We describe a case of melanotic Xp11 TRC arising in a 34-year old African American female, unique for a sarcoid-like histologic reaction within the tumor stroma. To our knowledge, this is the seventh report of this entity, the oldest patient thus far reported, and the first to describe this peculiar pattern of lymphocytic and granulomatous inflammation. This “sarcoid-like” pattern comprised compact, noncaseating epithelioid granulomas with prominent lymphocytic cuffing, numerous giant cells, and psammomatous microcalcifications (Figure 1D-F). An additional unique feature of this case was its occurrence in an adult patient. In contrast, five of the previous six confirmed cases of melanotic Xp11 TRCs were in patients aged 18 years or younger [1–3].
The present case demonstrated other clinical and histologic features previously described in melanotic Xp11 TRC, including presenting symptoms of abdominal pain and female predisposition (all but one reported case to date occurring in females). Also observed, as with other cases providing complete demographic data, the tumor reported herein occurred in a black/African-American patient. This demographic association has also been reported in four of the five cases with complete data as demonstrated in Table 1 (the fifth case occurring in a Taiwanese female). Histologically, features identified here and reported previously include tumor cells with epithelioid cytology and clear to eosinophilic cytoplasm, a nested growth pattern, and cytoplasmic melanin. Immunohistochemical positivity with melanocytic markers (HBM-45, tyrosinase, Melan-A), TFE3, and cathepsin K is an additional common finding across this and previously reported cases (see Table 1). As in previous cases, the tumor described here demonstrated diffuse TFE3 nuclear staining and an underlying TFE3 rearrangement was confirmed by break-apart FISH assay. In addition, almost all melanotic Xp11 TRCs have demonstrated negativity with markers of muscle differentiation (desmin, actin, caldesmon), epithelial and renal tubule markers (CD10, EMA, cytokeratins, carbonic anhydrase IX), and various additional markers such as MiTF, S-100, and PAX-8 (see Table 1). Two novel immunohistochemical results here were positivity with progesterone receptor (estrogen receptor was negative) and CD117 (C-kit), which is typically reported as negative. Studies of progesterone receptor and CD117 in additional melanotic XP11 TRCs will be required to explore the possible significance of these unique immunohistochemical findings.
The major differential diagnosis of melanotic Xp11 TRC includes conventional clear cell RCC, papillary RCC, translocation renal cell carcinomas (Xp11 RCC and t(6;11)), RCC unclassified, melanoma, and PEComa, including angiomyolipoma (AML) and its epithelioid variant. As described above, immunohistochemical negativity with all epithelial and renal tubule markers, S-100, desmin and actin eliminates many of these other diagnostic possibilities. Further differentiating them from renal epithelial tumors, melanotic Xp11 cancers are unique in their lack of reactivity with PAX-2 and PAX-8 . Immunohistochemical reactivity with HMB-45 and Melan-A, however, can also be seen in PEComa/AML, t(6;11) translocation carcinomas, and clear cell sarcoma [1, 11, 12]. Immunohistochemical studies for PAX-2 and CD10, both often positive in translocation RCCs, may prove useful in making this distinction as these stains are uniformly negative to date in melanotic Xp11 TRCs (Table 1). The immunohistochemical marker MiTF also may contribute to this differential, as it is frequently positive in melanoma, clear cell sarcoma, and PEComa, but is typically negative in melanotic Xp11 TRC .
The critical studies in the diagnosis of melanotic Xp11 TRCs remain the demonstration of TFE3 nuclear expression and underlying TFE3 rearrangement. TFE3 expression is also seen in alveolar soft part sarcoma, melanotic Xp11 TRCs, Xp11 RCC, and rare PEComas that are negative for MiTF [1, 13, 14]. Notably, these other three histologically similar, TFE3 positive tumors do not typically contain cytoplasmic melanin. Nonetheless, FISH and/or other molecular studies (such as reverse transcription polymerase chain reaction) are still recommended to rule out gene fusions diagnostic of these other entities. One caveat of molecular verification is that Chang and colleagues identified a PSF-TFE3 fusion in melanotic Xp11 TRC that is also reported in Xp11 RCC . This raises the possibility that melanotic Xp11 TRC and Xp11RCC are closely related, although in the majority of cases to date the gene fusion partner of TFE3 has not been described . TFE3-rearranged PEComas that exhibit strong TFE positivity and minimal desmin and actin positivity have also recently been described . Therefore, TFE3-rearranged PEComa should be carefully considered as a diagnostic possibility in tumors with histologic features that overlap with melanotic Xp11 TRC.
The sarcoid-like reaction described in this tumor has been reported in conventional RCC [6–10] and other malignancies [15–17], but has not previously been reported in melanotic Xp11 TRC. Non-neoplastic conditions associated with granulomatous inflammation, with and without necrosis, include infections (mycobacterial, fungal, parasitic), various autoimmune conditions (e.g., biliary cirrhosis, ankylosing spondylitis, and rheumatoid arthritis) , hyperprolactinemia , chemical exposures and foreign body-type reactions . To our knowledge, our patient had no history of these conditions and no prior biopsy diagnosis of granulomatous inflammation at any site. Thus the findings appear to be tumor specific. However, the pathogenesis and significance of these findings in this case, as well as in prior tumors, are not known. A similar sarcoid-like reaction was recently reported in the RCC of a 62-year-old Caucasian patient with no history of sarcoidosis . In contrast to our case, that study reported the granulomatous inflammation in the peritumoral region, but not within the tumor. It has been postulated that this process is the result of a T-cell mediated host response to antigens expressed or produced by tumor cells [6, 20]. In other instances, similar reactions have been reported following chemical exposure such as the use of contrast media in imaging studies . Similar sarcoid-like tumor reactions have been shown to have positive prognostic significance in patients with Hodgkin disease and gastric cancer [16, 17]. Their significance here and in conventional RCC remains unknown, but deserving of further investigation.
An important future direction will be to investigate the histologic and/or genetic features of these tumors that predispose to indolent or frankly malignant behavior. As demonstrated in Table 1, of the five patients with reported outcome data available, two patients presented with widely disseminated metastatic disease. One of these two patients was dead of disease within nine months of diagnosis despite chemotherapy. The remaining patients, including this case, were free of disease at 3, 9, and 22 months, respectively. There is no clear reason at this time for this significant discrepancy in metastatic potential and clinical outcome. Further investigation of the underlying TFE3 rearrangements is warranted. The gene fusion partners are rarely known (with the exception of the report by Chang and colleagues ), and this may provide valuable genetic information that relates to prognosis. Additional studies of melanotic Xp11 TRCs will be important to further define the prognostic implications and appropriate therapies for these rare tumors. Correct classification of these distinct neoplasms is important as the MiTF/TFE3-related cellular pathways may eventually provide targets for novel therapeutic agents.
Written informed consent was obtained from the patient for publication of this Case Report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.