Case 1: Verruciform Lichen Simplex Chronicus

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1 INTERACTIVE MICROSCOPY COURSE GYNECOLOGIC PATHOLOGY Marisa R. Nucci, M.D. Case 1: Verruciform Lichen Simplex Chronicus Lichen simplex chronicus (LSC) is defined as acanthosis, hyperkeratosis and hypergranulosis in response to repeated physical trauma and is often superimposed on an underlying pruritic lesion. While LSC can occur at any age, verruciform LSC seems to occur more commonly in postmenopausal women. Patients may present with pruritis or with a clinically evident lesion. LSC is typically solitary and circumscribed. When verruciform, it appears as a raised white plaque or thickening. LSC is characterized by hyperkeratosis, hypergranulosis and acanthosis with irregular elongation of the rete ridges. Vertically oriented papillary dermal fibrosis is common. When verruciform, there is marked hyperkeratosis with verrucopapillary configuration of the epithelium. Wild type p53 in basal epithelial layers Differentiated vulvar intraepithelial neoplasia Prominent basal atypia often with hyperchromatic nuclei Aberrant keratinocyte maturation Psoriasis Auspitz sign (punctate bleeding with removal of scale) Munro microabscesses (collections of neutrophils in stratum corneum) Confluent parakeratosis and hypogranulosis Uniform acanthosis Edematous papillary dermis Patients may have an increased risk of concurrent/subsequent squamous cell carcinoma.

2 Case 2: Invasive Well Differentiated Gastric Adenocarcinoma (Adenoma Malignum) The very well differentiated form of invasive gastric type adenocarcinoma of the cervix, also termed adenoma malignum and minimal deviation adenocarcinoma is uncommon it represents < 3% of all cervical adenocarcinomas. Patients typically present with abnormal vaginal bleeding or a mucoid/watery discharge. Mean age at presentation is in the fifth decade. These tumors typically form a clinically evident mass, either diffuse enlargement and induration of the cervix or a nodular mass. Adenoma malignum shows haphazard arrangment of irregularly shaped and variably sized glands; claw-shaped and bunny-ear configurations are common. The glands typically deeply invade the cervical wall with minimal stromal reaction; desmoplasia is usually seen in the most deeply invasive glands in the outer aspect of the cervical wall. Proximity to large vessels and perineural invasion is often a clue to the malignant nature of the glands. The glands are lined by columnar cells with abundant mucin rich cytoplasm with a gastric-type phenotype (paler, more eosinophilic cytoplasm). In general, the nuclei are small and basally located with small nucleoli; focal high grade cytologic atypia and mitotic activity is seen, but again usually in the deepest portion of the tumor. HIK1083 positive (gastric type mucin) Patchy positive p16 (HPV negative) ER, PR negative Lobular endocervical glandular hyperplasia Well-demarcated, lobular arrangement of glands No cytologic atypia No stromal response Adenomyoma, endocervical type Well circumscribed, often polypoid Biphasic growth of endocervical-type glands and myomatous stroma Lobular arrangement of glands No cytologic atypia Patients have a poor overall survival with only 30% survival at 2 years.

3 Case 3: Mesonephric Carcinoma of the Cervix This is a rare variant of cervical adenocarcinoma. It occurs over a wide age range affecting both reproductive and menopausal women. Patients typically present with abnormal vaginal bleeding or have an abnormal Papanicolaou smear. The cervix may be uniformly enlarged ( barrel shaped ) or there may be an exophytic lesion (ranging up to 7 cm). If the tumor is small, it is typically located in the lateral wall (correlating to the common location of mesonephric remnants, from which this tumor presumably arises). Mesonephric carcinomas can have a variety of different patterns that may be admixed. These include: 1) the ductal (or pseudo-endometrioid) pattern, which is the most common, and characterized by closely packed large ducts or glands with columnar cells and pseudo-stratified nuclei; 2) the retiform pattern composed of slit-like branching tubules that may have hyalinized papillae; 3) the tubular pattern composed of closely packed small and round tubules many of which contain brightly eosinophilic intraluminal secretions. A background of mesonephric hyperplasia is often present. Some tumors have a malignant spindle cell component resembling sarcoma NOS or endometrial stromal sarcoma; heterologous elements may be present. These are termed malignant mixed mesonephric carcinomas. AE1/AE3, EMA CAM5.2, CK 7 typically positive CD10 (apical), calretinin (nuclear) often positive GATA 3 may be positive Patchy p16 positive CK20, ER, PR, CEA negative Mesonephric Hyperplasia Separation of tubules (no back to back growth) No cytologic atypia or mitotic activity Endocervical Adenocarcinoma, Usual Type Complex glandular architecture Cytoplasmic mucin Apoptosis frequent Associated ACIS CEA usually positive Inhibin, calretinin, GATA 3 negative Cervical Extension of Endometrioid Endometrial Adenocarcinoma

