Fumarate hydratase-deficient renal cell carcinoma presenting as pelvicalyceal filling defect: an unusual presentation of a rare disease

Abstract

A 75-year-old man was referred to our urology service with painless haematuria. The delayed phase on a subsequent computed tomography (CT) abdomen and pelvis showed a filling defect in the left renal pelvicalyceal system, suspicious for a transitional cell carcinoma. The patient underwent ureteroscopic biopsy suggestive of a papillary neoplasia, before progressing to a laparoscopic radical left nephrouretectomy. Final histology revealed a fumarate hydratase-deficient renal cell carcinoma with clear margins. The patient was subsequently referred for genetic counselling.

Background

Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) is a rare, aggressive RCC which arises in patients suffering from hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC). FH-deficient RCC presents as an aggressive malignancy, arising due to mutations in the FH tumour suppressor gene. Here, we describe a case of FH-deficient RCC formally identified in a 75-year-old man after a radical nephrouretectomy, presenting initially as a pelvicalyceal filling defect.

Case presentation

A 75-year-old man was referred by his primary healthcare provider (PHP) to our urology service after a single episode of painless macroscopic haematuria. The patient had ongoing daily haematuria without passage of clots and moderately bothersome lower urinary tract symptoms. The patient’s medical history was significant for ischaemic heart disease, hypertension, dyslipidaemia, atrial fibrillation, peripheral vascular disease, chronic obstructive pulmonary disease and T1cN0M0 left upper lobe non-small-cell lung cancer. He was on regular atorvastatin, dabigatran, metoprolol and telmisartan. He was an ex-smoker with a 35 pack-year smoking history, consumed two standard drinks a week and was a retired butcher with no occupational exposure to aromatic amines.

Physical examination revealed an irregularly irregular pulse consistent with known atrial fibrillation, soft non-tender abdomen and non-tender testes bilaterally. A rectal examination revealed a smooth, firm, mildly enlarged prostate.

Investigations

Routine blood tests were unremarkable. Urine microscopy demonstrated persisting microhaematuria with 20 erythrocytes. Additionally, no malignant, atypical or other abnormal cells were noted on urine cytology. The patient was initially imaged with a renal tract ultrasound, showing normal kidneys with a 3 cm single left lower pole renal cyst. The delayed phase on a subsequent CT abdomen and pelvis organised by the patient’s PHP showed a left renal pelvic filling defect, raising concerns for a urothelial cell carcinoma without evidence of any other renal lesions (figure 1).

Figure 1.

Pelvicalyceal filling defect on CT imaging, initially suspicious for transitional cell carcinoma. Note that the filling defect has been highlighted by a red arrow.

Management

Initial management was via ureteroscopy and biopsy of the lesion noted on the CT abdomen and pelvis. A large, papillary mass was noted in the left upper pole, which was biopsied. The right collecting system was not examined. Histology of the left upper pole biopsy identified the tumour as potentially being an RCC with papillary architecture. The histopathology was based on a very small ureteroscopic biopsy sample and the final result was thought to be inconclusive. Given the discordance between the visualised tumour (presumed urothelial cell carcinoma) and biopsy result (papillary RCC), the patient underwent a laparoscopic left nephrouretectomy. Intraoperatively, the hilum was incised to assess the tumour, once the kidney had been removed from the patient. Intraoperative frozen section was considered, but not used, due to their limitations by architectural distortion and lack of immunostaining. Due to the high pretest probability that the lesion represented urothelial cell carcinoma, and to avoid return to theatre should the diagnosis confirm it, the decision was made to proceed with a nephroureterectomy. The bladder cuff was also excised.

Diagnosis

The gross sample (figure 2) was prepared into slides (figure 3). Histopathology proved to be difficult due to the challenge in interpreting the immunohistochemistry results from the specimen, noted as below:

Figure 2.

Image of the resected kidney, incised at the hilum. Note that the tumour has been bisected due to the incision and has been marked by two red circles.

Figure 3.

Histopathological images of the resected specimen stained with H&E. (A) Histopathological image at ×20 magnification showing two areas of tumour (dark pink tubular structures) and normal renal fat in between these two areas. (B) Histopathological image of the tumour at ×100 magnification. (C) Histopathological image of the tumour at ×400 magnification.

