Rare kidney tumor

CASE HISTORY A 33-year-old female patient presented to our hospital with complaints of intermittent fever, pain in the abdomen for one month, intermittent vomiting, and passing red-colored urine. Physical examination revealed a palpable soft right flank mass. An ultrasound performed earlier at another facility was suggestive of right-sided pyonephrosis; right-sided percutaneous nephrostomy (PCN) had been performed for this. Contrast-enhanced computerized tomography (CT) showed a right renal mass with a cystic appearance in the hilar region, compressing the inferior vena cava and causing encasement of the renal vessels in the right suprarenal and retrocaval space as shown in Figure 1. Ultrasonography repeated at our hospital showed an enlarged right kidney with echogenic debris and low-level internal echoes within a solid area, as shown in Figure 2. Urinary cytology revealed atypical cells suspicious for renal cell carcinoma. A biopsy of the renal mass was thus advised, which revealed necrosis predominantly, and scant viable tumor. Hence, a repeat biopsy was recommended, which showed conspicuous and eosinophilic nucleoli at 400× magnification, but not prominent at 100×, with abundant clear cytoplasm. As a result, they were graded as International Society of Urologic Pathology (ISUP) 2 (the ISUP grading for renal cell carcinoma is based on the evaluation of the nucleoli. It has been validated for clear cell and papillary cell variants of renal cell carcinoma, but not used for chromophobe variants).[1] On immunohistochemistry, the cells showed diffuse cytoplasmic positivity for alpha-methyacyl-CoA racemase (AMACR), transcription factor binding to IGHM enhancer 3 (TFE3) diffusely, and for paired-box gene 8 (PAX8) focally, while being negative for cytokeratin 7 (CK7) and carbonic anhydrase IX) (CAIX).Figure 1: (a) Axial, (b) sagittal, and (c) coronal sections of the tumor, showing a solid-cystic mass replacing the right kidney, compressing the inferior vena cava, and causing encasement of the renal vessels. There is a loss of the fat plane between the mass and the inferior surface of the liverFigure 2: (a) Ultrasonography images of the renal mass, showing an enlarged right kidney with echogenic debris and low-level internal echoes within. (b) The solid area of the mass is targeted under ultrasonography guidanceWhat is the diagnosis, and what should be done next? Once you have finalized your answer, read on. DIFFERENTIAL DIAGNOSIS AND FURTHER MANAGEMENT Patients with primary renal carcinoma may occasionally present with complications, such as pyonephrosis which was present in our case. However, urine cytology corroborated by cross-sectional imaging findings helped us in ruling out the non-malignant etiology and suspecting something more sinister. Based on the histomorphology and immunohistochemistry, the differential diagnoses for our case included clear cell papillary renal cell carcinoma and papillary renal cell carcinoma. Staging workup in the form of computed tomography (CT) scan revealed multiple enlarged preaortic and paraaortic lymph nodes with associated encasement of renal vessels, along with mild ascites. The mass was also observed to be encasing the inferior vena cava (IVC) entirely. However, no obvious distant metastases were observed. The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) score was 3. The patient was planned for tyrosine kinase inhibitor therapy (sunitinib), as the mass was deemed unresectable based on anatomical relations. However, the young age at presentation, presence of abundant cytoplasm in the tumor cells, positivity for AMACR and transcription factor E3 (TFE3), and negativity for CAIX and CK7 made the diagnoses of both clear cell papillary renal cell carcinoma and papillary renal cell carcinoma unlikely. Both these tumors usually present at approximately 60 years of age and show strong CK7 positivity. Histopathology and immunohistochemistry in our case predominantly revealed cells with clear abundant cytoplasm, positivity for AMACR, TFE3, and focal weak positivity for PAX8, whereas being negative for CK7 and CAIX. Based on the age of presentation in our patient, a final diagnosis of MiT family translocation renal cell carcinoma was suggested by our histopathologists. FINAL DIAGNOSIS Microphthalmia transcription factor (MiT) positive renal cell carcinoma. DISCUSSION Translocation-associated renal cell carcinomas (tRCCs) are a group of rare renal cell carcinomas, of which the MiT family translocation renal cell carcinomas have been included in the 2016 World Health Organization classification. They have two distinct subtypes, which vary in their presenting features, genetic makeup, diagnostic features, and prognosis. These include the TFE3 and the transcription factor EB (TFEB), both of which belong to the MiT family.