| Abstract|| |
Over the years, immunohistochemistry has emerged as a powerful tool for a more precise diagnosis of certain tumors in gynecologic oncopathology and resolving certain diagnostic dilemmas with significant treatment implications. Certain specific immunohistochemical (IHC) markers have been useful in the more correct identification of rare tumors, characterized by specific molecular signatures. Immunohistochemistry has also been useful in the identification of underlying genetic events, characterizing various tumors, as well as precancerous lesions. This review will focus upon the judicious application of various IHC antibody markers in gynec oncopathology, including authors' experience during “sign-outs” and especially during interaction with other oncology colleagues within the institutional disease management group. The updated references were retrieved from PubMed.
Keywords: Diagnostic dilemmas in gynec pathology, gynec oncopathology, immunohistochemistry
|How to cite this article:|
Rekhi B. Role of immunohistochemistry in gynec oncopathology including specific diagnostic scenarios with associated treatment implications. Indian J Pathol Microbiol 2020;63, Suppl S1:70-80
|How to cite this URL:|
Rekhi B. Role of immunohistochemistry in gynec oncopathology including specific diagnostic scenarios with associated treatment implications. Indian J Pathol Microbiol [serial online] 2020 [cited 2023 Jun 7];63, Suppl S1:70-80. Available from: https://www.ijpmonline.org/text.asp?2020/63/5/70/279549
| Introduction|| |
Invariably several tumors involving the female genital tract are diagnosed by time-honored morphological analysis, using the classic hematoxylin and eosin-stained microsections. Over the years, there has been an upsurge in the utilization of various immunohistochemical (IHC) markers in gynecologic oncopathology, especially in resolving certain diagnostic dilemmas, associated with significant treatment implications. This review will focus upon the judicious application of certain IHC makers in various clinicopathological scenarios of gynecologic oncopathology, including ovarian cancers, endometrial cancers, cervical lesions, and gestational trophoblastic tumors, especially those influencing significant treatment decisions.
Foremost, it is a differentiation of primary ovarian versus metastatic adenocarcinoma, especially from sites such as colorectum, in cases where in tumors are identified in both, ovary and colorectum and exact diagnosis is necessary for deciding upon a specific chemotherapy regimen (fluorouracil-based chemotherapy for colorectal primary vs cisplatin-based chemotherapy for ovarian primary). The recommended IHC panel in such a scenario would include cytokeratin (CK) 7, CK20, CDX2, carcinoembryonic antigen (CEA), estrogen receptor (ER)/progesterone receptor (PR), and PAX8 (a marker of Müllerian differentiation). CK7 negative (–)/CK20 positive (+), CEA+, CDX2+ are indicative of colorectal primary (mostly left-sided tumors are CK20+/CK7–). On the other hand, CK7+, CK20–, PAX8+, CA125+ (membranous), and ER/PR+ are indicative of an ovarian primary [Figure 1].,, The diagnosis of metastatic adenocarcinomas from pancreaticobiliary tract can be possibly reinforced with CA19.9 (although not very specific) and from the breast by utilizing gross cystic disease fluid protein (GCDFP), mammaglobin, and GATA3, the latter especially in triple-negative carcinomas that lack the expression of specific markers of mammary origin. GATA3, GCDFP, and mammaglobin are expressed in breast carcinomas, whereas Wilm's tumor (WT) 1 is expressed by ovarian serous carcinomas. It is noteworthy that GATA3 is a useful marker for characterizing not only breast and urothelial carcinomas but also renal tumors, germ cell tumor (GCT), mesotheliomas, and paragangliomas.
