Common Problems in Gynecologic Pathology Michael T. Deavers, M.D. Houston Methodist Hospital, Houston, Texas Common Problems in Gynecologic Pathology Adenocarcinoma in-situ (AIS) of the Cervix vs. Invasive Adenocarcinoma Neuroendocrine Carcinoma of the Cervix Endometrioid Adenocarcinoma vs. Serous Carcinoma of the Endometrium Uterine Mesenchymal Tumors Smooth Muscle Tumors Endometrial Stromal Tumors Ovarian LMP vs. Carcinoma AIS vs. Invasive Adenocarcinoma of the Cervix In many cases not a problem: Frank invasion Cytologic features of carcinoma 1
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AIS vs. Invasive Adenocarcinoma of the Cervix However in some cases: AIS and invasive endocervical adenocarcinoma can have similar cytologic features Desmoplastic reaction may not be present in invasive endocervical adenocarcinoma 3
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AIS vs. Invasive Adenocarcinoma of the Cervix Desmoplastic reaction may not be present Can have similar cytologic features Architecture Vertical extension AIS vs. Invasive Adenocarcinoma of the Cervix Architecture: Complexity Glands varying in size Irregular contours or branching pattern Complex papillary pattern, maze-like glandular pattern AIS vs. Invasive Adenocarcinoma of the Cervix Vertical extension: glands projecting below the level of normal endocervical glands (not necessarily 5 mm) Beware of deep Nabothian cysts and endocervical hyperplasia Stroma, and proximity to thick walled vessels 5
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AIS vs. Invasive Adenocarcinoma of the Cervix What is the significance of early invasion? The incidence of lymph node metastasis is <1% for tumors invading up to 3 mm in depth, without LVI 2.6% for tumors invading up to 3 mm in depth, with LVI 8% for tumors invading >3 mm up to 5 mm in depth 8
Small Cell Carcinoma (Neuroendocrine) ~ 2% of cervical carcinomas ~ 25% disease free survival at 5 yrs (more aggressive than squamous or adenocarcinoma of the cervix ~70%) MDACC no patient > Ib1 or with evidence of LN met survived Median time to relapse 8 mos Lymphatic and hematogenous mets (12 of 21) including liver, lung, bone, and brain Small Cell Carcinoma (Neuroendocrine) Histologic appearance similar to SCC of the lung Sheets, nests, trabeculae Necrosis, apoptosis, mitoses (>10/10 HPF) Small oval to spindle cells with scant cytoplasm HPV 18, 16 9
Small Cell Carcinoma (Neuroendocrine) Can be mixed with squamous carcinoma or adenocarcinoma (~25%) A small SCC component can be associated with aggressive behavior Can be mistaken for poorly differentiated squamous carcinoma or adenocarcinoma Variable staining for epithelial and neuroendocrine markers 10
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Chromogranin Large Cell Carcinoma (Neuroendocrine) Rare, < 1% of cervical carcinomas ~ 32% overall survival (squamous or adenocarcinoma of the cervix ~70%) Recurrences and death from disease occur < 2 years after diagnosis Lymphatic and hematogenous spread including liver, lung, brain, and bone Large Cell Carcinoma (Neuroendocrine) Often are exophytic, up to 6 cm Histologic appearance similar to LCNEC of the lung Organoid pattern Medium to large cells (> 3x lymphocyte) Vesicular to granular nuclei, some with nucleoli Prominent necrosis, apoptosis, and mitoses Neuroendocrine differentiation 12
Large Cell Carcinoma (Neuroendocrine) Can be mixed with squamous carcinoma or adenocarcinoma (~30%) Can be mistaken for poorly differentiated squamous carcinoma or adenocarcinoma HPV 16, 18 13
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Chromogranin 16
Endometrioid Adenocarcinoma vs. Serous Carcinoma of the Endometrium Uterine Serous Carcinoma with a glandular pattern can be mistaken for: hyperplasia in an endometrial polyp complex endometrial hyperplasia with atypia endometrioid adenocarcinoma 17
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p53 p53 p53 24
Serous vs. Endometrioid Ca of the Uterus The cytologic features are inappropriate for the degree of glandular differentiation Nuclear size/shape, N/C ratio, nuclear crowding, loss of polarity, mitotic activity Serous vs Endometrioid Ca of the Uterus Immunohistochemistry p53 p16 PAX8 ER/PR Serous Carcinoma (WT1 -) [Wt Endometrioid Adenoca 90% (null) diffuse positive 30-50% positive 10% patchy 80-90% p16 25
ENDOCERVICAL ADENOCARCINOMA 26
Endocervical Adenocarcinoma vs. Endometrial Serous Carcinoma Fractional curettage CEA High Risk HPV by In-Situ Hybridization p53 Not p16! Common Problems in Gynecologic Pathology Uterine Mesenchymal Tumors Smooth muscle tumors Atypical leiomyoma Smooth muscle tumor of uncertain malignant potential (STUMP) Leiomyosarcoma Endometrial stromal tumors Distinguish from cellular smooth muscle tumors Diagnosis on biopsy 27
Leiomyosarcoma At least two of three major features Spindle cells with diffuse significant (moderate to marked) nuclear atypia > 10 mitoses/10 HPF Coagulative tumor cell necrosis Confirmation of smooth muscle differentiation (if needed) Desmin, Caldesmon, SMMS (SMA) Negative for other markers if needed (S-100, c-kit) Leiomyosarcoma Bxs outside the uterus Diagnostic criteria for malignancy differ in gynecologic and soft tissue SMTs Gyn at least two of three: Coagulative tumor cell necrosis, diffuse significant atypia, 10 mitoses/10 hpf Soft tissue any of the following * : Atypia, > 4 mitoses/50 hpf, coagulative tumor cell necrosis Consider ER, PR, WT-1 (nuclear) for identification of gyn SMTs Leiomyosarcoma Caveat on biopsies Small sample can miss atypia, mitotic activity, necrosis in SMTs (heterogeneity) Smooth muscle neoplasm 28
