The Fallopian Tube and Broad Ligament





Keyeords

tumor-like lesions of the fallopian tube, inflammatory lesions of the fallopian tube, tubal epithelial hyperplasia, pregnancy-related changes in the fallopian tube, tubal metaplasias and ectopias, benign and borderline epithelial tumors of the fallopian tube, tumor-like lesions of the broad ligament, tumors of the broad ligament

 




Tumor-Like Lesions of the Fallopian Tube


Inflammatory Lesions


Usual Bacterial Salpingitis ( Figs. 11.1–11.6 )





  • Bacterial salpingitis, an important cause of infertility, is usually a result of ascending sexually transmitted infections ( Neisseria gonorrhoeae , Chlamydia trachomatis , mycoplasma). Other organisms may enter the tubes via lymphatics or blood vessels, especially after an abortion or pregnancy, such as streptococci, staphylococci, coliform bacilli, and anaerobic bacteria.



  • Acute salpingitis.




    • Gross examination may reveal a swollen erythematous tube with a luminal and/or serosal purulent exudate and fibrinous adhesions. Ovarian involvement can lead to a tubo-ovarian abscess.



    • Microscopic examination reveals a neutrophilic mucosal infiltrate, a fibrinopurulent luminal exudate, and in severe cases, transmural inflammation and serositis. Chronic inflammatory cells may also be present.



    • The differential includes the common physiologic endosalpingitis during menses and the early proliferative phase, likely due to endosalpingeal irritation by refluxed blood and debris. A sparse neutrophilic infiltrate is seen in the tubal lumen and mucosa in such cases.




  • Chronic salpingitis.




    • Gross examination may show peritubal and tubo-ovarian fibrous adhesions and occasionally hydrosalpinx. The last finding may be due to fimbrial coalescence, ostial obliteration, and/or tubal kinking. The tube may have a retort-like shape with the distal tube cystically distended with clear fluid.



    • Microscopic examination usually reveals inflammatory cells, mostly lymphocytes and plasma cells, although in later stages inflammatory cells may be sparse. The plicae are reduced in number, shortened, and fibrotic. Plical fusion with dilatation may result in follicle-like spaces (follicular salpingitis).



    • The tubal epithelium may show reactive changes (see Epithelial Hyperplasia, Usual Type).



    • A hydrosalpingiotic fallopian tube densely adherent to an ovary can mimic an ovarian cyst or cystadenoma on intraoperative and pathologic examination. The presence of occasional plicae, follicular salpingitis, and/or a thin myosalpinx point to the correct diagnosis.





Fig. 11.1


Acute salpingitis. Both tubes are distended, erythematous, and focally coated by a purulent exudate.



Fig. 11.2


Acute and chronic salpingitis. A dense acute and chronic inflammatory infiltrate is present in the tubal plicae and tubal lumen.



Fig. 11.3


Follicular salpingitis. The normal histology of the tube is effaced by the ramifying irregular cystically dilated spaces lined by tubal type epithelium.



Fig. 11.4


Follicular salpingitis. The tubal plicae are fibrotic and have fused and dilated to form follicle-like spaces.



Fig. 11.5


Hydrosalpinx. Note retort-like shape.



Fig. 11.6


Hydrosalpinx. Only rare plicae remain.


Actinomycotic Salpingitis





  • Actinomyces israelii , an anaerobic gram+ bacterium, is a rare cause of salpingitis, which can be related to an intrauterine device. Ovarian involvement can result in an ovarian or tubo-ovarian abscess.



  • Colonies of actinomyces (‘sulfur granules’) are usually found within a neutrophilic exudate. Sulfur granules should be distinguished from pseudoactinomycotic granules ( Chapter 7 ), which may also occur in tubo-ovarian abscesses.



  • Chronic inflammatory cells, including histiocytes, can also be present, and long-standing infections may be associated with granulation tissue and fibrosis.



Tuberculous Salpingitis ( Fig. 11.7 )





  • This lesion, which is usually bilateral, is common in cases of genital tuberculosis and is an important cause of infertility in some parts of the world.



  • The gross appearance may be nonspecific, but the occasional presence of luminal or serosal caseous material may suggest the diagnosis. In later stages, dense tubo-ovarian fibrous adhesions may be present.



  • Microscopic examination usually reveals typical tuberculous granulomas with focal caseous necrosis; the process may be transmural. Fusion of plicae can form multiple gland-like spaces, including a cribriform pattern, formed by mildly to moderately atypical epithelial cells with mitotic activity. The presence of granulomas and a lack of overtly malignant nuclear features facilitate the differential with carcinoma.




Fig. 11.7


Tuberculous salpingitis.


Other Causes of Granulomatous and Histiocytic Salpingitis ( Figs. 11.8–11.11 )





  • Rare causes of granulomatous salpingitis include parasites (schistosomiasis [usually Schistosoma haematobium ]; oxyuriasis [ Enterobius vermicularis ]), foreign material (lubricants, mineral oil, starch granules), and involvement by sarcoidosis or Crohn’s disease.



  • Long-standing chronic bacterial salpingitis can elicit an infiltrate of foamy histiocytes (xanthogranulomatous salpingitis) or a solid mass (xanthogranuloma).



  • Pelvic endometriosis can lead to brownish discoloration of the tubal mucosa due to numerous histiocytes containing lipofuscin pigment (pseudoxanthomatous salpingitis). In such cases, the tube itself is not usually involved by endometriosis.



  • Pulse granulomas may occur in the fallopian tube secondary to a rectosalpingeal fistula. These granulomas are an unusual reaction to vegetable material and appear as small to medium-sized hyaline rings.



  • Michal et al. described a massive accumulation of histiocytes within the tubal lumen associated with a tubal serous carcinoma.



  • Tran et al. reported a case of intralymphatic histiocytosis involving the fallopian tube (and appendix) associated with a high-grade primary müllerian-type peritoneal adenocarcinoma. An unusual feature of the intralymphatic histiocytosis was the present of multinucleated giant cells.




Fig. 11.8


Xanthogranulomatous salpingitis. Note yellow discoloration of the tubal mucosa.



Fig. 11.9


Xanthogranulomatous salpingitis. There is a dense inflammatory infiltrate, mostly of foamy histiocytes.