|Figure 1:Case of serous adenocarcinoma ovary metastasizing to the rectum (a and b). (a) Unremarkable rectal mucosa (upper left) with deposits of serous adenocarcinoma (right) (H and E, ×200). (b) Higher magnification: papillary serous adenocarcinoma (H and E, ×400). Immunohistochemical (IHC) results (c-f). (c) Tumor cells showing CK7 positivity, sparing rectal mucosa (upper left) (diaminobenzidine, ×200). (d) CK20 negativity in the tumor, positivity in rectal mucosa (diaminobenzidine, ×200). (e) WT1 positivity within the tumor (diaminobenzidine, ×200) (f). CA125 positivity (diaminobenzidine, ×200)|
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Diffuse WT1 and p53 immunostaining reinforce high-grade serous adenocarcinoma and adenocarcinoma in situ of the fallopian tube (“p53 signature” with high Ki-67/MIB1 co-expression) [Figure 2]a, [Figure 2]b, [Figure 2]c. It is noteworthy that diffuse and intense p53 immunoreactivity in more than 70% tumor cells or complete loss (null type) is interpreted as p53 “mutation type” expression. Focal staining indicates its “wild type” expression. Mucinous neoplasms, including carcinomas of the ovary, are mostly considered as extra ovarian in terms of their origin. CK20+, CK7-, CDX2+, CEA+ would indicate colorectal primary, whereas CK7+, CK20+, CEA+, and p16INK4+ would indicate endocervical differentiation. The recommended panel is CK7, CK20, CEA, CDX2, and PAX8. Mucinous carcinomas are invariably not chemosensitive.,,
|Figure 2: High-grade serous adenocarcinoma. (a) Markedly pleomorphic cells with interspersed frequent mitotic figures (H and E, ×400). IHC results (b and c). (b) Diffuse p53 immunostaining (mutation type), (diaminobenzidine, ×400). (c) Diffuse WT1 positivity, (diaminobenzidine, ×400). (d) Metastatic clear cell carcinoma in the lymph node in a patient treated initially as high-grade serous carcinoma, elsewhere (H and E, ×100). (e) Tumor cells showing “hob nailing,” vacuolated cytoplasm and eosinophilic bodies (H and E, ×200) (f) Napsin A positivity (diaminobenzidine, ×200), WT1 was negative|
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In cases of ascites, as a result of a suspected ovarian adenocarcinoma, tumor cells can be differentiated from mesothelial cells with the help of antibody markers, such as BerEP4, PAX8, and calretinin., Mesothelioma can be differentiated from reactive mesothelial cells, by desmin, considering the former in most cases shows a negative expression, while the latter marker shows diffuse positive immunoexpression. Epithelial membrane antigen (EMA) is another marker that can be utilized to resolve this diagnostic dilemma. The recommended panel is BerEP4 or MOC31, PAX8, calretinin, and desmin. Whereas an advanced high-grade serous carcinoma of the ovary is treated by cisplatin-based chemotherapy, mesothelioma is treated with surgical debulking, followed by intraabdominal chemotherapy.
Among primary ovarian tumors, the most frequent, high-grade serous carcinomas are invariably immunoreactive for WT1. At the same time, mesothelial cells display WT1 immunoexpression. This is important especially when one is evaluating effusion samples. Clear cell carcinomas (CCCs) are consistently positive for Napsin A and hepatocyte nuclear factor-1β (HNF-1β)., It is significant to differentiate both tumors, considering CCC ovary is relatively not sensitive to chemotherapy, in contrast to an HGSC and an endometrioid adenocarcinoma [Figure 2]d, [Figure 2]e, [Figure 2]f and [Figure 3]. Endometrioid carcinomas are consistently positive for ER and PR. Serous carcinomas are also variably immunoreactive to ER and PR, unlike CCCs, Uncommonly, malignant mixed müllerian tumors (MMMTs) can be identified in the ovary, similar to the uterine counterparts, wherein epithelial and mesenchymal markers can be applied for reinforcing carcinomatous and sarcomatous components, respectively [Figure 4]. Cases with advanced tumor stage, suboptimal cytoreduction, and predominant sarcomatous component are likely to behave more aggressively.
|Figure 3: Case of pelvic mass, initially diagnosed as a low-grade adenocarcinoma, elsewhere. (a) Tumor cells arranged in a solid pattern, exhibiting marked atypia and interspersed mitotic figures (H and E, ×200). (b) WT1 positivity (DAB, ×400). (c) PA × 8 positivity (DAB, ×400). (d) Complete absence of p53 immunostaining (null mutation type). (e) High Ki67/MIB1 immunostaining further reinforcing high-grade serous adenocarcinoma (DAB, ×400)|
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|Figure 4: A 61 year-old-lady with adnexal tumor; malignant mixed müllerian tumor (MMMT) with heterologous elements (a and b). (a) Cellular tumor with areas of necrosis (H and E, ×100). (b) Areas of glandular differentiation (H and E, ×200). Inset: rhabdomyoblastic de-differentiation (H and E, ×400). IHC results (c-e). (c) Pan cytokeratin (AE1/AE3) highlighting carcinomatous component (diaminobenzidine, ×400). (d) Desmin highlighting rhabdomyoblastic cells (diaminobenzidine, ×400). (e) Myogenin positivity, reinforcing rhabdomyoblastic de-differentiation (diaminobenzidine, ×400)|