4 Main mass centered in corpus or lower uterine segment Squamous differentiation may be seen ER, PR positive Calretinin, inhibin, GATA3 negative Aggressive behavior may be seen even in low stage tumors; the presence of a malignant spindle cell component is associated with more aggressive behavior. Case 4: Invasive Poorly Differentiated Squamous Cell Carcinoma of Cervix The majority of women with invasive squamous cell carcinoma of the cervix are between years of age. Most patients present with an abnormal Papanicolaou smear or vaginal bleeding. Occasionally, they present with pain or vaginal discharge. If early, tumors may appear as an indurated, ulcerated or elevated granular area. More advances tumors may appear polypoid, nodular or form an ulcerated mass or barrel shaped cervix. Invasive squamous cell carcinoma may be generally separated into the following categories: 1) large cell keratinizing (well differentiated), 2) large cell non-keratinizing (moderately differentiated) or 3) small cell non-keratinizing (poorly differentiated). The latter is composed of nests, cords, sheets of small cells with at most only focal keratinization. CK 7, p63, p16 positive Small cell neuroendocrine carcinoma Nuclear molding with crush artifact of ten present Brisk mitoses, apoptosis, geographic necrosis common p63 negative; chromogranin, synaptophysin often positive Outcome is stage dependent. Five years survival is 95% stage 1A, 70-85% stage IB1 and IIA, 30-50% stage II, 5-15% stage IV.

5 Case 5: Atypical Polypoid Adenomyoma This tumor most commonly occurs in pre- and perimenopausal women with a mean age of 40 years (range 23-73). Patients most commonly present with abnormal vaginal bleeding; some patients present with a polypoid mass protruding through the cervical os. Atypical polypoid adenomyoma most frequently involves the lower uterine segment and occasionally the endocervix. It is usually a solitary and well-circumscribed, bulging, pedunculated or lobulated solid mass with a yellow-tan to grey-white cut surface. The range in size from <1.0 to 6.0 (mean 2.0) cm. This tumor is typically well demarcated (or has only a slightly irregular margin) and is composed of a variably sized and shaped endometrioid type glands, often with a branching pattern, arranged in a vaguely lobulated distribution and set within a fibromyomatous stroma. Squamous morular metaplasia is frequent. Glands: Cytokeratin, ER, PR positive Beta-catenin nuclear positivity (morules > glands) Stroma: SMA, desmin positive CD 34, h-caldesmon, ER, PR variably positive Myoinvasive endometrial adenocarcinoma Lacks lobular architecture Desmoplastic stroma Adenomyoma, endometrioid type Typically uterine corpus Less abundant glandular component associated with variable amount of endometrial stroma Mullerian adenosarcoma Phyllodes-type architecture Intraglandular polypoid projections Periglandular cuffing by cellular stroma There is a high recurrence rate (up to 45%) if treated with curettage or local excision (especially if the glandular component is architecturally complex).

