Appendix I. A Summary of Common Pitfalls in Diagnostic Gynecologic and Obstetric Pathology

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1 Appendix I. A Summary of Common Pitfalls in Diagnostic Gynecologic and Obstetric Pathology Section Chapter Mistaken for Comments Candidiasis A premalignant lesion (VIN) Chronically rubbed skin can produce a striking acanthosis. A yeast infection must always be kept in mind if there is minimal atypia or any epithelial neutrophils. Syphilis Inflammatory dermatosis This is still a rare disease in vulvar pathology. However, any dense lymphoplasmacytic infiltrate, including those accompanied by acanthosis or which is arranged around vessels, should be investigated. Psoriasis VIN1 We have seen these occasionally misdiagnosed as VIN1. Chronic erosive herpes Sclerotic Hidradenoma Basal cell Pseudobowenoid papulosis VIN with superimposed lichen simplex chronicus Non- infectious inflammatory conditions Invasive adeno Adenoid basal HIVIL or Bowenoid Papulosis Differentiated VIN or lichen simplex chronicus Epithelial hyperplasia rather than erosion may be seen. The viral inclusions may not be obvious. The degree of sclerosis can be striking with epithelial entrapment. Adenocaricnoma can be excluded with a p63 stain, which will highlight the basal cells. These can be misclassified as adenoid cystic s. Basal- squamous lesions may be difficult to classify as well. The abundant pseudomitoses seen with apoptosis can be confusing. At the same time similar changes can be seen in high grade VIN so caution is needed in both directions. Presumably if a VIN is rubbed or scratched, a prominent superimposed lichen simplex chronicus can occur. This may either make the lesion less conspicuous or prompt a diagnosis of differentiated VIN. Classic VIN can be confirmed with a p16 immunostain. Pagetoid VIN Glandular or urothelial lesion A p16 stain may be helpful to support VIN; CK7/CK20/CDX2 can be used to investigate for spread from a GI or urothelial primary. VIN with columnar Paget Disease CK7 and GATA3 positivity is seen in

2 differentiation Paget disease cells (normal epithelium is CK 5/6 positive). EBV- like atypia Classic VIN or atypia NOS A history of immunosuppression may be helpful. Giant Condyloma (GC) Pseudoepithelioma tous hyperplasia (PEH) Keratoacanthoma Aggressive angiomyxoma Synovial sarcoma of Vulva Verrucous or papillary squamous Squamous cell Under or over- diagnosis of squamous Usually over- diagnosed Mullerian or vulvar adeno or carcinosarcoma GC can occur on the vulva, vagina and cervix. Care should be excercised in making the diagnosis of a "verrucous" in a young woman with an exophytic well differentiated squamous lesion in this region. The key is lack of atypia and the characteristic interlacing strands of epithelium. Also watch out for a Granular cell tumor, syphilis, etc., and be aware that some s can mimic PEH. Remains a controversial diagnosis. Look for the deep location and characteristic vascular pattern. Clinically it may be difficult to completely resect and it may be locally invasive. The epithelium, if prominent, is disarmingly benign appearing and the stroma may not be markedly atypical, mimicking endometrial stroma. Mullerian markers (PAX8) will be absent; the presence of TLE1 would support synovial sarcoma. Ill defined, asymmetric, prominent collagen deposition. Prepubertal Angiomyxoma fibroma Hymenal ring Condyloma A common pitfall. These are small filiform polyps without atypia. Melanoma Undifferentiated or sarcoma Vaginal melanoma may not have pigment and may not initially be clinically recognized. Always consider melanoma when confronted with apoorly differentiated spindle or epithelioid lesion in the vagina. Spindle cell epithelioma Sarcoma The epithelial component is often quite subtle but the spindle cells are bland appearing; well circumscribed. Cytokeratin stains will be focally positive. Pseudo crypt HSIL with crypt involvement Stromal reaction, loss of cell polarity