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An ovarian sex cord-stromal tumor expresses markers, such as inhibin and calretinin that are negative in a carcinoma [Figure 5]. OCT4 is a sensitive and specific marker for GCTs. A combination of CD30 and CKIT/CD117 is useful in differentiating an embryonal carcinoma from a dysgerminoma, wherein CD30 is positively expressed in embryonal carcinoma and CD117 is positively expressed in a dysgerminoma. Positive OCT4 and CD30 immunoexpression in cases of embryonal carcinoma are useful in differentiating it from a surface epithelial carcinoma. Glypican 3 is a useful marker for yolk sac tumors [Figure 6]. It is essential to differentiate a malignant GCT from ovarian carcinoma, in view of different chemotherapy regimens for either tumor. A GCT is relatively highly chemosensitive. CCC ovary can be a diagnostic mimic of a yolk sac tumor, and rarely, a metastatic renal cell carcinoma. Whereas a metastatic renal cell carcinoma is immunoreactive to CD10 and PAX8, a yolk sac tumor is immunopositive to glypican 3.,
|Figure 5: (a) Adult granulosa cell tumor with call exner bodies and intranuclear grooves (H and E, ×200). (b) Calretinin (nuclear and cytoplasmic) positivity (diaminobenzidine, ×400). (c) Focal inhibin positivity (diaminobenzidine, ×400). (d) Steroid cell tumor of the ovary, including cells showing granular to vacuolated/frothy cytoplasm (H and E, ×200). (e) Calretinin positivity (diaminobenzidine, ×400). (f) Focal inhibin positivity (diaminobenzidine, ×400)|
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|Figure 6: (a) Metastatic germ cell tumor (including a coexisting granuloma) in a case of the lymph node with an abdominal mass (H and E, ×400). (b) Diffuse OCT3/4 positivity, reinforcing diagnosis of germ cell (dysgerminoma) in this case. (c) Classical features of yolk sac tumor (H and E, ×200). (d) Tumor cells displaying focal glypican 3 positivity (diaminobenzidine, ×400)|
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Uncommonly, a round cell tumor is identified in an ovary. A recommended panel of IHC markers in such cases should include EMA, pan-cytokeratin (AE1/AE3), WT1, MIC2/CD99, inhibin, and calretinin. A small cell carcinoma ovary can be differentiated from a metastatic small cell carcinoma, including lung that expresses synaptophysin, chromogranin, and thyroid transcription factor (TTF1). A small cell carcinoma ovary is positive for epithelial markers, CD10, WT1, INI1, calretinin, and vimentin, while negative for inhibin, S100P, TTF1, and inhibin. It is also associated with hypercalcemia, treated on the lines of an ovarian carcinoma, combined with etoposide and an aggressive clinical course, especially in tumors with a “rhabdoid” phenotype MIC2, Fli1, and further molecular testing (EWSR1 rearrangement or EWS-FLI testing) would help in identifying rare cases of ovarian Ewing sarcoma, which is similarly treated with chemotherapy of Ewing sarcoma, at skeletal sites, but associated with an aggressive clinical course., Leukocyte common antigen (LCA) CD20 and myeloid peroxidase (MPO) would help in identifying a hematolymphoid neoplasm involving the ovary, associated with significant patient triaging (for bone marrow and lymph node assessment) management and therapeutic implications.,
An endometrioid carcinoma (ER+, vimentin+) can be differentiated from an endocervical-type carcinoma (CEA+, p16INK4+) using four IHC markers such as ER, vimentin, CEA, and p16IK4A in many cases [Figure 7]., However, this is not an absolute way of differentiating both the tumors. It is imperative to know tumor epicenter (cervical or endometria) in situ ations of endometrial versus endocervical tumors.
|Figure 7: (a) Endocervical-type adenocarcinoma (H and E, ×2000). IHC results (b and c). (b) Diffuse p16INK4A positivity (diaminobenzidine, ×400). (c) Luminal and focal cellular positivity for CEA (diaminobenzidine, ×400). (d) Endometrioid adenocarcinoma (H and E, ×200) IHC results (e and f). (e) Significant ER positivity (diaminobenzidine, ×200). (f) Vimentin positivity within tumor cells (diaminobenzidine, ×200)|
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Uterine serous carcinomas are treated more aggressively than endometrioid adenocarcinomas, in view of their relatively aggressive clinical behavior, including more propensity for recurrences and extrauterine spread. These tumors invariably show diffuse p53 immunostaining (mutation type) and diffuse p16INK4A immunostaining, in contrast to endometrioid carcinomas that show a relatively higher level of ER and PR immunoexpression, along with vimentin and β-catenin (nuclear) immunostaining, coupled with the loss of PTEN.,, Unlike ovarian serous carcinomas, uterine serous carcinomas much less frequently or rather rarely express WT1. High level of microsatellite instability as a result of mismatch repair defects (MMR-D) is observed in nearly 20% endometrial cancers, including sporadic and those associated with Lynch syndrome. MMR-D can be immunohistochemically identified by paired loss of expression of MLH1, PMS2 or MSH2, and MSH6. Certain endometrial carcinomas showing MMR defects are associated with uncommon clinical presentations and a relatively aggressive clinical course. MMMTs are included in the category of carcinomas and treated similar to carcinomas. At times, these tumors show divergent differentiation (heterologous elements), such as rhabdomyoblastic, osteo and chondrosarcomatous components, with relatively more aggressive clinical outcomes, especially tumors harboring high-grade, serous, and CCC components [Figure 8].
