Muir-Torre syndrome in a haemodialysis patient.

Muir-Torre syndrome (MTS) is a rare inherited cancer syndrome with variable penetrance. MTS follows an autosomal-dominant pattern of inheritance, and is a subtype of Lynch syndrome [formally known as hereditary non-polyposis colorectal cancer (HNPCC)]. MTS is caused by mutations in one of several mismatch repair genes. Patients typically present with sebaceous neoplasms (sebaceous adenoma, sebaceous epithelioma, or sebaceous carcinoma) or with multiple keratoacanthomas. These patients also have an increased lifetime risk of visceral malignancies, typically affecting the colon, ovary, endometrium, genitourinary tract and small bowel. We describe a case of MTS in a haemodialysis patient and implications for transplant listing.

Background

Malignancy is believed to be more common in patients with end-stage renal failure than in matched controls with normal renal function [1]. However, the role of cancer screening, if any, in maintenance dialysis patients remains unclear [2, 3]. Most cases of cancer in end-stage renal disease (ESRD) are picked up when they cause symptoms. Of note, these patients have above average exposure to doctors and organ imaging [4], resulting in the detection of asymptomatic malignancies [5]. In contrast, a diagnosis of malignancy in the context of an inherited cancer syndrome is exceedingly rare. We report the interesting case of a middle-aged dialysis patient who presented with recurrent sebaceous tumours and who was eventually diagnosed with Muir–Torre syndrome (MTS), a rare genetic cancer syndrome.

Case

A 45-year-old Asian female haemodialysis patient with underlying IgA nephropathy presented in 2009 with a 25-mm non-pigmented nodular lesion on her left shoulder. The patient had felt the lesion was probably non-specific and harmless. Of note, a 4 × 5 mm benign sebaceous epithelioma of the abdominal skin had been resected in 2007. At the time of her current presentation the patient was systemically well and asymptomatic. The patient was then referred to a surgeon for what appeared to be a simple sebaceous cyst and the lesion was removed. Histology showed a tumour with sebaceous differentiation, frequent and atypical mitoses and infiltration of the surrounding tissues (Figure 1). A diagnosis of sebaceous carcinoma was made. Wide excision was carried out and histology showed clear margins. Computed tomography of chest and abdomen showed no metastasis. The patient was suspended from the renal transplant waiting list and a literature search was performed, since none of the clinicians involved had ever encountered this malignancy before. MTS was suspected after reading one of the first references [6] retrieved in Google™. The patient was referred to the regional clinical genetics service. A three-generation family tree was taken which demonstrated that her father had been diagnosed with a sebaceous carcinoma at the age of 50 years, a squamous cell carcinoma at 51 years, colon carcinoma at 52 years and rectal carcinoma at 54 years. Her paternal aunt had endometrial carcinoma at 56 years, her cousin had endometrial carcinoma at 47 years and a further cousin was diagnosed with ovarian cancer at 41 years (Figure 2). This fulfils the Amsterdam criteria for Lynch syndrome [7] and the clinical diagnosis of MTS, a subset of Lynch syndrome, was made. This was confirmed by the identification of a pathogenic mutation in MSH2. Colonoscopy was normal. Prophylactic hysterectomy and bilateral salpingo-oophorectomy were carried out in July 2010, without evidence of malignancy. Since then, the patient has had various benign sebaceous neoplasms resected until in April 2012, another 15-mm sebaceous cell carcinoma on the patient's back was resected. Again, wide excision was carried out in May 2012, and resection margins were clear. The patient is currently well and without evidence of recurrence or metastasis. She remains suspended on the transplant waiting list.

Fig. 1.

Sebaceous carcinoma. (A) The tumour shows a lobular pattern, with predominantly peripheral basaloid cells. Centrally sebocytes are also seen (×40). (B) High-power view demonstrating basaloid cells with numerous mitoses (arrows) (×600).

Fig. 2.

Pedigree. We were unable to ascertain cases in her grandparents.

Discussion

Several studies have observed an increased incidence of malignancies in patients with ESRD [1, 8] although the magnitude of the effect appears to be moderate [1]. Malignancies that appear to be more common in ESRD than in matched controls with normal renal function typically include renal cell carcinoma and urothelial cancer [9], whereas cancer of the lung, colon and rectum, prostate, breast, and stomach were not increased in the largest study reported to date [8]. There are interesting geographical differences as well, with a higher incidence being observed in Australia and New Zealand, followed by the USA and Europe [5]. The pattern of cancers also varies, often in accordance with well-described risk factors. For example, hepato-cellular carcinoma is more common in dialysis patients in Asia [10], presumably due to increased exposure to viral disease. In contrast, squamous cell carcinoma of the skin is very common in Australia, most likely due to increased sun exposure [11].