Fig. 11.10


Pseudoxanthomatous salpingitis. There is brown pigmentation of the tubal mucosa in this patient with pelvic endometriosis.



Fig. 11.11


Pseudoxanthomatous salpingitis. The stroma of the tubal plicae is infiltrated by numerous pigmented and foamy histiocytes.


Ligneous Salpingitis





  • Rare cases of ligneous salpingitis have been reported, sometimes in association with involvement elsewhere in the female genital tract (FGT) ( Chapter 4 ) or peritoneum.



Arteritis ( Fig. 11.12 )





  • Giant cell arteritis in the FGT is most common in the cervix ( Chapter 4 ), but has been reported in the adnexa, including the fallopian tube. Polyarteritis nodosa may also involve the adnexa. In both types, the arteritis may be isolated or reflect systemic disease.




Fig. 11.12


Arteritis of polyarteritis nodosa type involving the tubal fimbria. The lesion was an incidental histologic finding.


Epithelial Hyperplasia


Usual Type, Including Those With Pseudocarcinomatous Changes ( Figs. 11.13–11.16 )





  • The prevalence, diagnostic criteria, and significance of hyperplasia of the tubal epithelium are not well established. Mild proliferation of the tubal epithelium is common and may be related to unopposed estrogenic stimulation in some cases.



  • The finding may be more common in patients with ovarian serous borderline tumors (SBTs) and carcinomas and in those with BRCA mutations but no evidence of neoplasia. Wolsky et al., however, found no increased frequency of tubal epithelial hyperplasias in women with low-grade serous tumors (cystadenomas, SBTs, low-grade serous carcinomas).



  • Severe nontuberculous and tuberculous salpingitis may cause epithelial stratification, a papillary or cribriform pattern, and reactive cellular atypia and mitoses (Cheung et al.).



  • Other findings that can suggest cancer include synchronous salpingitis isthmica nodosa, stromal reactive changes, artifactual intravascular epithelial cells and/or psammoma bodies, and reactive mesothelial hyperplasia of the tubal serosa with gland-like spaces.



  • Metastatic tumors to the tubal lamina propria can result in striking reactive hyperplasia that may incorrectly suggest that the tumor is of tubal origin.




Fig. 11.13


Hyperplastic tubal epithelium. The epithelial cells are focally stratified into multiple layers, but they have bland nuclear features and some of the cells have retained their cilia.



Fig. 11.14


Tubal atypia, NOS. A variety of epithelial abnormalities of the tube of no known significance are sporadically encountered. In this example, sporadic tubal epithelial cells are hyperchromatic, apically located, and appear to be sloughing off.



Fig. 11.15


Chronic salpingitis. Fused and expanded plicae have resulted in prominent intraluminal fronds, potentially mimicking carcinoma.



Fig. 11.16


Pseudocarcinomatous hyperplasia of tubal mucosa associated with chronic salpingitis. Note cribriform pattern and inflammatory cells.


Differential diagnosis





  • The histologic separation of reactive tubal epithelial proliferations from early tubal carcinomas, including serous tubal intraepithelial carcinoma (STIC), has become increasingly important because of the current practice of complete histologic examination of risk-reducing salpingo-oophorectomy specimens in BRCA carriers. The histologic and immunohistochemical features of BRCA-related lesions, including STIC and its potential precursors, are considered under a separate heading.



  • Evidence favoring a hyperplasia (vs carcinoma) include the presence of severe salpingitis (although occasional tubal carcinomas may be associated with salpingitis); a paucity of mitotic figures; a lack of severe nuclear atypicality or atypical mitotic figures; the presence of cilia; weak or absent staining for MIB1; wild-type p53 staining pattern; and recognition of any serosal proliferation as mesothelial on the basis of the architecture and immunoprofile of the cells ( Chapter 20 ).



Papillary Tubal Hyperplasia ( Figs. 11.17 11.18 )





  • Kurman et al. described ‘papillary tubal hyperplasia’ in the form of small rounded clusters of tubal epithelial cells and small papillae with or without psammoma bodies. This finding was associated with SBTs (many with peritoneal implants) in 75% of cases.




    • These authors concluded from their findings that tubal cells may implant on ovarian and peritoneal surfaces potentially representing a precursor of ovarian SBTs, noninvasive epithelial peritoneal implants, and endosalpingiosis.



    • Further study is warranted to confirm the limited information on this topic. We and others (see Wolsky et al. above) have not noted this finding to be associated with SBTs.




  • Laury et al. have described secretory cell outgrowths (SCOUTs) in the fallopian tube and found them to be more common in patients with SBTs. SCOUTs range from a single layer of low columnar or pseudostratified PAX2− secretory cells to papillary proliferations of secretory and ciliated epithelial cells, with or without psammoma bodies. SCOUTs are considered further (see BRCA-Related Lesions).




Fig. 11.17


Papillary tubal hyperplasia, consistent with secretory cell outgrowth.



Fig. 11.18


Papillary tubal hyperplasia.


Pregnancy-Related Findings


Ectopic Pregnancy ( Figs. 11.19–11.21 )





  • About 50% of tubal pregnancies are in the ampulla, which is often distended with a thinned wall, a dusky red serosa, and occasional rupture. Less commonly, the isthmus, the interstitial portion, or fimbria are involved. Hemorrhage into the broad ligament and even the contralateral adnexa may mimic a neoplasm.



  • One or more of viable or necrotic villi, trophoblast, or, less often, fetal parts, are usually found microscopically within blood clot, but thorough sampling of the latter may be required to find diagnostic tissue. Erol et al. found that invasion of trophoblast to the serosa correlated with a higher frequency of tubal rupture.



  • A predisposing lesion (chronic salpingitis, salpingitis isthmica nodosa, endometriosis, tumor) may be found in some cases.



  • The residue of an old, clinically unrecognized ectopic pregnancy may be found in salpingectomy specimens, such as intermediate trophoblast (including placental site nodule, see below) or fibrotic chorionic villi within the lumen, mucosa, myosalpinx, or even paratubal soft tissue.




Fig. 11.19


Tubal pregnancy. A hemorrhagic mass distends the tube.



Fig. 11.20


Ectopic pregnancy. The tubal lumen contains a confluent aggregate of chorionic villi and trophoblasts.



Fig. 11.21


Ectopic pregnancy. Striking cytotrophoblasts and syncytiotrophoblasts are seen, and villi are present at the top left.