Smooth Muscle Tumors of the Uterus Diffuse Significant Atypia Detectable at low magnification (4x or 10x objective) Diffuse = found throughout the tumor in multiple sections Significant atypia = moderate to severe (variation in nuclear size, shape, chromatin, nucleoli) Smooth Muscle Tumors of the Uterus Mitotic Count Counted in the most mitotically active areas and the highest count is taken Multiple (x multiple) sets may need to counted in difficult cases [mitotic activity can be heterogeneous] Uncertain figures are excluded Smooth Muscle Tumors of the Uterus Necrosis (Coagulative, Hyalin, Ulcerative) Coagulative: abrupt transition from viable cells to necrotic cells without an interposed zone of hypocellular or hyalinized tissue The interface is important! Individual cell necrosis (pyknosis) does not count 29
Smooth Muscle Tumors of the Uterus Necrosis (Coagulative, Hyalin, Ulcerative) Hyalin: an interposed zone of hypocellular or hyalinized tissue between viable cells and necrotic cells Ulcerative: inflammatory reaction associated with necrosis (often necrotic debris rather than ghost cells) associated with submucosal or prolapsed tumors Smooth Muscle Tumors of the Uterus Low power examination - Atypia - Coagulative necrosis Neither: not leiomyosarcoma Both: leiomyosarcoma Smooth Muscle Tumors of the Uterus Atypia, No coagulative necrosis Mitoses /10HPF < 10 Atypical leiomyoma with low risk of recurrence (STUMP) 10 Leiomyosarcoma 30
Smooth Muscle Tumors of the Uterus Coagulative necrosis, No atypia (At least STUMP) < 10 STUMP Mitoses 10 Leiomyosarcoma 31
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Smooth Muscle Tumors of the Uterus Special Types Epithelioid 34
Smooth Muscle Tumors of the Uterus Epithelioid STUMP Leiomyosarcoma Atypia Mild Moderate or severe Mitoses/10HPF 1 to 3 4 or more Coagulative necrosis Absent Present 35
Smooth Muscle Tumors of the Uterus Epithelioid Desmin +/- SMA, Caldesmon, SMMS-1 Desmin Caldesmon 36
Cellular Smooth Muscle Tumors Atypia, necrosis, mitotic activity same as typical SMTs Differential diagnosis: Endometrial Stromal Tumor Desmin/Caldesmon, CD10 37
Desmin 38
Endometrial Stromal Tumors Is it possible to diagnose an endometrial stromal tumor (ESN, ESS) on an EMB/EMC? The most frequent presenting symptom is vaginal bleeding 39
Endometrial Stromal Tumors DDx: polyp, cellular SMT, EST Small stromal fragments (1 to 2 mm, up to 4mm) can be seen secondary to benign causes including stromal predominant polyps and submucosal leiomyomas attenuating overlying glands in the endometrium Larger stromal fragments ( 5 mm) may be indicative of an EST 40
Endometrial Stromal Tumors Consider IHC (r/o smooth muscle tumor) Remember that distinguishing ESN and ESS requires myometrial interface Clinical and radiographic correlation Ovarian LMP vs. Carcinoma Types of LMPs Serous Mucinous Endometrioid Mixed Clear Cell Transitional (Brenner) 41
Serous LMP A serous neoplasm with increased epithelial proliferation, but without frank destructive stromal invasion. Nuclear atypia and mitotic activity between adenoma and (high grade) carcinoma. Stratification and tufting of epithelial cells. Detachment of cell clusters. Serous LMP High grade serous carcinoma may have an LMP-like appearance 42
Serous LMP vs. Low Grade Serous Carcinoma Clusters of cells and papillae in the stroma in an area > 3mm or Associated desmoplasia 43
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Endometrioid Borderline Tumor (LMP) No uniform criteria Atypical proliferative epithelium in a fibromatous background Mild to moderate atypia Marked = intraepithelial carcinoma Endometrioid Borderline Tumor (LMP) Nests (adenofibroma pattern) Glandular/papillary with crowding (< 5mm if back to back) Microinvasion 3mm 45
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Endometrioid Adenocarcinoma Resembles endometrial endometrioid adenocarcinoma Two forms - Confluent/expansile pattern 5mm - Frankly invasive Haphazard infiltrative pattern Stromal reaction 47
Confluent 48
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Mucinous LMP Gastrointestinal Type Endocervical / Müllerian type Mucinous LMP Gastrointestinal type proliferation of mucinous epithelium with stratification, bridging, and papillae or villous projections goblet cells, neuroendocrine cells variation from area to area (heterogeneous) 50
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Mucinous LMP Carcinoma in-situ (intraepithelial carcinoma) based on marked nuclear atypia; not number of cells Microinvasion: foci of stromal invasion < 5 mm (if the cytologic features are similar to the LMP) Confluent or expansile glandular pattern 5 mm: carcinoma Frank invasion: carcinoma 52
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Common Problems in Gynecologic Pathology Adenocarcinoma in-situ (AIS) of the Cervix vs. Invasive Adenocarcinoma Neuroendocrine Carcinoma of the Cervix Endometrioid Adenocarcinoma vs. Serous Carcinoma of the Endometrium Uterine Mesenchymal Tumors Smooth Muscle Tumors Endometrial Stromal Tumors Ovarian LMP vs. Carcinoma 54