3 pattern of invasive squamous Lymphoepithelial like Superficial adeno in situ Extensive cervical adeno in situ (AIS) Signet ring cell of the cervix Adenoid basal Prostatic metaplasia Microglandular hyperplasia (MGH) of the endocervix Mesonephric Minimal deviation adeno Endocervicosis Lymphoma, undifferentiated Tubal metaplasia, non- specific changes Invasive adeno Metastatic breast or gastrointestinal Squamous cell Adenoid basal, squamous intraepithelial lesion Adeno Sarcoma, conventional adeno Endocervical hyperplasia Adeno, adenosarcoma and central necrosis typify pseudo- crypt involvement by. The squamous nests may be subtle but are strongly p63 positive. Mitoses and atypia may be inconspicuous or absent; look for discrete appearance, apoptosis, luminal eosinophilia. P16 stain very helpful. Controversial and cut- offs difficult to define; however, approach any extensive AIS with caution. This is a diagnosis of exclusion but look for evidence of a precursor (ACIS) lesion. Immunostains can be helpful. Look for the uniform nests, lack of desmoplasia and the tell- tale rim of basal- type cells around the squamous nests. Look for the signature finding of small acini suspended in the squamo- transitional nests This can occur with solid growth, lacking signficant acinar architecture. P16 will be patchy in MGH versus diffuse in The spindled variety tends to be remarkably uniform; glandular elements can resemble endometrial or sex cord differentiation and are typically closer to the surface, with the typical mesonephric histology at the periphery. The presence of GATA3 is supportive of mesonephric origin. Can be mistaken for each other. Irregular glands and intraglandular papillae with mitoses and atypia are key for MDA or its precursor. Remember both MDA and SCTATs are associated with Peutz Jeghers syndrome. More typically the problem is not whether the lesion is malignant but why it is in the odd location. Best

4 explanation is misplaced endocervix from a prior C- section Adenosarcoma of the cervix, atypical polyp, adenomyoma All three can be confused with each other Beware that all three of these entities can have overlapping morphologic features. Smooth muscle fascicles are seen in adenomyoma. Stromal breakdown Adeno and visa versa The key is separating congealed aggregates of stroma from clusters of tumor cells. Rimming of stromal aggregates by reactive epithelium can help identify breakdown. Yolk sac tumor of the vagina Mullerian Adeno A primitive appearing vaginal in a young woman raises this possibility Pyometra Malignant and visa versa May need to resample to confirm or exclude malignancy. Exfoliation artifact Adeno or EIN Note the adjacent stroma will usually demonstrate preservation artifacts and hemorrhage. Transition from normal to abnormal may be gradual and superficial. Atypical polypoid adenomyoma Myoinvasive and visa versa A compact investing smooth muscle component typifies APA. Squamous cell of endometrium Microacinar endometrioid Involvement of adenomyosis by adeno Benign squamous epithelium or metaplasia Microglandular changes in the cervix Myoinvasive adeno The neoplastic squamous epithelium may be papillary and can be remarkably bland appearing in endometrial primaries Collagen stroma separates acini more typical in benign MGH; slightly more amphophilic glands and a soft appearance to the glands in. This cuts both ways. Extensive "vertical" growth or myxoid stromal reaction may indicate myoinvasion. Most important if present deeper than 50 of the myometrial thickness. Glandular epithelium absent Intraperitoneal Metastatic keratin granulomas Histiocytes Neoplastic cells Histiocytes can form sheets with mitotic activity; lack of cell polarity, nuclear folds/grooves, and indistinct edges Ischemic atypia Clear cell or serous Seen most commonly in necrotic polyps; typically there is stromal hyaline change in a zonal