Hydatidiform Mole





  • Tubal hydatidiform moles (HMs) are rare and are diagnosed using the same criteria as in the uterus. Nonmolar tubal pregnancies can be misdiagnosed as HMs due to the presence of hydropic villi, sheets of extravillous trophoblast, and in some cases, invasion of the tubal wall.




    • Sebire et al. confirmed only 8 cases of tubal HMs (5 complete, 2 partial, 1 HM, NOS) among 132 cases referred with that diagnosis. Lu et al. reported a tubal complete HM associated with a synchronous normal intrauterine gestation.



    • In contrast to tubal HMs, nonmolar tubal gestations have normal polar villous trophoblast and extravillous (intermediate) trophoblast that exhibits little or no atypia.




  • The risk of persistent gestational trophoblastic disease in tubal HMs is not known to differ from that of their uterine counterparts.



Placental Site Nodule





  • Placental site nodule ( Chapter 10 ) in the fallopian tube is an occasional incidental finding. The mucosa is typically involved, sometimes with luminal occlusion; some lesions have extended into the muscularis propria and even paratubal tissues.



Arias-Stella Reaction ( Fig. 11.22 )





  • This process, which resembles its endometrial counterpart ( Chapter 7 ), has been observed in ~15% of ectopic tubal pregnancies and occasionally an intrauterine pregnancy.



  • The differential features with very rare primary tubal clear cell carcinoma are as in the endometrium ( Chapter 7 ).




Fig. 11.22


Tubal mucosa showing Arias-Stella reaction.


Clear Cell Change





  • The one reported tubal example of this change was associated with a tubal pregnancy. Criteria for its distinction from clear cell carcinoma are as in the endometrium ( Chapter 7 ).



Ectopic Decidua ( Fig. 11.23 )





  • Microscopic foci of decidua occur in the tubal lamina propria in 5–8% of pregnant women at term, in one-third of cases of ectopic pregnancy, and rarely related to progestin treatment. Similar foci have also been identified in the serosal connective tissue in 5% of postpartum tubal-ligation specimens.



  • As discussed elsewhere ( Chapter 7 ), decidual cells can be confused with a signet-ring cell carcinoma when they exhibit prominent cytoplasmic vacuolation.




Fig. 11.23


Ectopic decidua within stroma of tubal plicae.


Metaplasias and Ectopias


Endometriosis ( Figs. 11.24 11.25 )





  • Serosal (and subserosal) tubal endometriosis is commonly associated with endometriosis elsewhere in the pelvis; the myosalpinx and mucosa are not usually involved but may contain pseudoxanthoma cells.



  • Mucosal endometriosis, due to extension of endometrial tissue from the uterine cornu, may replace the interstitial and isthmic mucosa or occlude the tubal lumen. The latter finding (intraluminal endometriosis), which may be bilateral, accounts for 15–20% of cases of infertility and may be a cause of tubal pregnancy.



  • Postsalpingectomy endometriosis occurs at the tip of the proximal tubal stump usually 1–4 years postligation; it may be associated with salpingitis isthmica nodosa. Endometrial glands and stroma extend from the endosalpinx into the muscularis, often to the serosa. Tuboperitoneal fistulas may lead to a postligation ectopic pregnancy.




Fig. 11.24


Endometrial tissue occluding the proximal tubal lumen (intraluminal endometriosis).



Fig. 11.25


Endometriosis of the tubal mucosa. These low- (left) and higher- (right) power views show papillarity due to expansion of the tubal lamina propria by prominent endometrial stroma, well seen on the right. Note the associated typical hemorrhage of endometriosis.


Mucinous Metaplasia ( Fig. 11.26 )





  • Mucinous metaplasia of the tubal epithelium is an uncommon microscopic finding. In about half the cases, it coexists with metaplastic or neoplastic mucinous or nonmucinous lesions in the tube or elsewhere in the genital or gastrointestinal tracts. Some cases have occurred in women with the Peutz–Jeghers syndrome.



  • The tubal epithelium is usually replaced by a single layer of bland endocervical-type cells, although occasionally there is atypia similar to that in ovarian mucinous borderline tumors.



  • Associated tubal findings in some cases have included chronic salpingitis and other forms of metaplasia (transitional, clear cell).



  • The differential, which may be difficult to resolve with certainty, includes tubal mucosal involvement by well-differentiated mucinous tumors arising elsewhere in the genital or intestinal tracts, such as the cervix and appendix.




Fig. 11.26


Mucinous metaplasia of tubal epithelium. There is an abrupt transition from the metaplastic tall mucinous epithelial cells to the normal tubal epithelium.


Transitional and Squamous Metaplasia ( Fig. 11.27 )





  • Transitional cell metaplasia (TCM) of the tubal epithelium is an uncommon incidental microscopic finding in the general population but occurs in about 25% of risk-reducing salpingo-oophorectomy (RRSO) specimens. It may be the origin of some tubal transitional cell carcinomas.




    • Tubal TCM histologically resembles its counterpart in the uterine cervix ( Chapter 4 ).



    • In RRSO specimens, there may be involvement of the fimbria, a finding that should not be confused with early tubal carcinoma. The transitional appearance of the cells, the bland nuclear features, low MIB-1 expression, and p53-negativity facilitate the correct diagnosis.



    • Walthard nests, which represent TCM of the tubal serosa, are discussed in Chapter 19 .




  • Squamous metaplasia of the tubal serosa (or more commonly the ovary [ Chapter 12 ]) may rarely occur in patients on peritoneal dialysis.




Fig. 11.27


Transitional metaplasia of the tubal epithelium. A small component of tubal epithelium remains (right). The tubal epithelium is otherwise replaced by transitional type cells.


Metaplastic Papillary Tumor ( Fig. 11.28 )





  • This rare lesion is typically an incidental microscopic finding in tubal segments removed postpartum, although occasionally it occurs in nonpregnant women.



  • The lesion is characterized by intraluminal papillae with cellular buds, both composed of epithelial cells with abundant eosinophilic cytoplasm and intracellular and extracellular mucin. Rare mitotic figures may be present.




Fig. 11.28


Metaplastic papillary tumor within the tube of a pregnant woman. Typical intraluminal proliferation of papillae whose cells have abundant eosinophilic cytoplasm.