It is not entirely clear why ESRD associates with an increased rate of some malignancies. One factor is surely the occurrence of acquired cystic kidney disease, which predisposes to renal cell carcinoma [12]. This increased risk persists after renal transplantation [13]. Smoking may also play a role and it has been suggested that renal failure may prolong the exposure to carcinogenic substances, which undergo glomerular filtration [14]. Other factors that have been invoked include oxidative stress and deficient DNA repair mechanisms [14].

We describe an interesting case of MTS in a female haemodialysis patient. We only arrived at the diagnosis when one of us suspended the patient from the renal transplant list, following her first presentation with sebaceous cell carcinoma, googled the words ‘sebaceous carcinoma’ and noted the association of this particular malignancy with MTS. Others have described this approach previously [15]. Referral to the regional genetic service confirmed the diagnosis.

MTS is an autosomal-dominant disease named after London surgeon Edward Grainger Muir [16] and New York dermatologist Douglas Torre [17] who first described cases in the 1960s. MTS is often diagnosed late due to its presentation with seemingly benign sebaceous cysts around the eyelids and, less frequently, other areas of the skin [18]. After the sebaceous carcinoma has manifested in MTS, nearly half of the individuals are estimated to develop two or more malignancies before, after or simultaneously with the initial tumour. The most common neoplasms connected to MTS are colorectal (proximal to or at the splenic flexure) and genitourinary [19]. MTS is caused by mutations in the mismatch repair genes, in particular MLH1 and MSH2, although mutations in MSH6 have also been described [20]. MTS is therefore recognized as a subset of Lynch syndrome. Regarding screening, the major risk to patients is 60–80% lifetime risk of bowel cancer and up to 60% of endometrial cancer. There are various suggestions of screening for endometrial and colon cancer (1–3 years depending on the mutation) with hysterectomy and bilateral oophorectomy largely preventing the development of endometrial and ovarian cancer [21]. Screening of MTS-associated skin lesions in patients with Lynch syndrome has been recommended with annual dermatological examination [22] and with screening protocols based on those used for Lynch syndrome [23]. The skin lesions are often situated in either the periocular or extraocular regions. These two categories of sebaceous carcinoma are important to differentiate as the former are less often associated with MTS than extraocular [24]. Periocular skin lesions can be mistaken for chalazion or blepharoconjunctivitis [25]. Extraocular lesions are less common, more likely to be malignant and aggressive in their clinical behaviour. Histologically, it can be difficult to distinguish between benign and malignant sebaceous tumours. The former show a lobular organization and feature peripheral basaloid cells, which are usually more than two cell layers thick [20]. High-power view will show mature sebocytes showing foamy cytoplasm and central nuclei. Mitoses are scanty and cellular atypia is minimal. In contrast, sebaceous carcinomas show pleomorphic enlarged basaloid cells showing significant atypia with frequent and atypical mitoses [21]. Foci of necrosis and infiltrative growth may also be seen. Only scanty mature sebocytes are seen.

The management of sebaceous carcinoma is surgical with wide excision. Radiotherapy is used in extensive disease. To our knowledge no chemotherapy has proved effective on the tumour [26]. There are anecdotal reports to suggest that isotretinoin and interferon alpha-2a may prevent the occurrence of new lesions [27].

Finally, a diagnosis of MTS has implications for a patient on the transplant list, although, due to the rarity of the syndrome, there are no data from which to draw recommendations. Levi et al. described the case of a 55-year-old man 5 years after renal transplantation who presented with sebaceous carcinoma, leading to a diagnosis of MTS. Switching his immunosuppressive treatment to a sirolimus-based regime resulted in halting new lesions [28]. Others have emphasised that sebaceous tumours can occur in transplant patients without MTS [29]. We felt it difficult to recommend transplantation in a patient with a genetic cancer syndrome and after several malignant tumours had already been diagnosed. However, individuals with MSH2 mutations who are compliant with the surveillance programme have a normal life expectancy. We presented the case to the Israel Penn International Transplant Tumour Registry (IPITTR), who recommended a 5-year suspension from the waiting list.

Conclusion

MTS is a rare inherited cancer syndrome. A high degree of suspicion should be employed by pathologists [30] and clinicians when patients present with recurrent sebaceous tumours. Clinicians need to take a full family history, in particular asking about a history of bowel and endometrial cancer. These patients should be referred to genetic services to investigate the family appropriately and if found to have an mismatch repair gene mutation, enter a surveillance programme. This would include dermatological surveillance, regular colonoscopies and hysteroscopies in women. The diagnosis of MTS in a patient with ESRD also mandates a discussion of transplant listing, taking into account the extent of sebaceous malignancies but also the predisposition to malignancy in general.