[2] We describe here a patient with MiT family tRCC who presented to our institution with pyonephrosis, and on further evaluation was diagnosed with this rare subtype of renal cell carcinoma. The MiT family of renal cell carcinomas comprises 3% of the total adult renal cell carcinomas.[2,3] They are predominantly observed in childhood, and the prognosis worsens with advancing age. Although uncommon in adults, there have been isolated incidents of incorrect diagnosis in the literature.[4-6] Additional diagnostic tests such as next-generation sequencing may be used when the diagnosis is doubtful. Next-generation sequencing was not performed in our case due to monetary constraints and also owing to the fact that the most probable diagnosis was obtained through immunohistochemistry.[7] Because our patient presented at an older age, the long-term prognosis would likely be relatively poor. Depending on the involvement of either of these transcription factors, we can classify the MiT family tRCCs into Xp11 translocation RCC, which harbors the TFE3 gene fusion to the proline-rich mitotic checkpoint control factor (PRCC) and alveolar soft part sarcoma (ASPL) loci on chromosomes 1q21 and 17q25,[8] respectively, and the t(6;11) renal cell carcinomas, which harbor the TFEB gene fusion with the 5’ portion of the alpha gene, an untranslated gene of unknown function on chromosome 11q12.[9] These translocations lead to the overexpression of TFE3 or TFEB proteins. Risk factors for these tumors include earlier exposure to chemotherapy with DNA topoisomerase II inhibitors or alkylating agents.[8] There was no history of earlier chemotherapy in our patient. In light of their immunochemistry, tRCCs are diagnosed by demonstrating nuclear staining for overexpressed proteins (), cluster of differentiation 10 (CD10), racemase/AMACR, and negative staining for CK7, CD9, epithelial membrane antigen (EMA), and CD117.[9] In our case, on immunohistochemistry, the tumor cells were diffusely positive for AMACR, TFE3, and PAX8 and negative for CK7 and CAIX. The current gold standard for diagnosing TFE3 rearrangement is fluorescence in situ hybridization (FISH) assays on formalin-fixed or paraffin-fixed tissue sections, which is also practiced at our institute; however, it was not performed in this case.[10] On gross pathology, these tumors typically have tan-yellow cut surfaces, solitary cortical masses with necrosis, and hemorrhagic foci within.[4] Microscopically, they show papillary architecture composed of epithelioid clear cells with voluminous eosinophilic to clear cytoplasm. In our patient, the histopathology showed areas of necrosis and hemorrhage with a scanty focus of viable tumor cells with eosinophilic cytoplasm in the first biopsy sample and clear abundant cytoplasm in the second biopsy sample. The most common differential diagnoses for this category of tumors are clear cell renal cell carcinoma, type I papillary renal cell carcinoma (where cathepsin K is positive on immunohistochemistry), and clear cell papillary renal cell carcinoma (where CK7 and GATA binding protein 3 [GATA3] are typically positive). Less common differentials include pure epithelioid perivascular epithelioid cell tumors/epithelioid angiomyolipoma (where PAX8 and CD68 are positive).[4] The treatment options for these tumors are still evolving and remain to be determined. For locoregional disease, surgery is the most effective option, even for patients with a positive regional lymph node status. Patients with distant hematogenous metastases are usually treated the same way as those with clear cell carcinomas, including the use of immunotherapy and targeted therapies.[11] Due to the aforementioned anatomical constraints, the tumor in our case was deemed unresectable and hence the patient was started on sunitinib, a tyrosine kinase inhibitor. However, novel therapeutic options are still being developed that may prove even more effective. CONCLUSION The above case demonstrates an atypical presentation of a rare renal cell carcinoma variant, in the form of pyonephrosis, which could mislead the clinician into thinking along the lines of a non-neoplastic etiology, thus missing out on the prompt diagnosis and treatment of the malignancy. Urinary cytology can be very helpful in leading the clinician to suspect a neoplastic etiology in addition to cross-sectional imaging, which may further clinch the diagnosis. This also highlights the importance of using biopsy techniques and immunohistochemistry beyond the available imaging modalities to reach the correct diagnosis. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for images and other clinical information to be reported in the journal. The patient understands that her name and initials will not be published, and due efforts will be made to conceal her identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.