Fumarate hydratase-deficient renal cell carcinoma (FHdRCC) is a molecularly defined renal cell carcinoma (RCC) according to the WHO classification of urinary and male genital tumors (1). It occurs due to the inactivation of the FH gene. FH deficiency causes the accumulation of fumarate in the mitochondria, which acts as an oncometabolite in the cytoplasm, leading to RCC (2). It is common in males and is a highly aggressive metastatic carcinoma. However, it has rarely been reported as dialysis-associated renal carcinoma.

RCC diagnosis relies on imaging techniques. Computed tomography (CT) or magnetic resonance imaging (MRI) are used to confirm RCC (3). However, it is sometimes difficult for imaging alone to identify renal masses as malignant tumors in cystic kidney diseases such as autosomal dominant polycystic kidney disease (ADPKD) or acquired cystic kidney disease (ACKD). In such cases, pathological confirmation by biopsy is required.

Here, we report a case of FHdRCC that was developed in a patient with ACKD who presented with fever and hematuria. This case indicates that it is important to perform a renal mass biopsy if its radiographic images are equivocal and that it can be performed in the same way as percutaneous kidney biopsies.

We encountered a rare case of FHdRCC arising from acquired cystic kidney disease as dialysis-associated renal carcinoma. This case highlights that imaging alone has limitations in diagnosing malignant tumors arising in an acquired cystic kidney. In addition, the rare carcinoma diagnosis was only achieved after obtaining a biopsy. Therefore, this case was regarded as a valuable model that demonstrates the importance of actively performing biopsies for suspected masses.

FHdRCC is uncommon in dialysis-associated renal carcinomas. In a Japanese multicenter study, ACKD-associated RCC was found to be the most common type, followed by clear-cell RCC, in patients undergoing long-term dialysis (4). FHdRCC has rarely been reported. Doi et al (5) reported a 75-year-old male with FHdRCC in the left kidney 7 years before the induction of dialysis; however, this case was not FHdRCC occurring in a patient undergoing dialysis as that observed in our case. ACKD-associated RCC often needs to be differentiated from FHdRCC owing to its histopathological similarities such as abundant granular eosinophilic cytoplasm. However, it differs by the presence of intratumoral oxalate crystals and absence of FH deficiency (6). Our case was diagnosed with FHdRCC based on 2SC positivity. Pollard et al (7) reported that FH deficiency causes the overexpression of hypoxia-inducible factors, leading to proliferative renal cyst development. Adam et al (8) reported that the loss of FH causes KEAP1 succination and Nrf2 dysregulation independent of hypoxia-inducible factors, leading to renal cysts and tumors. Considering these reports, it is interesting to speculate that FH deficiency may also be associated with ACKD.

Patients undergoing dialysis should undergo regular kidney imaging assessments for RCC surveillance; however, this may sometimes be insufficient for patients with ACKD. The standard diagnosis of RCC is based on the use of imaging techniques. Ultrasonography is recommended for the initial screening, while computed CT and MRI are used to confirm RCC. The Bosniak classification is recommended to categorize cystic renal masses (3). Rahbari-Oskoui and O'Neill (9) also suggested that a complex cyst categorized as Bosniak class III or IV should prompt contrast-enhanced CT or MRI. This classification is useful for evaluating single cystic masses, which is similar to the Bosniac Class IV case that was reported by Doi et al (5). However, it is difficult to evaluate masses that emerge in multiple cysts, which were observed in our case. Our case was considered a Bosniak class IIF, which typically indicates a benign or indolent lesion; however, this was not the case.

If imaging was insufficient to diagnose RCC, a biopsy was deemed as necessary. The European Association of Urology guidelines on RCC do not prohibit renal mass biopsy and propose situations for renal biopsy (10). Volpe et al (11) reported that among 100 biopsies of renal masses, 84 were malignant, with 93% of the RCCs accurately classified and graded with 100% concordance with surgical specimens. Although the outcome of our case was unfortunate, we consider that the biopsy enabled a definitive diagnosis of the rare aggressive tumor, leading to nephrectomy.

The 2020 Kidney Biopsy guidebook in Japan also supports the safety of renal tumor biopsy in cases of difficult diagnosis and reports a minimal risk of serious hemorrhagic complications or cancer cell dissemination after biopsy (12). Sawa et al (13) reported that renal biopsy which was performed for fever of unknown origin revealed an intravascular lymphoma. A perirenal mass biopsy was performed in the sitting position, which led to a diagnosis of extramedullary relapse of acute lymphoblastic leukemia (14). Both patients are still alive without any post-biopsy complications. Additionally, the present case demonstrates that renal tumor biopsies can be performed in the same manner as percutaneous kidney biopsies, even in the lateral position.

The biopsy technique was the same as that of ultrasound-guided biopsy using a biopsy gun, which has already been reported. However, conventional sequencing involves the suspicion of malignancy on imaging before performing a biopsy. In contrast, in our case, the puncture was initially intended for a presumed cyst, but a mass was incidentally discovered during the procedure, essentially reversing the sequence of events.

One limitation of our study is that we cannot exclude the possibility that this diagnosis was achieved, to some extent, by serendipity. A core needle biopsy, not limited to the kidney, may result in an insufficient sample volume (15). In our case, we were able to obtain a sufficient number of cores (six in total); however, if the mass had been smaller, an accurate diagnosis might not have been possible. Moreover, forcing the procedure may increase the risk of bleeding and metastasis. Although obtaining a biopsy cannot be considered as useful in all cases, a biopsy should be obtained whenever feasible.

In conclusion, we reported FHdRCC as a type of dialysis-associated kidney cancer. This case indicates that it is important for patients with ACKD undergoing dialysis to undergo imaging to detect RCC. If the findings are equivocal, a biopsy should be performed to establish a definitive diagnosis and guide appropriate management. Our case highlights the usefulness of needle biopsy using the same method used by nephrologists for renal biopsy in cases where determining the lesion nature using imaging alone is deemed as difficult.