Rare Ectopias ( Figs. 11.29–11.31 )





  • Microscopic sex cord proliferations rarely occur in the tube (or rarely paratubal cysts), especially in or near the fimbria, that histologically and immunohistochemically resemble adult-type granulosa cell tumors, SCTATs, and Sertoli cell tumors. In one case, a sertoliform proliferation merged with fimbrial ectopic ovarian-like stroma.



  • Nests of hilus cells occur in the endosalpinx (usually the fimbria) and paratubal connective tissue are a rare finding in salpingectomy specimens. Occasionally they are intraneural.



  • Microscopic foci of ovarian-type stroma are found in about 5% of fallopian tubes, usually at the fimbrial–peritoneal junction.



  • A single case of ectopic pancreatic tissue in the fallopian tube has been reported.




Fig. 11.29


Ectopic Leydig cells in the tubal mucosa.



Fig. 11.30


Ovarian-type stroma in tubal fimbria.



Fig. 11.31


Intramucosal proliferation of sex cord-type cells. Sex cord-type proliferations may be encountered in the tube, either submucosal (left) or involving the mucosal surface (center right). These proliferations vary in appearance, some with cording (left) and others with Call–Exner like bodies (center right). Sex cord markers such as inhibin (center left and right) highlight such proliferations.


Miscellaneous Tumor-Like Lesions


Salpingitis Isthmica Nodosa ( Figs. 11.32–11.34 )





  • This lesion of uncertain pathogenesis is usually found in young women (mean age, 26 years) and may cause infertility or predispose to ectopic pregnancy.



  • It is bilateral in ~80% of cases and typically forms a yellow–white nodular swelling up to 2 cm in diameter that is usually, but not invariably, isthmic; occasionally it is grossly inconspicuous. Sectioning shows firm, rubbery tissue, often with small cysts.



  • Variably sized glands (some cystic) lined by tubal epithelium lie within a typically thickened myosalpinx. The glands are actually diverticula that communicate with the tubal lumen.



  • The regular distribution of the glands, the lack of significant cellular atypia, and the absence of a desmoplastic stroma facilitate distinction from carcinoma, but this may be challenging if the tube is inflamed with reactive atypia (see Epithelial Hyperplasia ).




Fig. 11.32


Salpingitis isthmica nodosa. The isthmic portions of each tube demonstrate nodular expansion.



Fig. 11.33


Salpingitis isthmica nodosa. The tubal lumen is seen to the right. Irregular penetration of the muscularis is seen to the left. Note the lack of a stromal reaction to the ‘misplaced’ glands.



Fig. 11.34


Salpingitis isthmica nodosa.


Torsion





  • Tubal torsion may be an isolated finding, but usually accompanies ipsilateral ovarian torsion. Gross inspection usually reveals a swollen and hemorrhagic tube. Rarely, torsion is synchronously or metachronously bilateral.



Microcalcification





  • found luminal or mucosal microcalcification (sometimes in the form of psammoma bodies) in 29% and 26% of cases of acute and chronic salpingitis, respectively, compared to only 5% of cases without salpingitis. The differential diagnosis is with spread from an ovarian serous borderline tumor.



  • found microcalcification in 9% of women who were high-risk for serous tubal cancers vs in only 1.8% of non-high-risk women.



Artifacts ( Figs. 11.35–11.37 )





  • Cautery-induced thermal damage to the tubal epithelium results in cellular pseudostratification and marked nuclear elongation. This distinctive appearance facilitates its differentiation from intraepithelial carcinoma.



  • Contamination of the tubal lumen by detached tumor cells from a nontubal tumor may occur during prosection or tissue processing.



  • Normal granulosa cells can be artifactually displaced into the fallopian tube; aggregates of such cells with crushed hyperchromatic nuclei can suggest small cell carcinoma. Awareness of this finding and reactivity for inhibin facilitate the correct diagnosis.



  • The tubal mucosa can be the site of pseudolipomatosis, an artifactual microscopic change that resembles fatty infiltration. The fat-like spaces are air or gas bubbles that enter the mucosa during gaseous insufflation.




Fig. 11.35


Surgical procedures can displace portions of normal endometrium (right) into the tubal lumen.



Fig. 11.36


Tubal epithelium showing cautery artifact. The nuclei have a distinctive ‘stretched’ appearance.



Fig. 11.37


Air bubbles within the lamina propria of the tube related to tubal insufflation (‘pseudolipomatosis’).


Prolapse Into Vagina


( Chapter 3 )




Tumors of the Fallopian Tube


Benign and Borderline Epithelial Tumors


Endometrioid Polyp





  • This lesion, also referred to as ‘adenomatous polyp’, is the most common benign tumor of the fallopian tube. The polyps may obstruct the tubal lumen, resulting in infertility or ectopic pregnancy.



  • The frequency of polyps in women undergoing hysterosalpingography has varied from 2.5% to 18%, the latter figure from a study of infertile women.



  • The polyps are usually within the intramural portion of the tube (‘tubo-cornual’ polyps), and are frequently associated with, and presumably arise from, mucosal endometrial tissue (see Endometriosis ).



  • Although most lesions are not recognized grossly, they can be several cm in size. They are commonly attached to the tubal epithelium by a broad base and microscopically resemble typical endometrial polyps.



Papilloma, Adenoma, and Cystadenoma





  • These lesions, some of which are fimbrial, are rare. Papillomas range up to 3 cm and are loosely attached to the tubal mucosa and consist of delicate, branching fibrovascular stalks lined by indifferent or tubal-type epithelium. One clear cell adenoma of the tubal mucosa has been reported.



Adenofibroma and Cystadenofibroma ( Fig. 11.38 )





  • The reported examples of these tumors have resembled those encountered in the ovary, including rare bilateral cases.



  • Bossuyt et al. found adenofibromas in 30% of tubes that were completely examined histologically. All were fimbrial and most were <3 mm. Uncommon features include multicentricity, bilaterality, and/or association with an ovarian adenofibroma.



  • found adenofibromas in ~10% of women who were high risk for serous tubal cancers vs in 2.5% of non-high-risk women.



  • Most tumors are of serous type; others are endometrioid.




Fig. 11.38


Fimbrial adenofibroma.