|Figure 8: MMMT of the endometrium. (a) Malignant tumor with glandular architecture (H and E, ×200). (b) Areas of sarcomatous differentiation (H and E, ×200). (c) Distinct rhabdomyoblastic cells (heterologous differentiation) (H and E, ×400). (d) Desmin highlighting rhabdomyoblasts (diaminobenzidine, ×400)|
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A uterine endometrial stromal neoplasm can be differentiated from smooth muscle by CD10, SMA, desmin, and h-caldesmon, the latter three are mostly diffusely positive in smooth muscle neoplasms. An endometrial stromal sarcoma (ESS) (low-grade) invariably expresses CD10 and PR, diffusely [Figure 9]a, [Figure 9]b, [Figure 9]c, [Figure 9]d. Lately, certain ESS lacking CD10 immunoexpression but showing diffuse cyclin D1 positivity (high-grade) have been identified [Figure 9]e, [Figure 9]h., ESSs can show sex cord differentiation that can be reinforced by calretinin and inhibin immunostaining [Figure 10]. Lately, certain uterine mesenchymal tumors resembling sex cord tumors (UTROSCT) have been described. The lack of an index of suspicion and awareness of this entity can lead to a mistaken diagnosis of adenocarcinoma, which constitutes their differential diagnosis. Despite their overlapping IHC profile with ovarian sex cord tumors, lack of FOXL2 and DICER mutations (noted in ovarian sex cord tumors), as reported in some studies, suggests these might be genetically different from ovarian sex cord tumors.
|Figure 9: Low-grade ESS (a-b). (a) Tumor composed of short spindly cells with interspersed blood vessels (H and E, ×200). (b) Periateriolar arrangements (H and E, ×400). IHC results (c-d). (c) Diffuse CD10 immunopositivity (diaminobenzidine, ×200) (d) PR positivity (diaminobenzidine, ×400). High-grade ESS (e-f). (e) Spindle cells with intercellular collagen (H and E, ×200). (f) Diffuse cyclinD1 positivity (CD10, focal) (diaminobenzidine, ×200). (g) Recurrence (H and E, ×400). Inset: YWHAE rearrangement (red-green split signals) (DAP1, ×1000) (h) Cyclin D1 positive recurrent ESS (diaminobenzidine, ×400)|
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|Figure 10: ESS with sex cord differentiation (a and b). (a) Tumor showing features of ESS H and E, ×200. (b) Intervening tubular structures, reminiscent of sex cord differentiation including in the inset (H and E, ×400). IHC results (c-g). (c) Diffuse CD10 immunopositivity (diaminobenzidine, ×400). (d) PR positivity (diaminobenzidine, ×400). (e) MIC2 highlighting interspersed sex cord elements (diaminobenzidine, ×400). (f) Calretinin highlighting sex cord elements (diaminobenzidine, ×400). (g) Focal, distinct inhibin positivity (diaminobenzidine, ×400)|
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Another mesenchymal tumor that constitutes the differential diagnosis of ESS and smooth muscle tumor is a perivascular epithelioid cell tumor (PEComa), which is composed of epithelioid and spindle cells with granular to vacuolated cytoplasm arranged around blood vessels, including nesting arrangement. The cells show melanocytic and myogenic differentiation. In the form of immunoreactivity for human melanoma black (HMB) 45, Melan A and MART-1, along with co-expression of SMA, desmin.,
Immunohistochemistry has been useful in uncovering certain rare tumors, such as solitary fibrous tumor (SFT), in the female genital tract with the help of a recently discovered immunomarker, signal transducer and activator of transcription 6 (STAT6), which is consistently expressed within this tumor, characterized by a specific gene fusion, NAB2-STAT6.,
A proximal-type epithelioid sarcoma, in sites, such as vulva can be mistakenly diagnosed as a carcinoma, in view of morphological features, as well as immunoexpression of epithelial antibody markers, such as cytokeratin and EMA, leading to inadvertent treatment with chemotherapy. The loss of INI1 and co-expression of CD34 (in a subset of such tumors) is useful in the distinction of this tumor from a metastatic carcinoma [Figure 11]., Epithelioid sarcomas, irrespective of their subtypes, are invariably treated with complete surgical excision and radiation therapy for locoregional clearance, considering these are relatively chemosensitive. Unlike, a patient harboring a metastatic carcinoma would be a candidate for specific chemotherapy.
|Figure 11: Vulvar tumor. Epithelioid sarcoma, proximal-type. (a) Cut surface of vulvectomy specimen displaying gray-white tumor in the dermis. (b) Microscopy: tumor composed of cells with polygonal shapes, prominent nucleoli and moderate to abundant eosinophilic cytoplasm, forming “rhabdoid-like “inclusions (H and E, ×200). (c) CK positivity (diaminobenzidine, ×400). (d). Diffuse CD34 positivity (cytoplasmic membranous) (diaminobenzidine, ×400). (e) Tumor cells displaying loss of INI1. Interspersed nuclei and endothelial cells showing intranuclear staining (control) (diaminobenzidine, ×400)|
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MIB1/Ki67 is useful in reinforcing the diagnosis of cervical intraepithelial neoplasia (CIN III) that shows full-thickness positive staining. The diffuse/“block staining” pattern of p16INK4 is seen in a high-grade squamous intraepithelial lesion (SIL)/CIN associated with high-risk human papillomavirus (HPV) infection than its mimic, that is, atrophy [Figure 12].
