This patient had a prior history of RCC of the left kidney that had been resected. He then presented with a neoplasm of the lung. Fine-needle aspiration analysis of hilar lymph node biopsies showed histological patterns consistent with a metastatic RCC. Given the known history of potential MiT family translocation RCC, the FNA samples were stained for TFE3 which showed diffuse uptake confirming the diagnosis of recurrent RCC, that had metastasized and transformed into an MiT family translocation RCC. The patient passed away from the disease in 2022.

Renal cell carcinoma (RCC) is the 9th most common cancer in the United States¹. Although a “classic triad” of hematuria, flank pain, and palpable abdominal mass has been described for RCC, only about 10% of cases present this way. Another 20% of diagnoses are made following onset of paraneoplastic syndromes such as pulmonary emboli, Cushing syndrome, polycythemia, or hypercalcemia. Most cases are discovered as incidental imaging findings. Because of the incidental nature of most RCCs, prognosis is based on stage and grade of the tumor at the time of its resection.

The majority of RCCs are acquired, with a hypothesis being due to Western lifestyle. There can be a hereditary component to the onset of RCC with the most common hereditary RCCs being due to von Hippel-Lindau syndrome, hereditary papillary RCC, Britt-Hogg-Dube syndrome, tuberous sclerosis, and hereditary leiomyomatosis and papillary RCC ².

When examining fine needle aspirates of potential RCCs, there are several notable microscopic features common to all subtypes. Importantly, a heterogenous cell population, small cytoplasmic vacuoles, and the presence of hemosiderin have been noted to be predictive of the diagnosis of RCC as compared to other metastatic cancers³. These features, except for hemosiderin, can be seen in pretest figures 1-4. Additional histological features are present depending on the subtype of RCC. Of the different subtypes, the most common type of RCC is clear cell RCC⁴. Clear cell RCC presents histologically with a characteristic clear cytoplasm with a distinct cell membrane. Other features of clear cell RCC are arborizing thin-walled vessels interspersed amongst the tumor cells, granular and eosinophilic cytoplasm, and large areas of hemorrhage or necrosis. A small focus of cells displaying classical features of clear cell RCC features can be seen in post-test figure 1.

Immunohistochemically, most clear cell RCCs stain positive for PAX2, PAX8, and CAIX. In the past 20 years, a new and unique subtype of RCC has been characterized. This new class of RCC is due to fusion genes in MiT family transcription factors, most notably TFE3 and TFEB5, and are labeled “MiT family translocation RCC”⁶. Cases of these kinds of RCC are rare in adults when compared to other RCCs, but an understanding of their morphological features could lead to increased rates of accurate diagnosis. In this case, the patient presented two years following resection of an RCC that did not fit neatly into one subtype at the time of resection. On admission, the patient’s tumor burden was primarily in his lungs, but histologically, the patient’s tumor appears more consistent with metastasized RCC. Foci of clear cell RCC morphology can be seen, in addition to features that are seen in MiT family translocation RCCs.

Specifically, this subtype of RCC is classified histologically as large epithelioid cells with clear to eosinophilic cytoplasm. They tend to arrange themselves in papillary or nested patterns and psammomatous calcifications can often be seen. In this case, there were no calcifications present, but a papillary architecture is prominent in pre-test figure 4, and nested architecture can be seen in the other pre and post-test figures. Since these features are like other subtypes of RCC, diagnosis on histology alone is difficult. Staining for the affected transcription factors of TFEB and TFE3 can help narrow the differential, but adult MiT family translocation RCCs often stain poorly for TFE3⁷. This particular immunohistochemical stain is known to have poor sensitivity and specificity (between 70-85% and 57-95% respectively). The sensitivity and specificity vary on a case-by-case basis often based on individual laboratory protocols. Additionally, since two genetic anomalies, an Xp11.2 and a t(6;11) translocation have been identified as the causative aberrations of this particular subtype of RCC, florescent in-situ hybridization (FISH) analysis is often the only way to diagnose these subtypes of RCC. In our case, because the hilar lymph node biopsy stained diffusely positive for TFE3, it supported the diagnosis of MiTF translocation RCC. A subsequent FISH analysis was ordered, but the patient unfortunately passed before the analysis was completed, as it is a send out test for our institution. As a result, it was never performed. In order to make the definitive diagnosis, a FISH analysis would have been required.

To date, there are no targeted therapies against MiT family translocation RCC. Potential targets of therapy including CathepsinK, VEGF, and MET have been identified⁸. There is some older data that shows targeted therapy with anti-VEGF monoclonal antibodies is associated with a progression-free survival and overall survival of 7.1 and 14.3 months⁹. Further clinical trials are needed to identify more targeted agents.