Borderline Tumors





  • Rare tubal tumors resemble ovarian serous or endometrioid borderline tumors; some have arisen from the fimbria. As SBTs are much more often paratubal than tubal, diligent gross examination is required before a tubal origin is diagnosed.



  • Four ‘mucinous borderline tumors’ of the tube have been reported, three in association with pseudomyxoma peritonei. These tumors may have arisen from foci of mucinous metaplasia of the tubal epithelium (see corresponding heading) or represented spread from an undetected appendiceal mucinous tumor.



Carcinomas





  • Tubal carcinomas (TCs) have been traditionally considered rare, but recent studies of women with and without BRCA mutations suggest that many nonuterine high-grade serous carcinomas (HGSCs) may be of tubal origin. We believe that this issue needs further study before definite conclusions can be drawn and some of us and others are unconvinced that a tubal origin explains as many ovarian carcinomas as has been suggested (see Prat and Young).



  • Carriers of BRCA1 or BRCA2 germ-line mutations have a TC risk that begins early in the fifth decade of life, and may reach 60% with prolonged follow-up. Many carriers and those with unknown mutational status now undergo risk-reducing salpingo-oophorectomy (RRSO) with the specimens examined by the SEE-FIM protocol (sectioning and extensive examination of the fimbria).



  • Findings in SEE-FIM specimens indicate that many BRCA-related and sporadic nonuterine HGSCs are of fimbrial origin.




    • Serous tubal intraepithelial carcinomas (STICs) or small invasive HGSCs (both usually fimbrial) are found in BRCA women and in those with benign conditions or unrelated pelvic tumors (Gilks et al., ).



    • STIC (usually fimbrial) has been found in ≥40% of sporadic pelvic nonuterine HGSCs that would be considered of ovarian or peritoneal origin by traditional criteria (Meserve, Mirkovic et al.). Some such STICs have a background of dysplastic tubal lesions and/or TP53 mutations identical to the extratubal tumor (Kindelberger et al., Przybycin et al).



    • Lessard-Anderson et al. found a 64% decreased risk for ovarian and peritoneal HGSCs after RRSO.



    • found tubal mucosal involvement in 95% of low-stage HGSCs and a higher frequency of bilaterality (suggestive of metastases) in the ovaries (35%) than the tubes (9%). They also found that all cases had tubal or ovarian involvement questioning the existence of primary peritoneal serous carcinomas.




  • It has been proposed that some ovarian and peritoneal HGSCs unassociated with tubal lesions may arise indirectly from tubal epithelial cells but definite conclusions await further studies.




    • Kurman and Shih suggest that normal fimbrial epithelial cells (or those of papillary tubal hyperplasia and secretory cell outgrowths [SCOUTS]) may implant on ovarian and peritoneal surfaces resulting in, respectively, ovarian epithelial inclusion glands and endosalpingiosis, from which may arise, respectively, ovarian and peritoneal HGSCs, a phenomenon referred to as ‘precursor escape’ by Meserve and Crum.



    • Other findings supporting this theory include PAX8 and hormone receptor staining in tubal secretory cells, ovarian inclusion glands ( Chapter 12 ), and HGSCs but not in ovarian and peritoneal mesothelium.




  • Hereditary nonuterine pelvic cancer syndromes are considered in more detail in Chapter 13 .



Clinical features and staging





  • Women with symptomatic TCs are usually postmenopausal (mean ages of 57 64 years) and present with abnormal vaginal bleeding or discharge, abdominal pain, and an elevated serum CA125. Rare presentations have included a positive Pap smear, tumor in a curettage specimen, lymphadenopathy, and paraneoplastic cerebellar degeneration.



  • The stage distribution of TCs varied widely among series antedating the FIGO 2014 staging system: 21–5 7 % stage I, 9–20% stage II, 16–55% stage III, 4–12% stage IV. found survival rates of 57%, 15%, 22%, and 6% for stages I to IV, respectively. In contrast, TCs currently found in BRCA and non-BRCA women undergoing RRSO and SEE-FIM examination are typically microscopic, asymptomatic, stage I tumors.



  • TCs are now staged using the single 2014 FIGO staging system for ovarian, tubal, and peritoneal cancers ( Table 11.1 ). Potential problems with the staging include:




    • No substages of TCs within stage IA, obscuring potential prognostic differences between the substages proposed by : IA–0 (no extension into lamina propria), IA–1 (extension into lamina propria), IA–2 (extension into muscularis), and I–F (fimbrial).



    • No inclusion of serous tubal intraepithelial carcinoma (STIC; see corresponding heading). Some authors conclude that STIC should be considered stage IA given its metastatic potential. However, the malignant potential of STIC may be overestimated if insufficiently strict criteria for STIC are used leading to inclusion in this category of small overt serous carcinomas.



    Table 11.1

    FIGO staging of cancer of the ovary, fallopian tube, and peritoneum








    • Stage I Tumor is confined to ovaries or fallopian tube(s)




      • IA Tumor limited to one ovary (capsule intact) or fallopian tube, no malignant cells in ascites or peritoneal washings



      • IB Tumor limited to both ovaries or fallopian tubes, no malignant cells in ascites or peritoneal washings



      • IC Tumor limited to one or both ovaries or fallopian tubes with any of the following



      • IC1 Surgical spill



      • IC2 Capsule ruptured before surgery or tumor on ovarian or fallopian tube surface



      • IC3 Malignant cells in the ascites or peritoneal washings




    • Stage II Tumor involves one or both ovaries or fallopian tubes with pelvic extension or primary peritoneal cancer




      • IIA Extension and/or implants on uterus and/or fallopian tubes and/or ovaries



      • IIB Extension to and/or implants on other pelvis tissues




    • Stage III Tumor involves one or both ovaries or fallopian tubes, or primary peritoneal cancer, with microscopically confirmed peritoneal metastasis outside the pelvis and/or metastasis to the retroperitoneal (pelvic and/or para-aortic) lymph nodes




      • IIIA1 Positive retroperitoneal lymph nodes only (histologically confirmed)



      • IIIA1(i) Metastasis ≤10 mm in greatest dimension



      • IIIA1(ii) Metastasis >10 mm in greatest dimension



      • IIIA2 Microscopic extrapelvic (above the pelvic brim) peritoneal involvement with or without positive retroperitoneal lymph nodes



      • IIIB Macroscopic peritoneal metastasis beyond pelvis 2 cm or less in greatest dimension with or without metastasis to the retroperitoneal lymph nodes



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




    • Stage IV Distant metastasis excluding peritoneal metastases




      • IVA Pleural effusion with positive cytology



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





  • The AJCC eighth edition of staging for ovarian, tubal, and peritoneal cancers combined fallopian tube staging into the same staging system as ovary and peritoneal carcinomas. Similar to other gynecologic cancers in the AJCC eighth edition, the reporting of isolated tumor cells as N0i(+) was added.