|Figure 12: Cervical biopsy. (a) Significantly dysplastic, dyskeratotic squamous epithelium (H and E, ×200). (b) Diffuse p16INK4 (block-staining pattern) reinforcing a markedly dysplastic (CIN/SIL) epithelium (diaminobenzidine, ×400). Vaginal biopsy (c-f). (c) Full-thickness dysplasia with Koilocytic atypia (H and E, ×200). (d) Koilocytic atypia (H and E, ×400). (e) Diffuse p16INK4A immunostaining (block-staining pattern). (f) Ki67/MIB1 highlighting cells of the full thickness, reinforcing in situ carcinoma (diaminobenzidine, ×400)|
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While most endocervical adenocarcinomas display p16INK4A and CEA immunostaining, certain unusual patterns of cervical adenocarcinoma include clear cell, gastric-type, minimal deviation, serous, MMMT, and mesonephric types. A neuroendocrine carcinoma of cervix (NECC) can be differentiated from a poorly differentiated (PD) or basaloid squamous cell carcinoma (SCC), especially on a limited biopsy by CD56/neural cell adhesion molecule (NCAM), synaptophysin, and chromogranin that are variably positive in the NECC, while p63 and p40 are more diffusely expressed by PDSCC. Rare case scenarios of metastatic tumors can be resolved by the application of certain tumor-specific markers [Figure 13] and [Figure 14]. NECCs of the cervix also display p16INK4 immunopositivity.
|Figure 13: Cervical biopsy in a case of posttreatment in breast carcinoma (a) Focus of tumor cells in the proximity of strips of the benign endocervical lining (H and E, ×200). (b) Tumor cells showing epithelioid appearance and focal intracytoplasmic vacuoles, suggestive of metastatic lobular carcinoma (H and E, ×400). (c) GATA immunostaining is indicative of metastatic breast carcinoma (in this case) (DAB, ×400). (d) Mammaglobin immunostaining, further reinforcing metastatic breast carcinoma in this case (DAB, ×400)|
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|Figure 14: Cervix biopsy. High-grade neuroendocrine carcinoma. (a) Tumor cells showing “salt and pepper” like nuclear chromatin (H and E, ×400). (b) Synaptophysin immunopositivity (diaminobenzidine, ×400). (c) Diffuse chromogranin positivity (diaminobenzidine, ×400)|
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Melanomas, although rare in the vulvovaginal sites, are mimics of carcinomas, sarcomas, and lymphomas. The optimal panel of IHC markers for identification of melanomas includes S100 protein, HMB45, and Melan A with SOX10 a new marker of melanocytic and neural differentiation [Figures 15].,, Application of IHC markers, such as leukocyte common antigen (LCA), along with lineage specific markers, namely CD3 and CD20 are helpful in accurately diagnosing specific types of non-Hodgkin's lymphomas [Figure 16]. Diagnosis of a high-grade Non-Hodgkin's lymphoma of B cell type would lead to subjecting the patient to a specific chemotherapy regimen, unlike other tumors, including carcinomas and sarcomas.
|Figure 15: Cervical biopsy. Malignant melanoma (amelanotic type). (a) Poorly differentiated malignant tumors with cells displaying marked nuclear pleomorphism, sudden anisonucleosis, and intranuclear inclusions (H and E, ×400). (b) Focal pan-cytokeratin (AE1/AE3) immunoexpression raising an erroneous suspicion for a carcinoma (diaminobenzidine, ×400). (c). Significant S100P immunoexpression in tumor cells (diaminobenzidine, ×400). (d). HMB45 immunostaining confirming a diagnosis of melanoma (diaminobenzidine, ×400)|
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|Figure 16: Cervical tumor. High-grade non-Hodgkin's lymphoma of B cell type. (a) Ectocervical epithelium with a poorly differentiated tumor below, showing focal “crushing” artifacts (H and E, ×200). (b) Malignant round cells mostly arranged in a dyscohesive pattern (H and E, ×400). IHC results (c-f). (c) Diffuse LCA immunoexpression (diaminobenzidine, ×400). (d) Diffuse CD20 immunopositivity (diaminobenzidine, ×400). (c-e) CD3 highlighting interspersed reactive T lymphocytes. (f) High Ki67/MIB1 exceeding 90% reinforcing a high-grade type (diaminobenzidine, ×400)|
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Gestational trophoblastic tumors
Within the realm of gestational trophoblastic tumors, p57 is useful in the diagnosis and molecular triage of molar specimens, such as differentiating complete hydatidiform moles from partial moles and non-molar specimens. In an earlier study, McConnell et al. identified diffuse p57 immunostaining in 4/7 partial moles and in all 17 non-molar specimens; while the same was absent in 23/24 cases of complete moles, including seven cases of early complete hydatidiform mole.
P63, human placental lactogen, and ki67 are useful in separating out trophoblastic lesions. p63 immunostaining is associated with the chorionic trophoblastic disease, whereas HPL, secreted by syncytiotrophoblasts, is highly expressed in the trophoblasts of placental site trophoblastic tumors (PTT) and exaggerated placental site reaction (EPS), but minimally expressed in epithelioid trophoblastic tumors (ETT) and placental site nodules (PSN). In PSTTs and ETT, 8–20% of cells stain positive for Ki-67, whereas, in EPS, the intermediate trophoblasts stain negatively for Ki-67. Beta-human chorionic gonadotropin (B-hCG) is used to identify choriocarcinoma that also shows high Ki-67. In early-stage disease, choriocarcinomas are treated with chemotherapy, in contrast to trophoblastic tumors that are treated with surgical removal/hysterectomy. High-grade carcinomas that are mimics of these tumors might be chosen for aggressive chemotherapy regimes.