6 Case 6: Clear Cell Borderline Tumor of the Ovary This is a rare tumor that typically occurs in postmenopausal women (mean seventh decade). Patients may present with pelvic pain and symptoms related to a mass. The majority are unilateral masses (mean 6 cm) with a smooth lobulated surface. They have a solid, firm cut surface with a similar yellow to white appearance of a fibroma, but also show a variable number of small cysts imparting a spongy appearance. These tumors are composed of variably sized typically rounded cysts lined by flattened or cuboidal cells showing a variable degree of cytologic atypia and variable amounts of clear to eosinophilic cytoplasm. The cysts are widely or uniformly spaced and are set within a bland fibromatous background. Inspissated eosinophilic material within the cysts is common. Mitotic activity is rare. CK 7, HNF1beta positive ER, PR, WT1 negative Clear cell carcinoma Gross areas of hemorrhage or necrosis Confluent growth of tubules Admixture of other growth patterns (papillary, solid, tubulocystic) Patients have an excellent prognosis. Case 7: Low Grade Serous Carcinoma arising in a Serous Borderline Tumor of the Ovary Low grade serous carcinoma represents <4% of all ovarian carcinomas and ~10% of serous carcinomas. It is highly associated with serous borderline tumors as these two lesions often coexist in up to 75% of cases in variable combinations. Patients are younger than those with high-grade tumors with a mean age in the sixth decade. Patients typically present with abdominal swelling or pain, or symptoms related to a mass. Low-grade serous carcinomas are typically solid and cystic with areas of firm white nodularity.

7 The background serous borderline tumor usually has a micropapillary growth. The areas of invasion (>5 mm to be called carcinoma rather than microinvasion) may have a variety of different patterns floating within cleft-like spaces including: micropapillae, small papillae, small or large nests, or inverted macropapillae. The cells show low-grade nuclear atypia with less than 3X variation in size with visible cherry red nucleoli. Mitotic activity should not exceed 12 per 10 high power fields (useful criterion when considering other features to confirm grading). Psamomma bodies are frequent and when abundant (>75% of tumor nests represent calcifications without epithelium) the term psammocarcinoma has been applied. Necrosis and pleomorphism are uncommon. PAX8, WT-1, ER, PR positive Wild type pattern of p53 Patchy or negative p16 High-grade serous carcinoma 3X variation in nuclear size > 12 mitoses/10 HPF (less if treated with neoadjuvant chemotherapy) p53 either strongly, diffusely positive or absent (deletion mutation) Patients with low-grade serous carcinoma typically have an indolent course with progressive disease. 5-year survival is 40% and outcome at 10 years is comparable to high-grade serous carcinoma. Case 8: Small Cell Carcinoma Hypercalcemic Type (SCCOH) SCOOH is thankfully rare with an age range from the first to the fifth decade (mean 24 years). Patients typically present with abdominal distention and/or pain or they may present with symptoms related to bowel obstruction (due to intraabdominal spread). Approximately two thirds of patients are hypercalcemic and may also present with fatigue, lethargy, polydipsia and polyuria. SCCOH typically presents as a large (mean 15 cm) unilateral solid (or solid and cystic) mass with a lobulated or nodular external surface and a creamy tan to yellow fleshy cut surface. The tumor commonly has areas of hemorrhage and necrosis. The tumor cells most commonly have a diffuse, sheet-like growth pattern; nested, trabecular, corded and single-file growth may also be seen. Follicle-like spaces of variable size are characteristic but only present in 80% of cases. The intervening stroma

