Diagnostic pitfall: <scp>GATA3</scp> expression in mesonephric/mesonephric‐like adenocarcinoma involving the breast

Mesonephric and mesonephric-like adenocarcinoma (MA/MLA) of the female genital tract are an interesting group of neoplasms that characteristically show diverse architectural patterns and a peculiar immunophenotype, with expression of multiple transcription factors commonly used for lineage determination (Table 1). While MA is a rare but relatively well-described cervical neoplasm arising from mesonephric remnants, MLA is an entity that has been more recently recognized, with the endometrium and ovary documented as primary sites. Both MA and MLA may show papillary, tubular, glandular, solid, and spindled arrangements, and cytologically, they most commonly exhibit scant cytoplasm, grooved/cleared nuclei, and inconspicuous nucleoli. Diagnosing this likely underrecognized group of tumours can be challenging, particularly in biopsy material, but it is also crucial to do so, as these neoplasms are associated with aggressive behaviour and rapid disease progression. MA and MLA are known to spread to the lungs in a high proportion of cases, with less common metastatic sites including the liver, brain, urinary bladder, and spleen.1 Highly unusual metastatic sites such as the orbit have also been reported.2 To the best of our knowledge, there are no previously documented cases in the literature of metastatic MA/MLA involving the breast; however, we have come across this scenario and believe it is useful to highlight the possibility of misdiagnosis due to strong GATA3 expression in this nonmammary adenocarcinoma. A 74-year-old woman presented with postmenopausal bleeding and material from an endometrial biopsy showed fragments of adenocarcinoma with compressed tubular/glandular, solid and spindled architecture, and oval-shaped cleared nuclei. The tumour cells were diffusely positive for PAX8 and GATA3 and did not express TTF1 and oestrogen/progesterone receptors. In addition, there was intact nuclear expression of MLH1, PMS2, MSH2, and MSH6 and wildtype expression of p53. The combined morphology and immunophenotype were indicative of a tumour with mesonephric differentiation, and a diagnosis of endometrial MLA was favoured, although the possibility of cervical MA could not be excluded. Follow-up cross-sectional imaging showed an obstructing neoplasm centred within the cervix, with associated endometrial cavity distention, bilateral pelvic lymph node involvement, and lytic bone metastases in the left iliac bone. Treatment with chemotherapy and radiation to the pelvis and bone involvement was recommended, but the patient declined any therapeutic intervention at that time. Nine months later, a new palpable mass in the left breast was identified and subsequent imaging demonstrated a corresponding 6.0 mm lobulated dense nodule with spiculated margins (BIRADS4), concerning for a small primary mammary carcinoma. A core biopsy was performed, and the limited biopsy material revealed an infiltrative adenocarcinoma with a predominantly slit-like architecture (Figure 1A,B). The tumour cells were diffusely and strongly positive for both GATA3 and PAX8 and did not express TTF1, GCDFP-15, mammaglobin, or oestrogen/progesterone receptors (Figure 1C–F). There was also no expression of HER2 (score of 0). Given the known history and combined morphology and immunophenotype, a diagnosis of metastatic MA/MLA was established. The patient is currently being treated with chemotherapy. Due to its rarity and morphological diversity, accurate diagnosis of MA/MLA can be very challenging, especially at metastatic sites including the breast, and there is a significant risk of misdiagnosis as a primary carcinoma, particularly if the patient's clinical history of a gynaecological malignancy is unknown or overlooked. The case presented here illustrates the importance of always considering the possibility of a metastasis involving the breast, even when there is diffuse GATA3 expression. While GATA3 is a useful marker for confirming breast origin, its expression in MA/MLA may lead to diagnostic confusion. It is important to note that a similar diagnostic dilemma can also occur in the evaluation of metastatic MA/MLA involving the lung, due to frequent TTF1 expression. In the appropriate clinical and morphological context, an immunohistochemical panel including PAX8 is extremely valuable in supporting the diagnosis of metastatic MA/MLA. It should be noted, however, that while PAX8 expression primarily supports gynaecologic as well as renal and thyroid gland origins as primary sites, it may infrequently be expressed in breast carcinomas,3, 4 including those which show an overlapping morphology with serous carcinoma from the gynaecologic tract.5 From a molecular perspective, most MA/MLA harbour alterations involving members in the MAPK pathway, with the most common somatic mutations occurring in KRAS.6, 7 Although this molecular finding can be helpful in supporting a diagnosis of metastatic MA/MLA to the breast, pathologists should be aware of the rare occurrence of KRAS mutations in triple-negative breast carcinoma, as well.8 In summary, the accurate diagnosis of metastatic MA/MLA involving the breast (as well as other organs) can be challenging from a number of different perspectives. If one is unaware of a previous diagnosis of MA/MLA or is unfamiliar with MA/MLA morphology, the observed immunophenotype may be misleading. There is no funding to declare. HA and AH contributed equally to the drafting and final preparation of this article. HA has nothing to disclose. AH has received honoraria from Merck, AbbVie, and AstraZeneca, unrelated to this work. None. Data sharing is not applicable to this article.

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