It is noteworthy that immunostaining results of tumors involving the female genital tract, similar to tumors occurring at other sites should be interpreted with clinicopathologic features and. Morphology guides toward ordering a correct, optimal panel of IHC markers for a particular case that would have further therapeutic implications.
The contents of this manuscript (in most part) were included in a presentation by BR during the 15th Head Quarter CME at National Head Quarter of the Indian Association of Pathologists and Microbiologist on 3rd-4th March, 2019, Cuttack, Odisha.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Rekhi B, George S, Madur B, Chinoy RF, Dikshit R, Maheshwari A. Clinicopathological features and the value of differential Cytokeratin 7 and 20 expression in resolving diagnostic dilemmas of ovarian involvement by colorectal adenocarcinoma and vice-versa. Diagn Pathol 2008;3:39.
McCluggage WG. Immunohistochemical and functional biomarkers of value in female genital tract lesions. Int J Gynecol Pathol 2006;25:101-20.
McCluggage WG. Young RH. Immunohistochemistry as a diagnostic aid in the evaluation of ovarian tumors. Semin Diagn Pathol 2005;22:3-32.
Cimino-Mathews A, Subhawong AP, Illei PB, Sharma R, Halushka MK, Vang R, et al.
GATA3 expression in breast carcinoma: Utility in triple-negative, sarcomatoid, and metastatic carcinomas. Hum Pathol 2013;44:1341-9.
Miettinen M, McCue PA, Sarlomo-Rikala M, Rys J, Czapiewski P, Wazny K, et al.
GATA3: A multispecific but potentially useful marker in surgical pathology: A systematic analysis of 2500 epithelial and nonepithelial tumors. Am J Surg Pathol 2014;38:13-22.
Rekhi B, Gupta C, Kulkarni M, Deodhar KK, Menon S, Dighe S, et al.
Evaluation of Cell Blocks and Smears from Gynaecologic Effusion Specimens: Experience at a Tertiary Cancer Referral Centre. Cytopathol 2015;26(Suppl 1):19-37. FP-3-1 (Abstract).
Ordóñez NG. Role of immunohistochemistry in distinguishing epithelial peritoneal mesotheliomas from peritoneal and ovarian serous carcinomas. Am J Surg Pathol 1998;22:1203-14.
Ordóñez NG. Value of PAX8, PAX2, Claudin-4, and h-Caldesmon immunostaining in distinguishing peritoneal epithelioid mesotheliomas from serous carcinomas. Mod Pathol 2013;26:553-62.
Hasteh F, Lin GY, Weidner N, Michael CW. The use of immunohistochemistry to distinguish reactive mesothelial cells from malignant mesothelioma in cytologic effusions. Cancer Cytopathol 2010;118:90-6.
Alexander HR, Bartlett DL, Pingpank JF, Libutti SK, Royal R, Hughes MS, et al.
Treatment factors associated with long-term survival after cytoreductive surgery and regional chemotherapy for patients with malignant peritoneal mesothelioma. Surgery 2013;15:779-86.
Rekhi B, Deodhar KK, Menon S, Maheshwari A, Bajpai J, Ghosh J, et al.
Napsin A and WT 1 are useful immunohistochemical markers for differentiating clear cell carcinoma ovary from high-grade serous carcinoma. APMIS 2018;126:45-55.
Li Q, Zeng X, Cheng X, Zhang J, Ji J, Wang J, et al.
Diagnostic value of dual detection of hepatocyte nuclear factor 1 beta (HNF-1β) and Napsin A for diagnosing ovarian clear cell carcinoma. Int J Clin Exp Pathol 2015;8:8305-10.
Tangjitgamol S, Manusirivithaya S, Khunnarong J, Jesadapatarakul S, Tanwanich S. Expressions of estrogen and progesterone receptors in epithelial ovarian cancer: A clinicopathologic study. Int J Gynecol Cancer 2009;19:620-7.
Menon S, Deodhar K, Rekhi B, Dhake R, Gupta S, Ghosh J, et al.
Clinico-pathological spectrum of primary ovarian malignant mixed Mullerian tumors (OMMMT) from a tertiary cancer institute: A series of 27 cases. Indian J Pathol Microbiol 2013;56:365-71.
] [Full text]
Cathro HP, Stoler MH. The utility of calretinin, inhibin and WT1 immunohistochemical staining in the differential diagnosis of ovarian tumors. Hum Pathol 2005;36:195-201.
Lau SK, Chang KL. OCT4: A sensitive and specific immunohistochemical marker for metastatic GCTs. Adv Anat Pathol 2006;13:76-9.