8 can be edematous, myxoid or hyalinized. In approximately 15%, glands or cysts lined by mucinous epithelium may be seen. The tumor cells are small and round with scant cytoplasm, hyperchromatic nuclei and small nucleoli. In ~50% of cases there is a large cell component with the cells having moderate to abundant eosinophilic cytoplasm, large vesicular nuclei, and prominent nucleoli. CAM5.2 > AE1/AE3 positive EMA may be positive (large cell component) p53 and p16 diffusely positive WT1, CD 10, calretinin usually positive Neuroendocrine markers may be positive Inhibin, desmin, CD 99, S100 negative Granulosa cell tumor, adult and juvenile type Typically stage I No hypercalcemia; may have estrogenic manifestations Nuclear grooves (if adult) More conspicuous follicle like spaces (if juvenile) Fibrothecomatous stroma Inhibin positive, EMA negative Small cell carcinoma, pulmonary type (primary) Typically older age (peri/postmenopausal) No hypercalcemia Commonly associated with other primary epithelial malignancy Rare to absent follicle like spaces Unusual to have large cells CK 20 dot like positivity Lymphoma Lacks follicle like spaces Keratin, EMA, WT-1 negative Lymphoid marker positive Intraabdominal Desmoplastic Small Round Cell Tumor Nested growth Desmoplastic stroma EMA and desmin positive Patients have a dismal outcome regardless of stage with only 10% overall survival. Two thirds of patients die within 5 years.

9 Case 9: Adult Granulosa Cell Tumor Adult granulosa cell tumors can occur at any age, but are most common in peri and postmenopausal women (median 50 years). Estrogenic manifestations occur in up to 2/3 of patients who frequently present with menometrorrhagia or postmenopausal bleeding (associated with risk for concurrent endometrial neoplasia). Isosexual pseudoprecocity may occur in prepubertal girls. Less commonly, the tumor is androgenic and can be virilizing (10%) or presents with hemoperitoneum secondary to rupture (10%). Gross Findings They are typically are unilateral (>95%) and can range from microscopic incidental findings to remarkably large masses (> 20 cm), with an average size of 12 cm. They are usually solid, or solid and cystic with a yellow to white cut surface. Rarely they form a unilocular or multilocular smooth walled cyst filled with serous to sanguineous fluid. Microscopic Findings An admixture of different patterns may be seen. A diffuse or solid growth of cells is most frequent, followed by trabecular (cords), microfollicular, macrofollicular, and insular patterns; gyriform, watered silk and pseudo-papillary patterns are less common. Call-Exner bodies, the hallmark of the microfollicular pattern, are microcystic spaces that can contain deeply eosinophilic basal lamina material. The presence of Call-Exner bodies in the multiple layers of granulosa cells in a cystic tumor is helpful in establishing the diagnosis. The granulosa cell proliferation frequently has a fibrothecomatous background, which can be variably abundant. The neoplastic granulosa cells generally have scant cytoplasm and round to oval or angular nuclei with a longitudinal groove. Nuclear grooves, however, are not limited to AGCT (also seen in Brenner tumors, some Sertoli cell tumors, cellular fibromas and transitional cell carcinomas) and may be present only in scattered cells in some cases. Mitotic activity is variable, but it is usually < 5 mitoses per 10 HPFs. Rare findings include: a) hyperchromatic, irregular, enlarged nuclei (bizarre nuclei) typically with a focal distribution in the tumor; b) extensive luteinization of the cells (luteinized AGCT) characterized by abundant eosinophilic to vacuolated cytoplasm and oval to round nuclei lacking nuclear grooves; c) hepatic differentiation with cells arranged in acini, nests and trabeculae. Histochemical and Immunohistochemical findings Inhibin, calretinin, CD 99, CD 56, SF1, FOXL2 positive AE1/AE3, CAM 5.2, CD 10, S100, WT1, SMA, desmin, ER, PR variably positive EMA, CK7 negative Reticulin surrounds groups of cells Hepatic differentiation: CEA, EMA, CAM5.2, α-fetoprotein positive but negative for inhibin and vimentin.