Gross features ( figs. 11.39 11.40 )





  • Up to 20% of TCs are bilateral in some studies, although only 3% were bilateral in one large study ( ). The ratio of ampullary to isthmic tumors is 2 : 1. About 8% of all TCs are confined to the fimbria, whereas most BRCA-related TCs in risk-reducing salpingo-oophorectomy (RRSO) specimens are fimbrial.



  • Tubal distension by luminal watery fluid or blood can result in an external appearance resembling that of hydrosalpinx or hematosalpinx. Serosal tumor or infiltration of adjacent structures may be seen.



  • Opening the tube usually reveals a localized or diffuse, soft, gray to pink, friable mucosal tumor; rarely the tumor is multifocal. The sectioned surface is usually solid, often with focal hemorrhage and necrosis. Some tumors may be discrete firm masses.



  • Some tumors form a mass that replaces the distal tube and ovary (‘tubo-ovarian carcinoma’) (see Differential Diagnosis ).




Fig. 11.39


Tubal carcinoma. The tubal lumen is distended by a fleshy lobulated tumor that was a serous carcinoma.



Fig. 11.40


Tubal carcinoma. A nodular mass has expanded the tubal lumen.


Findings in RRSO specimens





  • The SEE-FIM protocol requires sectioning the entire tube at 2–3 mm intervals (with longitudinal sections of the fimbria) and in toto histologic examination. Multiple deeper sections have increased the frequency of detection of STIC in some studies but not others (Mahe et al., Rabban, Krasik et al.).



  • Five studies of RRSO specimens from BRCA patients have found carcinomas (including STIC) in 3.62%, 5.4%, 7.1%, 8.6%, and 9.1% of specimens. The ratio of tubal to ovarian carcinomas is ~4 : 1. Only STIC was found in 2% (Wethington et al.) and 4% (Conner et al., Poon et al.) of specimens.



  • In contrast, found no STICs in 111 RRSO specimens from high-risk women (those with BRCA mutations, personal/family history of breast/ovarian cancer), but 3 STICs in 277 (0.8%) non-high-risk cases. Meserve, Mirkovic et al. found STIC in only 0.1% of non-high-risk women.



  • The frequency of BRCA-related cancers in RRSO specimens is age-dependent, being much higher in women >50 years of age. The frequency is expected to decline as women undergo RRSO by the currently recommended age of 40.



  • The frequency of TC is usually higher in BRCA1 vs BRCA2 carriers. Walts et al. found that 85.7% of RRSO specimens harboring occult cancers were BRCA1 patients. Conner et al. found cancer frequencies of 9.2% ( BRCA1 ) and 3.4% ( BRCA2 ).



  • BRCA-related TCs are almost always fimbrial, with STIC often being localized to the tubal–peritoneal junction (Seidman); only rare tumors are found in the ampulla or more proximal tube. Most TCs found in RRSO specimens are STIC or a microscopic superficially invasive HGSC; rare tumors have been synchronously bilateral (Gurda et al.). Rare tumors have been endometrioid carcinomas.



  • Wong et al. found that in a third of RRSO specimens harboring a malignancy submitted for intraoperative examination, the lesion was grossly visible and diagnosable on frozen-section examination.



Histologic features of STIC ( Figs. 11.41–11.46 )





  • As noted above, STICs are typically located within 1–2 mm of the tubal-peritoneal junction (Schmoeckel et al., Seidman).



  • Low-power examination reveals epithelium composed of usually stratified hyperchromatic cells with loss of polarity, a high N/C ratio, moderate to severe nuclear pleomorphism, and prominent nucleoli; ciliated cells are absent. The epithelium may be thickened.



  • Exfoliated tumor cells may be found in the tubal lumen in cases interpreted as STIC but should raise concern for a small serous carcinoma particularly if the involved epithelium is unusually thick and there is papillary tufting with detachment of papillae.




Fig. 11.41


Serous tubal intraepithelial carcinoma (STIC). The surface epithelium and that of subjacent glands shows marked hyperchromasia and nuclear contour irregularities, morphologically suspicious for a STIC lesion, which was confirmed by abnormal p53 and Ki-67 staining (not pictured).



Fig. 11.42


Serous tubal intraepithelial carcinoma (STIC). This example has striking mitotic activity and scattered apoptotic bodies.



Fig. 11.43


Serous tubal intraepithelial carcinoma (STIC). On low power the abnormal focus markedly contrasts with the otherwise normal tubal epithelium (left). High-power view shows cellular stratification, prominent nucleoli, and mitotic figures (right).



Fig. 11.44


Serous tubal intraepithelial carcinoma (STIC). Intraepithelial neoplasia often appears as hyperchromasia and focal marked stratification (left). Higher power more clearly shows nuclear irregularity, focally prominent nucleoli, and a prominent mitotic figure (center). The process abnormally overexpresses p53 (right) and has a high proliferation index (not pictured).



Fig. 11.45


Serous tubal intraepithelial carcinoma (STIC). Extreme left: The striated cells of STIC contrast with the normal cells (bottom). Left center: The carcinomatous cells show striking nuclear pleomorphism and stratification. Right center: The cells are strongly and diffusely immunoreactive for p53. Extreme right: The cells are strongly and diffusely immunoreactive for Ki-67.



Fig. 11.46


Fimbrial tubal epithelium in a RRSO specimen showing an appearance on H&E (top) that was suspicious for STIC (but without the latter’s marked cellular stratification) and that exhibited strong diffuse p53 staining (bottom). The Ki-67 index (not shown) was low (<10%). These findings would be considered a serous tubal intraepithelial lesion (STIL) or tubal intraepithelial lesion in transition (TILT) (see text).