Leroy X, Augusto D, Leteurtre E, Gosselin B. CD30 and CD117 (c-kit) used in combination are useful for distinguishing embryonal carcinoma from seminoma. J Histochem Cytochem 2002;50:283-5.
Zynger DL, McCallum JC, Luan C, Chou PM, Yang XJ. Glypican 3 has a higher sensitivity than alpha-fetoprotein for testicular and ovarian yolk sac tumour: Immunohistochemical investigation with analysis of histological growth patterns. Histopathology 2010;56:750-7.
Hainsworth JD, Greco FA. Poorly differentiated carcinoma and germ cell tumors. Hematol Oncol Clin North Am 1991;5:1223-31.
Skinnider BF, Amin MB. An immunohistochemical approach to the differential diagnosis of renal tumors. Semin Diagn Pathol 2005;22:51-68.
Kascak P, Zamecnik M, Bystricky B. Small cell carcinoma of the ovary (Hypercalcemic Type): Malignant rhabdoid tumor. Case Rep Oncol 2016;9:305-11.
Ostwal V, Rekhi B, Noronha V, Basak R, Desai SB, Maheshwari A, et al.
Primitive neuroectodermal tumor of ovary in a young lady, confirmed with molecular and cytogenetic results--A rare case report with a diagnostic and therapeutic challenge. Pathol Oncol Res 2012;18:1101-6.
Rekhi B, Agrawal R, Shetty O, Deodhar KK, Menon S, Ghosh J, et al.
Five rare cases of Ewing sarcoma, including with epithelial differentiation, involving the female genital tract, displaying EWSR1 rearrangement: Diagnostic challenge and treatment implications. Ann Diagn Pathol 2019;41:1-7.
Vang R, Medeiros LJ, Warnke RA, Higgins JP, Deavers MT. Ovarian non-Hodgkin's lymphoma: A clinicopathologic study of eight primary cases. Mod Pathol 2001;14:1093-9.
Ding J, Li H, Qi YK, Wu J, Liu ZB, Huang BC, et al.
Ovarian granulocytic sarcoma as the primary manifestation of acute myelogenous leukemia. Int J Clin Exp Pathol 2015;8:13552-6.
Mc Cluggage G, Jenkns D. p16 immunoreactivity may assist in the distinction between endometrial and endocervical adenocarcinoma. Int J Gynecol Pathol 2003;22:231-5.
Reid-Nicholson M, Iyengar P, Hummer AJ, Linkov I, Asher M, Soslow RA. Immunophenotypic diversity of endometrial adenocarcinomas: Implications for differential diagnosis. Mod Pathol 2006;19:1091-100.
Darvishian F, Hummer AJ, Thaler HT, Bhargava R, Linkov I, Asher M, et al.
Serous endometrial cancers that mimic endometrioid adenocarcinomas: A clinicopathologic and immunohistochemical study of a group of problematic cases. Am J Surg Pathol 2004;28:1568-78.
Lomo L, Nucci MR, Lee KR, Lin MC, Hirsch MS, Crum CP, et al.
Histologic and immunohistochemical decision making in endometrial adenocarcinoma. Mod Pathol 2008;21:937-42.
Risinger JL, Hayes K, Maxwell GL. PTEN mutation in endometrial cancers is associated with favorable clinical and pathologic characteristics. Clin Cancer Res 1998;4:3005-10.
Al-Hussaini M, Stockman A, Foster H, McCluggage WG. WT-1 assists in distinguishing ovarian from uterine serous carcinoma and in distinguishing between serous and endometrioid ovarian carcinoma. Histopathology 2004;44:109-15.
Okoye EI, Bruegl AS, Fellman B, Luthra R, Broaddus RR. Defective DNA mismatch repair influences expression of endometrial carcinoma biomarkers. Int J Gynecol Pathol 2016;35:8-15.
Rekhi B. Mismatch repair (MMR) protein deficient endometrioid adenocarcinomas, metastasizing to adrenal gland and lymph nodes: Unusual cases with diagnostic implications. Indian J Pathol Microbiol 2015;58:491-5.
] [Full text]
Silverberg SG, Major FJ, Blessing JA, Fetter B, Askin FB, Liao SY, et al.
Carcinosarcoma (malignant mixed mesodermal tumor) of the uterus. A Gynecologic Oncology Group pathologic study of 203 cases. Int J Gynecol Pathol 1990;9:1-19.
Chu PG, Arber DA, Weiss LM, Chang KL. Utility of CD10 in distinguishing between endometrial stromal sarcoma and uterine smooth muscle tumors: An immunohistochemical comparison of 34 cases. Mod Pathol 2001;14:465-71.
Rekhi B, Motghare P. Cyclin D1 and p16INK4 positive endometrial stromal sarcoma – A case report with new insights. Indian J Pathol Microbiol 2014;57:606-8.
] [Full text]
Verma A, Menon S, Rekhi B, Pai T, Maheshwari A, Ghosh J, et al.
