Skin rash, a kidney mass and a family mystery dating back to World War II

A 25-year-old white man presented with a year-long history of malaise, a palpable right loin mass and a painless nodular rash over his back of indeterminate duration. Computed tomography (CT) showed a right renal mass with para-aortic and retroperitoneal lymphadenopathy. The patient underwent radical nephrectomy and paraaortic lymphadenectomy. Examination of the kidney showed a 14 cm tumour centred in the renal medulla (Box, A). The tumour cells were organised in papillary fronds and featured abundant eosinophilic cytoplasm, large nuclei and prominent inclusion-like eosinophilic nucleoli (Box, B). There was widespread vascular space invasion and involvement of the renal sinus fat and hilar vein. All four para-aortic lymph nodes contained metastatic disease. The patient’s longstanding skin rash (Box, C) was reviewed and confi rmed on biopsy to represent multiple cutaneous leiomyomata.1 The patient’s mother was found to have had multiple cutaneous and uterine leiomyomata. The death certifi cate of his maternal grandfather stated that he died of metastatic renal carcinoma at the age of 44. He had returned from active service in World War II with a mysterious and longstanding rash, the pattern of which was consistent with cutaneous leiomyomatosis. On this basis a provisional diagnosis of hereditary leiomyomatosis and renal cell cancer (HLRCC) was made.1 After the patient underwent genetic counselling and provided informed consent, blood was drawn for molecular analysis of the fumarate hydratase (FH) gene locus by Sanger sequencing and multiplex ligation-dependent probe amplifi cation assay (MLPA). MLPA showed complete deletion of the FH gene in one allele, confi rmed by comparative genomic hybridisation on an Agilent custom oligonucleotide array (Agilent Technologies Inc) to be a 0.5 Mb deletion including FH and OPN3. No further cascade genetic testing has been undertaken in this family to date. The patient’s postoperative recovery was uneventful. Fluorodeoxyglucose positron emission tomography 6 months after surgery showed multiple hepatic and left fl ank chest wall subcutaneous metastatic deposits. There was no evidence of recurrence in the nephrectomy bed. First-line therapy with sunitinib (50 mg daily, orally) was commenced and well tolerated. Eighteen months after the patient’s surgery, CT imaging showed a reduction in the volume of the hepatic tumour and complete regression of the previously identifi ed extrahepatic disease. Subsequent planned subtotal hepatectomy was aborted due to the size and location of hepatic disease apparent only at exploratory laparotomy. Therapy was changed to everolimus (10 mg daily, orally). This resulted in symptomatic anaemia requiring transfusion. A restaging CT scan performed 8 months after commencement of therapy with everolimus showed progression in the size of the hepatic metastatic deposits. Treatment was then changed to combination therapy with bevacizumab (15 mg/kg intravenous infusion every 3 weeks) and erlotinib (150 mg daily, orally) based on the treatment arm of a current National Cancer Institute phase II clinical trial (NCI-10-C-0114). The disease was stable for 16 months after commencement of the combination regimen, with the patient able to return to full-time employment. However he subsequently developed progressive disease and, despite a brief trial of sorafenib, died with widespread metastases 64 months after his initial presentation.