Immunohistochemical and molecular features of STIC





  • Most STICs show ‘all or nothing’ p53 staining patterns consistent with a p53 mutation: nuclear positivity in >75% of secretory cells, or, in 10–15% of cases, completely negative staining; both patterns contrast with wild-type (patchy) p53 staining.



  • found a high Ki-67 index in STICs, ranging from 11.7% to 71.1% with a mean of 35.6% (vs 2% for normal tubal epithelium).



  • Novak et al. found that the use of p16 and stathmin 1 (STMN1) with p53 and Ki-67 improves diagnostic accuracy of STIC and compensates for the practical limitations of p53 and Ki-67.



  • Other markers commonly present in STICs are p16, WT1, HMGA2, β-catenin (cytoplasmic), LEF1 (a stem cell marker), and EZH2. Most STICs have at least focal loss of PAX2 and ALDH1 staining.



  • found strong diffuse laminin γ1 expression in STIC (a marker also found in HGSCs), including those that were p53− due to null mutations. In normal tubal epithelium, laminin γ1 was confined to the basement membrane and the apical surface of ciliated cells.



  • STICs upregulate markers associated with high-grade serous carcinomas, including Rsf-1, cyclin E, and fatty acid synthase.



  • found CCNE1 copy number gain/amplification in 22% of STICs and 28% of HGSCs; the CCNE1 copy number in STIC and HGSC correlated in the same patient. They concluded that CCNE1 copy number gain/amplification occurs early in tumor progression and precedes centrosome amplification. That the latter finding is less common in STICs than in HGSCs suggests that STIC precedes the development of many HGSCs.



Proposed diagnostic criteria for STIC





  • Visvanathan et al. devised an algorithm that achieves a diagnosis of STIC vs ‘non-STIC’ with 95% reproducibility in their original study and 93% in a subsequent validation study (Vang et al.).




    • STIC: the focus exhibits morphologic features of STIC or suspicious for STIC, p53 mutational patterns (see above), and a Ki-67 index of >10%.



    • STIL (serous tubal intraepithelial lesion): (a) the morphologic features are those of STIC or suspicious for STIC with a p53 mutational pattern or a Ki-67 index of >10%; (b) the morphologic features are those of STIC but there is wild-type p53 staining and a Ki-67 index of <10%; (c) the morphologic features are not suspicious of STIC but there is a p53 mutational pattern and a Ki-67 index of >10%.



    • p53 signature: unremarkable morphologic features with a p53 mutational pattern and a Ki-67 index of <10%.



    • Normal/reactive: (a) normal: morphologic features not suspicious for STIC and with a wild-type p53 pattern and Ki-67 <10%; (b) reactive: morphologic features not suspicious for STIC with a wild-type p53 pattern and Ki-67 index of >10%.




  • have found that the diagnosis of STIC is typically clear cut (but ideally supported by a second opinion) without immunostaining, the latter being reserved for problematic cases and to exclude potential mimics (see Differential Diagnosis ).



  • Chan and Rabban found that chemotherapy-related changes complicating the detection of residual STIC and assignment of primary site included mucosal denudation/granulation tissue and treatment-induced cytologic alterations.



Behavior of STIC and occult serous carcinomas in RRSO specimens





  • Although most BRCA-related TCs in RRSO specimens are confined to the tube, some (including STICs) have positive peritoneal cytology or disseminated peritoneal disease (Bijron et al.).



  • found that 10% of occult serous carcinomas in RRSO specimens recurred after a median follow-up of 5 years. , in a later study with a median follow-up of 88 months, found that 47% of occult invasive carcinomas recurred whereas only 6% of STICs recurred.



  • Conner et al. found that 9% of STICs recurred at a mean post-RRSO interval of 4 years. Wethington et al., however, found that 12 patients with STIC had no evidence of metastatic or recurrent tumor (except for positive peritoneal cytology in one case), although this study had relatively short follow-up periods (16-44 months).



Histologic features of potential STIC precursors





  • Accumulating evidence has identified a potential precursor of (or risk factor for) STIC, the serous tubal intraepithelial lesion (STIL) and the p53 signature, which is fimbrial in 90% of cases.



  • The p53 signature (considered a subset of SCOUTS, see below) consists of discrete foci of ≥12 consecutive normal-appearing secretory cells with p53+ nuclei; the secretory cells may be interrupted by p53− ciliated cells. The Ki-67 index of p53 signatures has ranged from 0 to 30%.



  • There is typically cytoplasmic staining for β-catenin (Schmoeckel et al.). Ning et al. found concordant loss of PAX2 and ALDH1 in 80% of p53 signatures.



  • In ~60% of cases, p53 mutations are present, in some cases identical to those in a contiguous STIC.



  • p53 signatures occur in a third of RRSO specimens in BRCA+ women and in a third of controls, but are more common (53%) and multifocal (67%) in tubes with STIC.



  • p53 signatures may be continuous with STIC and/or atypical lesions with an appearance intermediate between the two (see below).



  • Staff et al. found that p53 and γ-H2AX nuclear staining levels were significantly higher in tubal epithelium in BRCA1/2+ women than ovarian epithelium in the same subjects and in control tubal epithelium. In another study, two-thirds of p53 signatures in BRCA+ cases had evidence of DNA damage by localization of γ-H2AX.



  • SCOUTs may also play a role in serous tubal carcinogenesis. Quick et al. found that they increase with age and correlate with the presence of serous carcinoma.




    • define SCOUTs as a discrete focus of ≥30 secretory cells within the tubal epithelium. SCOUTs were present in 12% of controls, 18% of BRCA+ healthy women, and 83% of those with HGSC. Eighty-nine percent of SCOUTs had loss of PAX2; 25% of the PAX2-null SCOUTs had p53 signatures. All HGSCs and 92% of STICs in the same series also had loss of PAX2.



    • Schmoeckel et al., however, found that unlike STICs, SCOUTs had a nonfimbrial location and strong nuclear expression of β-catenin (versus cytoplasmic staining in STICs and p53 signatures) suggesting that the pathogenesis of SCOUTs is distinct from that of the latter two lesions.




  • Atypical tubal lesions with a phenotype and immunoprofile intermediate between those of a p53 signature and STIC have been referred to as tubal atypias, serous tubal intraepithelial lesions (STILs), and tubal intraepithelial lesions in transition (TILTs). As the diagnostic reproducibility of these ‘less than STIC’ lesions is suboptimal and their clinical significance is uncertain, the use of these diagnostic terms in a pathology report is currently not recommended .



