primary tubal carcinoma. The distinction of fallopian tube vs. ovarian origin for serous carcinoma is discussed in the above section “Determination of Site of Origin of Serous Carcinoma.”
Primary tubal lymphoma is rare and is associated almost invariably with simultaneous involvement of the ipsilateral ovary (Vang et al. 2001). Undifferentiated carcinoma and other small round blue cell tumors must be ruled out with appropriate immunohistochemical stains. For details, see chapter on “Hematolymphoid Neoplasms”.
Gestational Trophoblastic Disease of the Fallopian Tube
Trophoblastic tubal lesions are exceedingly uncommon. Patients have risk factors for ectopic pregnancy such as prior salpingitis and tubal occlusion (Muto et al. 1991). The clinical presentation of a tubal hydatidiform mole or choriocarcinoma is similar to that of a tubal ectopic pregnancy; thus, rarely, an apparent ectopic pregnancy will prove to be a mole or choriocarcinoma. Hydatidiform moles usually occur as isolated growths but may be associated with intrauterine pregnancy. The histologic appearance resembles complete or partial moles as seen in the uterus. However, tubal moles are frequently overdiagnosed because ectopic pregnancies in the fallopian tube commonly have an exuberant extra-villous trophoblastic proliferation (Burton et al. 2001; Sebire et al. 2005). Intraoperatively, the appearance of a tubal choriocarcinoma may be that of a large, hemorrhagic, and fleshy mass mostly destroying the tube. Histologically, the malignant trophoblastic proliferation resembles uterine choriocarcinoma. Response to modern chemotherapy in general has been excellent. Lesions of intermediate trophoblast, including placental site nodule, placental site trophoblastic tumor, and epithelioid trophoblastic tumor, are rare (see chapter on “Gestational Trophoblastic Disease and Related Lesions”) (Baergen et al. 2003; Jacques et al. 1997; Nayar et al. 1996; Parker et al. 2003; Su et al. 1999).
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)
Patients have been treated surgically, usually with a benign outcome. Malignant behavior is uncommon and includes multiple local recurrences and fatal metastases (Brescia et al. 1985; Daya 1994). It is difficult to predict which cases will exhibit malignant behavior. The tumors that demonstrate malignant behavior generally have nuclear atypia and mitotic activity; however, bland histology has been noted in some FATWOs that exhibit malignant behavior.
The differential diagnosis includes the FATWO-like variant of tubal endometrioid carcinoma (see above section “Differential Diagnosis of Carcinoma”). Many of the histologic and immunohistochemical features of FATWO overlap with those of Sertoli cell tumor; however, the admixture of multiple growth patterns (particularly cystic architecture with a sieve-like pattern) and cell types in FATWO is generally greater than is typically seen in Sertoli cell tumor, and sex cord-stromal tumors are rare in extra-ovarian sites.
Papillary Cystadenoma Associated with Von Hippel-Lindau Disease
The importance of diagnosing this tumor (or suggesting it as a diagnostic possibility in ambiguous cases) is because of the association with von Hippel-Lindau disease (and, hence, various tumors of other organs, including renal cell carcinoma) and to not confuse it with other histologically similar neoplasms that do not have this association. The differential diagnosis includes cystadenofibromas of müllerian type with prominent papillary architecture that are not associated with von Hippel-Lindau disease. Those generally contain papillae which are much larger and less complex and contain cilia. They should also have areas which appear more conventionally adenofibromatous, including distinctive cleft-like architecture. Histologic overlap can also occur with atypical proliferative (borderline) serous tumor, but this tumor exhibits a hierarchical degree of papillae branching with epithelial stratification (including cellular tufts), ciliated cells, and psammoma bodies. Papillary cystadenomas associated with von Hippel-Lindau disease that are predominantly of clear cell type can mimic metastatic renal cell carcinoma (Aydin et al. 2005). In contrast with the latter, papillary cystadenoma diffusely expresses CK7 and is negative for RCC marker. CD10 can be positive or negative. Other positive markers that have been described include WT-1, PAX2, and PAX8. ER/PR have been reported as negative, but experience is limited. Specifically, it is not clear cell renal cell carcinoma that papillary cystadenoma resembles as the latter is more histologically and immunohistochemically similar to clear cell papillary renal cell carcinoma (Cox et al. 2014).
Other Paratubal/Para-ovarian and Pelvic Ligament Lesions
Atypical proliferative (borderline) tumor occurs more commonly in the broad ligament and paratubal/para-ovarian locations compared with carcinoma. Most of the atypical proliferative (borderline) tumors are of serous type (Aslani et al. 1988). These patients range in age from 19 to 67 years (mean, 32 years). The tumors are typically unilateral, and they range in size from 1 to 13 cm. They are usually confined to the broad ligament and histologically similar to their ovarian counterparts. The behavior appears to be favorable. Primary carcinoma of the broad ligament is rare (Aslani and Scully 1989). Many of the patients are relatively young, and the tumors are usually unilateral. Some are associated with pelvic endometriosis. In most cases, disease is limited to the broad ligament. Various histologic types have been described, including endometrioid and clear cell.
Most mesenchymal tumors in paratubal/para-ovarian locations and pelvic ligaments are leiomyomas. Criteria for classification of benign, atypical, and malignant smooth muscle tumors in paratubal/para-ovarian locations have not been developed; however, some authors have advocated using the same criteria as used for uterine locations (Kempson et al. 2001; Lax et al. 2003). It should be noted that criteria have been suggested for classifying smooth muscle tumors in the ovary (Lerwill et al. 2004). For additional details regarding extrauterine smooth muscle tumors, see the chapter on Soft Tissue Tumors. Sarcomas (leiomyosarcoma being the most common one) are rare.
Other primary lesions, some of which are rare, that may occur in paratubal/para-ovarian locations and pelvic ligaments include endometriosis, uterus-like mass, ectopic hilus cell nests, benign epithelial tumors (including serous cystadenoma and Brenner tumor; cystadenofibromas are occasional, usually incidental findings), adenomyoma, benign mesenchymal tumors (including lipoma, benign mesenchymoma, neurofibroma, and schwannoma), sex cord-stromal tumors (including fibroma, thecoma, and steroid cell tumor), ependymoma, teratoma, pheochromocytoma, carcinoid, perivascular epithelioid cell tumor (PEComa), malignant mesenchymal tumors (including extra-skeletal Ewing’s sarcoma/PNET, adenosarcoma, endometrioid stromal sarcoma, rhabdomyosarcoma, “mixed mesenchymal sarcoma,” liposarcoma, and alveolar soft part sarcoma), yolk sac tumor, and choriocarcinoma (Lax et al. 2003). Various gynecologic and non-gynecologic tumors may secondarily involve paratubal/para-ovarian locations and pelvic ligaments. Such mesenchymal gynecologic tumors in particular include intravenous leiomyomatosis, diffuse uterine leiomyomatosis, cotyledenoid dissecting leiomyoma (“Sternberg tumor”), uterine leiomyosarcoma, and endometrial stromal sarcoma.
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