10 Endometrioid adenocarcinoma with sex-cord like differentiation: Squamous and/or mucinous differentiation, association with endometriosis; EMA positive, CK 7 negative Transitional cell carcinoma: Often spread beyond ovary, high-grade cytologic atypia and necrosis, associated serous component; EMA positive Carcinoid tumor: Salt and pepper chromatin; chromogranin, synaptophysin positive Fibroma/Thecoma: Sex cord elements, if present, comprise < 10% of tumor; lack of nested pattern on reticulin stain Sex cord tumor with annular tubules: Associated with Peutz-Jegher syndrome, complex annular tubules with peripheral nuclei, dense deposits of basement membrane-like material Endometrioid stromal sarcoma: Characteristic spiral-arteriole-like vascular pattern, lack of nuclear grooves; CD 10 positive, inhibin negative Stage is the most important prognostic factor. Patients with stage I tumors have a 10 year survival rate of 84-87% compared to 38 to 60% for those with advanced stage disease. These tumors have a propensity for late recurrences, with an average time to recurrence of 5 years and some developing up to 30 years after initial diagnosis. Pathologic factors such as size (>5 cm), mitotic activity (>5 mitoses/10 HPFs), and tumor rupture have been associated with a worse prognosis. Serum levels of inhibin may be used to monitor tumor recurrence. Selected References Case 1: Verruciform vulvar lesions 1) Nascimento AF et al. Vulvar acanthosis with altered differentiation: a precursor to verrucous carcinoma? Am J Surg Pathol 2004;28: ) Reich O et al. Recurrent verruciform xanthoma of the vulva. Int J Gynecol Pathol 2004;23: ) Fite C et al. Vulvar verruciform xanthoma: ten cases associated with lichen sclerosus, lichen planus or other conditions. Arch Dermatol 2011;147: Case 2: Invasive Well Differentiated Gastric Adenocarcinoma (Adenoma Malignum) 4) McKelvey JL, Goodlin RR. Adenoma malignum of the cervix. Cancer 1963;16: ) Silverberg SG, Hurt WG. Minimal deviation adenocarcinoma ("adenoma malignum") of the cervix: a reappraisal. Am J Obstet Gynecol 1975;121: ) Kaku T, Enjoji M. Extremely well-differentiated adenocarcinoma ("adenoma malignum") of the cervix. Int J Gynecol Pathol 1983;2: ) Kaminski PF, Norris HJ. Minimal deviation carcinoma (adenoma malignum) of

11 the cervix. Int J Gynecol Pathol 1983;2: ) Michael H, Grawe L, Kraus FT. Minimal deviation endocervical adenocarcinoma: clinical and histologic features, immunohistochemical staining for carcinoembryonic antigen, and differentiation from confusing benign lesions. Int J Gynecol Pathol 1984;3: ) Gilks CB, Young RH, Aguirre P, DeLellis RA, Scully RE. Adenoma malignum (minimal deviation adenocarcinoma) of the uterine cervix. A clinicopathological and immunohistochemical analysis of 26 cases. Am J Surg Pathol 1989;13: Case 3: Mesonephric Carcinoma of the Cervix 10) Clement PB et al. Malignant mesonephric neoplasms of the uterine cervix. A report of eight cases including four with a malignant spindle cell component. Am J Surg Pathol 1995;19: ) Silver SA et al. Mesonephric adenocarcinomas of the uterine cervix: a study of 11 cases with immunohistochemical findings. Am J Surg Pathol 2001;25: ) Bague S et al. Malignant mesonephric tumors of the female genital tract: a clinicopathologic study of 9 cases. Am J Surg Pathol 2004;28: Case 4: Invasive Squamous Cell Carcinoma of Cervix vs Small Cell Carcinoma 13) Houghton O et al. The expression and diagnostic utility of p63 in the female genital tract. Adv Anat Pathol 2009;16: ) Li JD et al. A clinicopathologic aspect of primary small cell carcinoma of the uterine cervix: a single-centre study of 25 cases. J Clin Pathol 2011;64: ) Carlson JW et al. Biomarker assisted diagnosis of ovarian, cervical and pulmonary small cell carcinoma: the role of TTF-1, WT-1, and HPV analysis. Histopathology 2007;51: Case 5: Atypical polypoid adenomyoma 16) Horita A et al: Immunohistochemical characteristics of atypical polypoid adenomyoma with special reference to h-caldesmon. Int J Gyncol Pathol 2011;30: ) Ota S et al. Molecular pathology of atypical polypoid adenomyoma of the uterus. Hum Pathol 2003;34: ) Longacre TA et al. Atypical polypoid adenomyofibromas (atypical polypoid adenomyomas) of the uterus: A clinicopathologic study of 55 cases. Am J Surg Pathol 1996; 20: ) Soslow RA et al. Atypical polypoid adenomyofibroma (APA) versus welldifferentiated endometrial carcinoma with prominent stromal matrix: an immunohistochemical study. Int J Gynecol Pathol 1996;15: ) Young RH et al. Atypical polypoid adenomyoma of the uterus. A report of 27 cases. Am J Clin Pathol 1986;86: Case 6: Clear Cell Borderline Tumor of the Ovary 21) Zhao C et al. Pathogenesis of ovarian clear cell adenofibroma, atypical prolifertive (borderline) tumor, and carcinoma: clinicopathologic features of