  • Mingels et al. found tubal hyperplasia and ‘minor epithelial atypia’ in different parts of the tube in 41.6% of BRCA-mutation carriers and in 58.1% of controls. The authors concluded that these epithelial changes represented variations of the normal tubal epithelium rather than a premalignant change.



Differential diagnosis of STIC





  • A variety of tubal epithelial atypias, as recently summarized by Kaur et al., belong in the differential of STIC. Most are considered elsewhere in this chapter, and include reactive atypia NOS, postradiation atypia, thermal damage, Arias-Stella reaction, transitional and other metaplasias, mucosal endometriosis (including occasional presence of papillary syncytial change), STILs, and TILTs. All of these lesions lack the features that define STIC: loss of ciliated cells, diffuse high-grade atypia, high Ki-67 index, and ‘all or nothing’ p53 staining.



  • STIC can be mimicked by fimbrial implants of an extratubal serous carcinoma (Tang et al. found STIC in 14% of endometrial HGSCs) and extratubal nonserous carcinomas, including extragenital carcinomas (see Singh and Cho, and Secondary Tumors). The synchronous presence of lower grade tubal intraepithelial lesions ‘less than STIC’ (see above) favors a primary lesion.



Microscopic features of invasive tubal carcinomas ( figs. 11.47–11.60 )





  • Although there is considerable variation in the reported frequency of the various microscopic subtypes of tubal carcinomas (TCs), in our experience ~70% are serous, ~10% are endometrioid, and the rest are other types (see below). Mucinous and clear cell carcinomas, which are common in the ovary, are rare. In a large series (all subtypes included), 8% were grade 1, 20% grade 2, and 72% grade 3.



  • Serous carcinomas.




    • These are almost always high grade (HGSC) and resemble those traditionally considered of ovarian origin ( Chapter 13 ), with papillae, cellular buds, slit-like glandular spaces, solid sheets, and occasional tumor giant cells and psammoma bodies. Necrosis and vascular space invasion are common.



    • The tumors may be entirely intraluminal or partly so and be associated with invasion of the lamina propria or deeper tissues.



    • Synchronous contiguous or non-contiguous STIC (see corresponding heading) may be found in the ipsilateral or contralateral tube.



    • Howitt et al. found that HGSCs that were >50% Solid, PseudoEndometrioid, or Transitional (usually in combination, so-called SET morphology) were more commonly BRCA+ (50% vs 28%), occurred at a younger age (56.2 vs 64.8 years), and had a better clinical outcome than typical HGSCs. STIC was more common in BRCA− women with typical morphology compared to those with SET morphology.




  • Endometrioid carcinomas.




    • Unlike tubal HGSCs, many tubal endometrioid carcinomas are entirely luminal with absent or minimal invasion of the lamina propria.



    • The histologic features usually recapitulate those of endometrial endometrioid carcinoma (EEC) with tubular glands. Navani et al. found that 5 of 26 tumors were grade 1, 11 were grade 2, and 10 were grade 3. Some tumors have prominent stromal hyalinization. The various forms of squamous metaplasia seen in EECs may be encountered



    • Solid rounded foci of spindle-cells, sometimes in whorls, probably represent abortive squamous differentiation. The solid areas may be punctuated by small endometrioid glands with a luminal eosinophilic secretion, resulting in an appearance that may mimic FATWO (see Differential Diagnosis ). In other cases, spindled epithelial cells grow in a more sarcoma-like fashion and when punctuated by glands, a striking biphasic pattern may be seen,



    • Occasional to rare features include sex cord-like patterns, prominent oxyphilic cells, and an association with endometriosis.



    • Some tumors are associated with a synchronous EEC. Culton et al. found that most of the latter were low-stage and grade 1 or 2 and that the tubal and endometrial carcinomas often differed in grade. All the tubal tumors had an situ component and some were only in situ. These findings and the generally favorable prognosis suggest that the tumors are independent primaries.




  • Uncommon subtypes include transitional cell and undifferentiated carcinoma. Rare mucinous, clear cell, squamous cell, lymphoepithelioma-like, hepatoid, and glassy cell carcinomas have also been reported, as well as a mixed serous-neuroendocrine carcinoma.




Fig. 11.47


Early serous carcinoma. The tubal epithelium is markedly abnormal and particularly at the bottom right small papillae are detached within the tubal lumen indicating a diagnosis of carcinoma rather than an entirely intraepithelial process.



Fig. 11.48


Serous carcinomas of tubal fimbria in BRCA carriers. Left and middle panels: A 3 mm invasive serous carcinoma involves the tubal fimbria. Right: Another case in which this microscopic serous carcinoma was the only finding in a RRSO specimen.



Fig. 11.49


Intraluminal serous carcinoma. Much of the tubal lumen is effaced by carcinoma. Note the lack of invasion into the tubal wall.



Fig. 11.50


Fimbrial serous carcinoma. The fimbrial epithelium is largely replaced by a prominent exophytic papillary proliferation of serous carcinoma.



Fig. 11.51


Serous carcinoma. In contrast to serous tubal intraepithelial carcinoma (STIC), the tumor, although noninvasive, forms a mass that projects into the tubal lumen.



Fig. 11.52


Serous carcinoma. The tumor infiltrates the lamina propria.



Fig. 11.53


Serous carcinoma. Note slit-like spaces.



Fig. 11.54


Serous carcinoma. Typical papillary pattern.



Fig. 11.55


Serous carcinoma. This example is entirely solid and imparts a transitional-like pattern.



Fig. 11.56


Endometrioid adenocarcinoma. A rounded nodule composed of typical low-grade malignant endometrioid glands protrudes into and largely replaces the tubal lumen. Note the lack of invasion of the underlying lamina propria.



Fig. 11.57


Endometrioid adenocarcinoma. Typical tubular glands of endometrioid type are seen (left) in association with more closely packed glands showing a cribriform pattern (right).



Fig. 11.58


Endometrioid adenocarcinoma. Small neoplastic endometrioid glands on the background of a solid proliferation of largely spindled cells impart a biphasic pattern.

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Feb 9, 2020 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on The Fallopian Tube and Broad Ligament
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