• Alpha-methylacyl-CoA racemase (AMACR): patchy positive staining.

• Cytokeratin 7 (CK7) and GATA-binding protein 3 (GATA3): negative staining.

• Paired-box gene 8 (PAX8): focal positive staining.

• Succinate dehydrogenase (SDHA and SDHB): both positive staining.

• Fumarate Hydratase (FH): positive staining (figure 4).

• 2-succinocysteine (2SC): positive staining (figure 5).

Figure 4.

Histopathological image of the resected specimen stained for fumarate hydratase.

Figure 5.

Histopathological image of the resected specimen stained for 2-succinocysteine.

Positive staining for 2SC is highly sensitive for FH-deficient RCC. Unusually, the immunohistochemistry showed positive staining for FH. While loss of expression of FH is highly specific for FH-deficient RCC, not all FH-deficient RCCs show loss of expression for FH. The samples were sent for an expert opinion given the diagnostic challenge. Based on the histological findings (prominent nucleoli and diversity of architectures including papillary and solid cribriform) and the positive 2SC staining, the diagnosis of FH-deficient RCC (HLRCC) was made.

Outcome and follow-up

The patient was reviewed 1-month postprocedure and was well. Due to the familial predisposition of his malignancy, the patient was referred for genetic counselling and planned for rereview in 6 months’ time with repeated blood tests and a CT chest, abdomen and pelvis.

Discussion

Introduction

HLRCC is a rare disorder caused by mutations in the FH gene, resulting in cutaneous piloleiomyomas, uterine leiomyomas in females and FH deficient RCC.¹ The condition is typically autosomal dominant, though can arise in patients who are heterozygotes for the FH gene with an inactivating mutation in the normal FH gene.

Overview of malignant potential

Patients with the disorder have an approximately 15% risk of manifesting RCC, which is typically an aggressive carcinoma that often resembles type 2 papillary RCC. It is worth noting that several FH mutations have been described which may result in the disorder; however, there have been no clear genotype-phenotype correlations found to date.

Novelty of the presentation

While there have been several cases of HLRCC described in the literature, to the best of our knowledge, none have presented as a pelvicalyceal filling defect mimicking a urothelial tract carcinoma. Unusually, our patient is of an older age compared with the cases described in the literature. Thus, our case represents a novel addition to the body of literature surrounding this already rare condition.

Management options for HLRCC

Given that germline mutations are the cause for HLRCC, an important part of the management process is to offer genetic screening to identify mutations of the FH gene to the patient and family members. Menko et al proposed that genetic testing should be offered first to those at risk prior to renal cancer surveillance, to avoid unnecessary investigations. In this way, individuals who do not possess familial FH mutations predisposing them to RCC may avoid the need for ongoing surveillance that can be associated with radiation exposure and psychological impact.¹

Should a patient be positive for FH mutations, they require surveillance imaging to ensure early detection of RCC. There has been no consensus regarding the age of screening and imaging modality. Some argue that since there have been reported cases of HLRCC in young patients, imaging should be offered as early as at the age of 5.² Others argue that the risk of HLRCC in young patients is extremely small and that therefore surveillance should only commence around the age of 18–20.^{3 4} Additionally, while most authors suggest MRI as the imaging of choice, some have outlined CT and ultrasound as modalities for surveillance imaging.^{2 4}

Outcomes of HLRCC

If HLRCC is suspected on imaging, prompt surgical management is required. Active surveillance is not appropriate due to the highly aggressive nature of the disease, in which metastatic disease can occur with even small lesions.¹ The gold-standard treatment for HLRCC is a radical nephrectomy. Another reason for high vigilance is the difficulty associated with managing metastatic HLRCC, which is thought to be standard systemic treatment and immunotherapy resistant.

Learning points.

• Hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC) is a rare disorder characterised by cutaneous piloleiomyomas, uterine leiomyomas in females and papillary RCC.

• When faced with a pelvicalyceal filling defect, tissue biopsy may provide important information such as histopathological differentiation of rare type of cancers.

• Genetic testing and surveillance are important processes in the treatment of HLRCC.

• The gold-standard treatment for HLRCC suspected on imaging is a radical nephrectomy.