5 configuration reflecting partial ischemic degenerative changes. Adeno with spindle features Carcinosarcoma Juxtaposed well differentiated adeno and plump spindled cells (keratin positive). PECOMA Epithelioid smooth muscle tumor Inherent overlap between the two tumor types. Prominent capillary vascular network and clear or eosinophilic cytoplasm in PECOMA, including ESS- like invasion. HMB- 45 stain helpful but will not always discriminate he two. Myxoid low grade endometrial stromal sarcoma Adenomyosis or adenomyomatosis, leiomyoma Exceedingly bland with numerous normal appearing vessels but the growth pattern is distinctly ESS- like. Leiomyoma in Reed s syndrome STUMP, leiomyosarcoma The key is a diffuse mild hypercellularity and nuclear atypia with prominent nucleoli. If suspected stain for FH. Pregnancy and inflammatory related tubal atypia Tubal intraepithelial or invasive Look for cilia, normal/wild- type p53 expression pattern, low N/C ratio in Arias- Stella like atypias. Secretory cell outgrowths (benign epithelial hyperplasia) Endometrioid/tubal neoplasia These foci closely resemble endometrioid epithelium and have an increased proliferative index but are self limited with normal p53 expression. Tangentially sectioned follicle Stromal tumor Typically small and concentric with indistinct interface with the ovarian stroma; mitoses common. Clear cell and yolk sac s Either and occasionally both in one tumor Classic Schiller- Duval bodies and SALL4 favor YST; HNF1b present in CC s. Spindled Granulosa cell tumor Fibro- thecoma and rarely a smooth muscle tumor Carefully evaluate highly cellular "thecomas", particularly with foci of nested epithelioid areas, high mitotic index. Pericellular reticulin preservation is common in fibo- thecomas. Follicle Cyst Cystic granulosa cell tumor Look for monotonous growth pattern of granulosa cells, call- exner bodies, nuclear grooves in the cystic GCT. Juvenile granulosa cell tumor Retiform Sertoli Leydig cell tumor Small cell, hypercalcemic type Borderline serous tumor Granulosa cell tumors can exhibit considerable nuclear atypia. WT1 positive in small cell. Young patients, retiform pattern in a portion of the lesion, heterologous

6 (RSLCT) Heterologous elements in sex cord tumors Benign germinal matrix in teratomas Extravillous trophoblast Degenerating decidual cells Focal mature villi or an old implantation site in first trimester curetting Localized endometrial proliferation of pregnancy Early complete mole Intraplacental chorio Placental site trophoblastic tumor Epithelioid leiomyoma Mesenchymal dysplasia Histiocytic intervillositis Metastatic, sex cord differentiation, sarcomas Immature teratoma Chorio Can mimic mature extravillous trophoblast and visa versa Intrauterine pregnancy EIN or adeno Hydropic abortus Infarct Exaggerated implantation site Epithelioid trophoblastic tumor in a small sample Partial Mole Unremarkable abortus elements, strong inhibin staining typify RSLCT Hepatic differentiation can mimic breast, the latter is positive for GATA3. Be aware of normal cerebellar differentiation. Immature neuroepithelium typically contains abundant mitoses and apoptosis. No necrosis or marked trophoblastic atypia. Be familiar with pre- villous trophoblast. Cytokeratin stains Mature villi, old implantation site and even recent implantation site (via contamination) can mimic a current intrauterine pregnancy. Found typically in a 'products of conception' specimen. Watch out for stromal basophilia and karyorrhexis, mild concentric thickening of the trophoblastic rim. Sample all infarcts for histologic exam! Mel- Cam/MIB1 staining should highlight over 15% of cells in PSTT. Look for sheets of tumor cells between smooth muscle fascicles. Desmin positive. Cytokeratins may stain both tumors. Abnormally large stem villi. Lack of cistern formation in mesenchymal dysplasia. The histiocytes can be present but unappreciated in early second trimester pregnancy. This can recur and be associated with repeated pregnancy loss. Listeria Conventional intervillositis Acute intervillositis; order appropriate stains for microorganisms Fetal vascular thrombosis (FTV) Chronic villitis, fetal death Chronic villitis can be inconspicuous in villitis mediated villous sclerosis;

7 Maternal- fetal hemorrhage Candida Chorioamnionitis No abnormality Conventional chorioamnionitis remote fetal death will cause widespread villous changes mimicking FTV. Look for pale placenta, bloodless villi, normoblastemia Order a Kleihauer- Betke test Can be lethal if undetected Search for neutrophils on the surface of the cord.