余秉軒¹、張延驊^1,2,3、黃志賢^1,2,3

¹臺北榮總泌尿部；²國立陽明大學醫學系泌尿學科；³國立陽明大學書田泌尿科學研究中心

Ping-Hsuan Yu¹, Yen-Hwa Chang ^1,2,3, William J.S. Huang^1,2,3

¹ Department of Urology, Taipei Veterans General Hospital;

² Department of Urology, School of Medicine, National Yang-Ming University;

³Shu-Tien Urological Science Research Center, National Yang-Ming University

 

Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) is a less common and newly described subtype. Most patients have locally advanced or metastatic disease at diagnosis, and often with poor prognosis. Hereditary leiomyomatosis renal cell cancer (HLRCC) syndrome may be found among these patients. Here we would like to share two FH-deficient RCC cases in our institute. One received surgical intervention while the other was treated with systemic therapy. The clinical presentations and treatment courses are illustrated below.

 

The first case is a 60-year-old ex-smoker without systemic disease. He had a fainting episode, and bilateral pulmonary emboli were depicted in chest CT scan by other local institute. He was admitted to intensive care unit and anti-coagulant therapy was given. However after discharge, the follow-up chest X-ray showed newly developed bilateral lung opacities. Therefore, the patient came to our hospital for second opinion. He visited chest medicine and cardiovascular surgery outpatient clinics at first. The repeated CT showed not only filling defects at bilateral main and left inferior pulmonary arteries, but also revealed left renal tumor with renal vein tumor thrombus, retroperitoneal lymphadenopathies, multiple lung and liver metastases. He was then referred to our section for further management. Sono-guided biopsy of the left renal tumor was done on 2017/10/27 and fumarate hydratase-deficient renal cell carcinoma was diagnosed with clinical staging of cT3bN1M1 disease.

We discussed the potential treatment regimen with the patient and his families, since there was no reimbursed systemic therapy for this subtype of metastatic RCC and the potential outcome of his disease is poor. They decided surveillance at that time.

 

He developed painless gross hematuaria three months later, and CT scan disclosed disease progression at both primary and metastatic lesions. He then started immunotherapy (pembrolizumab 200 mg iv q3w) with anti-VEGF targeted agent (axitinib 5 mg bid) combination regimen since 2018/02/23 on self-pay basis till 2020/04/06. With treatment duration of 26 months, he experienced best treatment response of near-CR of liver metastasis at three months following the combination therapy and currently with stable disease of all lesions but new soft tissue metastasis at left iliac bone. Further local radiotherapy is planned. Until now, the patient has already taken total 26 doses of pembrolizumab with axitinib. During the treatment course, he has ever been admitted to chest surgery ward for lung biopsy to diagnose the non-tuberculosis mycobacterium infection. Another admission to cardiology department was for pulmonary hypertension secondary to the chronic pulmonary emboli.                  

 

The other case is a 44-year-old male without significant underlying disease. Some non-specific symptoms such as epigastric discomfort and nausea/vomiting were observed at diagnosis. He denied any family cancer history. Computed tomogram disclosed a huge heterogeneous enhancing tumor arising from right kidney upper pole (8.7x16.35 cm) with regional lymphadenopathies compressing the inferior vena cava, with negative finding in both chest CT and bone scan. He underwent right radical nephrectomy, adrenalectomy and para-caval lymph node dissection on 2020/03/09 for pT3aN1 fumarate hydratase-deficient RCC with two positive para-caval lymph nodes. Capsular penetration, hilar vein invasion, perirenal fat invasion were observed microscopically. High risk of disease progression was informed to the patient and intensive follow-up protocol is undergoing now. Genetic evaluation of hereditary leiomyomatosis renal cell cancer syndrome associated RCC (HLRCC) will be performed.

 

Fumarate hydratase-deficient renal cell carcinoma can occur in both germline and somatic setting, while germline alterations are associated with the hereditary leiomyomatosis and renal cell carcinoma. The disease is known for clinically aggressive behavior and poor prognosis. Thus, metastasis or symptoms in other organ systems may be the first manifestation. Nephrectomy still benefits patients with curative intent if indicated. As for systemic therapy, combined pembrolizumab with axitinib shows promising results with possible long-term disease control in our limited experience.