Utility of YWHAE fluorescent in-situ
hybridisation in mesenchymal tumors of uterus- An initial experience from tertiary oncology centre in India. Indian J Cancer 2019;56:335-40.
] [Full text]
Richmond AM, Rohrer AJ, Davidson SA, Post MD. Low-grade endometrial stromal sarcoma with extensive sex cord differentiation, heterologous elements, and complex atypical hyperplasia: Case report and review of literature. Gynecol Oncol Rep 2016;19:34-8.
Croce S, de Kock L, Boshari T, Hostein I, Velasco V, Foulkes WD, et al.
Uterine tumor resembling ovarian sex cord tumor (UTROSCT) commonly exhibits positivity with sex cord markers FOXL2 and SF-1 but lacks FOXL2 and DICER1 mutations. Int J Gynecol Pathol 2016;35:301-8.
Folpe AL, Mentzel T, Lehr HA, Fisher C, Balzer BL, Weiss SW. Perivascular epithelioid cell neoplasms of soft tissue and gynecologic origin: A clinicopathologic study of 26 cases and review of the literature. Am J Surg Pathol 2005;29:1558-75.
Rekhi B, Sable M, Desai SB. Retroperitoneal sclerosing PEComa with melanin pigmentation and granulomatous inflammation-A rare association within an uncommon tumor. Indian J Pathol Microbiol 2012;55:395-8. [Full text]
Doyle LA, Vivero M, Fletcher CD, Mertens F, Hornick JL. Nuclear expression of STAT6 distinguishes solitary fibrous tumor from histologic mimics. Mod Pathol 2014;27:390-5.
Rekhi B, Bapat P, Shetty O. A rare case of a vaginal solitary fibrous tumor, presenting as a cystic mass, showing NAB2ex4-STAT6ex2 fusion and STAT6 immunostaining. Int J Gynecol Pathol 2019;38:21-6.
Rekhi B, Jambhekar NA. Immunohistochemical validation of INI1/SMARCB1 in a spectrum of musculoskeletal tumors: An experience at a Tertiary Cancer Referral Centre. Pathol Res Pract 2013;209:758-66.
Cossu A, Paliogiannis P, Capobianco G, Sini MC, Dessole M, Dessole S, et al.
Immunoreactivity for Ca 125 and INI 1 loss of expression are useful markers in the diagnosis of vulvar proximal-type epithelioid sarcomas: Report of two cases. Eur J Gynaecol Oncol 2013;34:469-72.
Rekhi B, Gorad BD, Chinoy RF. Clinicopathological features with outcomes of a series of conventional and proximal-type epithelioid sarcomas, diagnosed over a period of 10 years at a tertiary cancer hospital in India. Virchows Arch 2008;453:141-53.
Lim S, Lee MJ, Cho I, Hong R, Lim SC. Efficacy of p16 and Ki-67 immunostaining in the detection of squamous intraepithelial lesions in a high-risk HPV group. Oncol Lett 2016;11:1447-52.
Park KJ, Kiyokawa T, Soslow RA, Lamb CA, Oliva E, Zivanovic O, et al.
Unusual endocervical adenocarcinomas: An immunohistochemical analysis with molecular detection of human papillomavirus. Am J Surg Pathol 2011;35:633-46.
Rekhi B, Patil B, Deodhar KK, Maheshwari A, A Kerkar R, Gupta S, et al.
Spectrum of neuroendocrine carcinomas of the uterine cervix, including histopathological features, terminology, immunohistochemical profile and clinical outcomes, in a series of 50 cases from a single Institution in India. Ann Diagn Pathol 2013;17:1-9.
Rekhi B, Dubey A, Deodhar KK, Menon S, Maheshwari A, Kerkar K, et al.
Clinicopathological spectrum of a series of melanomas of cervix and vagina from a single tertiary cancer referral centre, India. Arch Pathol Lab Med 2015; 139:e165. (Poster 137) (Abstract).
Deng S, Young B, Vilian R. Primary vaginal melanoma – Report of 2 cases. Pathol 2018;50(Suppl 1):S68-9.
Mohamed A, Gonzalez RS, Lawson D, Wang J, Cohen C. SOX10 expression in malignant melanoma, carcinoma, and normal tissues. Appl Immunohistochem Mol Morphol 2013;21:506-10.
McConnell TG, Murphy KM, Hafez M, Vang R, Ronnett BM. Diagnosis and subclassification of hydatidiform moles using p57 immunohistochemistry and molecular genotyping: Validation and prospective analysis in routine and consultation practice settings with development of an algorithmic approach. Am J SurgPathol 2009;33:805-17.
Shih IeM. Trophogram, an immunohistochemistry-based algorithmic approach, in the differential diagnosis of trophoblastic tumors and tumor like lesions. Ann Diagn Pathol 2007;11:228-34.
Department of Surgical Pathology, Room Number: 818, 8th Floor, Annex Building, Tata Memorial Hospital, Dr E.B. Road, Parel, Mumbai - 400 012, Maharashtra
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11], [Figure 12], [Figure 13], [Figure 14], [Figure 15], [Figure 16]