ANATOMICAL PATHOLOGYExpression of neuroendocrine markers in non-neuroendocrine endometrial carcinomas
Introduction
Neuroendocrine (NE) tumours of the endometrium are uncommon neoplasms that range from low grade, well differentiated tumours (carcinoid) to high grade carcinomas with poor prognosis, such as small cell and large cell NE carcinomas.1 Despite limited data, available evidence suggests that these high grade NE tumours may also exhibit aggressive behaviour, similar to other organ systems.1, 2
The approach to diagnosis of NE tumours is largely based on haematoxylin and eosin (H&E) microscopy. Classic features of small cell neuroendocrine carcinomas include diffuse growth of round, poorly cohesive cells with condensed chromatin and scant cytoplasm, showing necrosis, brisk mitotic activity and crushing artifact.3 Large cell neuroendocrine carcinomas exhibit, at least focally, well demarcated nests, trabeculae, or cords, with peripheral palisading, containing large polygonal cells that have vesicular or hyperchromatic nuclei, abundant cytoplasm and prominent nucleoli.3
Immunohistochemical markers to confirm NE differentiation include staining for chromogranin-A (here referred to as chromogranin only), synaptophysin, and neural cell adhesion molecule (CD56).4 With respect to the expression of these IHC stains in endometrial NE tumours, the World Health Organization (WHO) criteria requires >10% of tumour cells to express any one of the aforementioned NE markers to establish the diagnosis of large cell neuroendocrine carcinoma, with the caveat that CD56 may not be as specific.3 Other studies have recommended expression of two or more NE markers, or that >20% of tumour cells should be positive in this setting.5, 6 Finally, expression of NE stains in small cell neuroendocrine carcinoma is supportive, but not required to establish the diagnosis.
In addition to the aforementioned NE markers, pulmonary NE tumours consistently stain for thyroid transcription factor (TTF-1), including more than 90% of small cell neuroendocrine carcinomas.7 However, many NE carcinomas outside of the lung can express TTF-1. One study found that seven of 16 (43%) non-pulmonary small cell neuroendocrine carcinomas were positive for TTF-1, along with 100% (8/8) medullary thyroid carcinomas.8 In the endometrium, TTF-1 expression appears to be non-specific, as one study found expression in six of 32 (18%) cases of endometrial carcinomas of endometrioid type (EMCA), and in three of 13 (23%) endometrial serous carcinomas.9
There are very limited published data regarding the presence, distribution and intensity of NE markers in endometrial carcinomas without ‘classic’ NE histology. Some of these studies were hindered by small sample sizes of poorly and/or undifferentiated endometrial carcinomas, or only evaluated a limited number of NE markers or histological types.5, 9, 10, 11, 12, 13, 14, 15 Description of the staining properties of NE markers in serous and clear cell carcinomas, in particular, is lacking.
The aim of this study was to examine the presence, distribution and intensity of NE markers (as well as TTF-1) in a large group of endometrial carcinomas of various grades and histological subtypes, but without histological evidence of NE differentiation.
Section snippets
Materials and methods
Following the Institutional Review Board approval, our surgical pathology database was searched for hysterectomy specimens spanning an 8-year period (2010–2017) with the diagnosis of endometrial carcinoma. A variety of histological subtypes, grades, and stages was selected randomly with the goal of obtaining a diverse number of tumours.
Slides were re-reviewed by two pathologists (AP, AM) utilising diagnostic criteria from the 2014 WHO Classification.3 Pathological staging was evaluated at the
Results
A total of 26 EMCA [12 International Federation of Gynecology and Obstetrics (FIGO) grade 1, six FIGO grade 2, and eight FIGO grade 3)], 20 serous carcinomas, 12 clear cell carcinomas, two undifferentiated carcinomas, and one dedifferentiated carcinoma were included in the study, along with 10 carcinosarcomas. The ages of the patients at diagnosis ranged from 31 to 87 years (mean 63.9). The mean tumour size was 52.9 mm (range 20–135 mm). Basic demographic information of patients in the cohort
Discussion
While the National Comprehensive Cancer Network provides recommendations for the treatment of high-risk endometrial cancer, there are no specific recommendations for the management of NE carcinoma.17 However, as NE tumours of other disease sites are treated with chemotherapeutic agents which are not standardly used for other endometrial histologies, differentiating these tumours from other types of endometrial carcinomas is crucial for directing care.
The IHC expression of NE markers in
Conclusion
IHC expression of NE markers in tumours lacking carcinoid, small cell or large cell neuroendocrine morphologies was commonly observed in our study, mostly in a patchy pattern. This reinforces the importance of proper morphological characterisation before considering the diagnosis of a neuroendocrine tumour (or ‘component’) based solely on IHC.
Conflicts of interest and sources of funding
The authors state that there are no conflicts of interest to disclose.
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Cited by (15)
Synaptophysin and chromogranin A expression analysis in human tumors
2022, Molecular and Cellular EndocrinologyCitation Excerpt :These findings are consistent with the existing literature as low fractions of cases with “neuroendocrine differentiation” have been described in many different tumor entities. Tumors particularly well known for occasional expression of neuroendocrine markers include for example prostate cancer (reviewed in (Puca et al., 2019)), breast cancer (reviewed in (Tsang and Tse, 2021)), colon cancer (reviewed in (Kleist and Poetsch, 2015)), ovarian carcinoma (Taube et al., 2015; Sasaki et al., 1989) and endometrial carcinomas (Moritz et al., 2019), as well as non-epithelial tumors, such as Ewing sarcoma (Machado et al., 2021). That chromogranin A and synaptophysin positivity was largely unrelated to histopathological features of cancer aggressiveness in endometrium cancers, pancreatic adenocarcinomas, gastric adenocarcinomas and colorectal adenocarcinomas in this study further argues against a clinical importance of neuroendocrine differentiation as long as a tumor retains its typical morphology.
Neuroendocrine Neoplasia of the Female Genital Tract
2022, Surgical Pathology ClinicsCitation Excerpt :A diagnosis of LCNEC requires positive staining with at least one neuroendocrine marker in the appropriate morphologic context, and most LCNECs are diffusely positive with broad spectrum CKs. Importantly, neuroendocrine marker positivity, usually focal, can be seen in poorly differentiated carcinomas and should not be interpreted as diagnostic of NEC if the morphology is not classic or at least highly suggestive of neuroendocrine differentiation.25 Immunohistochemistry may help identify the primary site of origin of a NEN and guide management with targeted therapies.26,27
Low grade endometrial endometrioid adenocarcinoma: A review and update with emphasis on morphologic variants, mimics, immunohistochemical and molecular features
2022, Seminars in Diagnostic PathologyCitation Excerpt :CDX2 stains positively in endometrial adenocarcinoma with intestinal differentiation.38,39 Neuroendocrine marking (synaptophysin, chromogranin, CD56, INSM1, TTF-1) in endometrioid adenocarcinoma is relatively common.40 It has been our experience that neuroendocrine markers are often expressed in a focal to patchy fashion in various non-neuroendocrine carcinomas, thus this marking should not be interpreted as “neuroendocrine carcinoma” or a “neuroendocrine component” in the absence of clearly identifiable cytologic and architectural features of neuroendocrine neoplasia (meaning, morphologic features of small cell neuroendocrine carcinoma or large cell neuroendocrine carcinoma).
Immunosensitivity and specificity of insulinoma-associated protein 1 (INSM1) for neuroendocrine neoplasms of the uterine cervix
2023, Journal of Gynecologic Oncology