12 tumors with endometriosis or adenofibromatous components support two related pathways of tumor development J Cancer 2011;2: ) Bell DA et al. Benign and borderline clear cell adenofibromas of the ovary Cancer 1985;56: Case 7: Low Grade Serous Adenocarcinoma arising in a Borderline Tumor of Ovary 23) Diaz-Padilla I et al. Ovarian low grade serous carcinoma: a comprehensive update. Gynecol Oncol 2012;126: ) Silva EG et al. Patterns of low-grade serous carcinoma with emphasis on the nonepithelial-lined spaces pattern of invasion and the disorganized orphan papillae. Int J Gynecol Pathol 2010;29: ) Dehari R et al. The development of high-grade serous carcinoma from atypical proliferative (borderline) serous tumors and low-grade micropapillary serous carcinoma; a morphologic and molecular genetic analysis. Am J Surg Pahol 2007; ) Malpica A et al. Interobserver and intraobserver variability of a two-tier system for grading ovarian serous carcinoma. Am J Surg Pathol 2007;31: Case 8: Small Cell Carcinoma Hypercalcemic Type 27) McCluggage WD et al. An immunohistochemical analysis of ovarian small cell carcinoma of hypercalcemic type. Int J Gynecol Pathol 2004;23: ) Riopel MA et al. Inhibin and epithelial membrane antigen immunohistochemistry assist in the diagnosis of sex cord stromal tumors and provide clues to the histogenesis of hypercalcemic small cell carcinomas. Int J Gynecol Pathol 1998;17: ) Young RH et al. Small cell carcinoma of the ovary, hypercalcemic type. A clinicopathologic analysis of 150 cases. Am J Surg Pathol 1994;18: Case 9: Adult Granulosa Cell Tumor 30) Sun HD et al. A long term followup study of 176 cases with adult type ovarian granulosa cell tumors. Gynecol Oncol 2012;124: ) Irving JA et al. Granulosa cell tumros of the ovary with a pseudopapillary pattern: a study of 14 cases of an unusual morphologic variant emphasizing their distinction from transitional cell neoplasms and other papillary ovarian tumors. AMSP 2008;32: ) Villella J; Herrmann FR, Kaul S, Lele S, Marchetti D, Natiella, J, Odunsi K, Mhawech-Fauceglia P. Clinical and pathological predictive factors in women with adult-type granulosa cell tumor of the ovary. Int J Gynecol Pathol. 2007;26: ) Fox H. Pathologic prognostic factors in early stage adult-type granulosa cell tumors of the ovary. Int J Gynecol Cancer 2003; 13: ) Ahmed E, Young RH, Scully RE. Adult granulosa cell tumor of the ovary with foci of hepatic cell differentiation: a report of four cases and comparison with two cases of granulosa cell tumor with Leydig cells. Am J Surg Pathol. 1999;23:

13 35) Young RH, Oliva E. Scully RE. Luteinized adult granulosa cell tumors of the ovary: a report of four cases. Int J Gynecol Pathol. 1994;13: ) Nakashima M, Young RH, Scully RE. Androgenic granulosa cell tumors of the ovary. A clinicopathologic analysis of 17 cases and review of the literature. Arch Pathol Lab Med. 1984;108:786-91