Muir-Torre Syndrome Presenting as A Sebaceous Carcinoma of the Nasal Ala

Muir-Torre Syndrome (MTS) is a rare genodermatosis that is inherited in an autosomal dominant fashion. MTS is characterized by the presence of at least one sebaceous neoplasm concomitant with a visceral primary malignancy and represents a subtype of hereditary nonpolyposis colorectal carcinoma (HNPCC), also known as Lynch syndrome. Sebaceous carcinomas are one type of neoplasm associated with MTS, although they often occur sporadically.¹ Most sebaceous carcinomas arise from the adnexal epithelium of sebaceous glands. While they may occur anywhere that sebaceous glands are present, only a minority of cases occur in extraocular regions. Although cases of MTS have been well reported in the literature, only a handful describe extraocular manifestations of sebaceous carcinoma.

We present the case of 56-year-old female patient who came to the plastic surgery clinic with biopsy proven sebaceous carcinoma of the right nasal ala. Her past medical and surgical history was significant for a sebaceous carcinoma of the right flank that was previously excised. The patient also had a family history of Lynch syndrome (sister). On physical exam, the lesion appeared as a pearly pink papule, approximately 5 mm in size (Figure 1, A) which had slowly enlarged over course of several years. Wide local excision with 3 mm margins was performed and the defect was reconstructed with local tissue rearrangement. Histology demonstrated negative margins. At a one-year post-operative follow up, she had an excellent cosmetic result.

Figure 1:

Sebaceous carcinoma (A) of the right nasal ala is pictured at the time of presentation

Given the patient’s diagnosis of a second sebaceous carcinoma and family history of Lynch Syndrome, she underwent genetic testing. Single site genetic analysis of a blood specimen revealed germline MSH-2 deleterious mutations in exons 1 - 6, resulting in deletion of exons 1 - 5 which confirmed the MTS diagnosis. This conferred an 82% risk of colorectal cancer and 60% risk of endometrial cancer by age 70. After her skin cancer was treated, she underwent a routine screening colonoscopy and an endoscopically unresectable colon polyp was discovered. Pathology revealed high-grade dysplasia/carcinoma in situ with suspicion of an invasive component; thus, she underwent a total abdominal colectomy with ileorectal anastomosis. Further screening recommendations for other MSH2-associated cancers were advised, including an upper endoscopy every two to three years (should begin at age 30 - 35), screening for uterine and ovarian cancer with transvaginal ultrasound, and CA-125 blood test (should start at age 35) every six months, and annual urinalysis to screen for cancers of the urinary tract.

MTS is a rare genetic subtype of Lynch syndrome with a high degree of penetrance and variable expression.¹ While sebaceous adenomas are the cutaneous neoplasm most associated with MTS, sebaceous carcinoma, sebaceous epithelioma, and multiple keratoacanthomas have also been described. Sebaceous carcinomas appear as skin colored to pink slowly enlarging papules or nodules that can sometimes ulcerate or bleed. They occur most commonly in the periocular region, although extraocular SCs comprise approximately 25% of cases.² Among extraocular cases, about 70% occur in the head and neck region. In contrast with their sporadic counterparts, sebaceous carcinomas associated with MTS frequently present in multiples and occur at an earlier age (mean 53 years).

The majority of cases of MTS are due to germline mutations in mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2, with mutations in MSH2 being the most common.³ Defects in these genes lead to microsatellite instability which can disrupt tumor suppressor gene function. Recently, a second phenotype of MTS has been proposed comprising a subgroup that does not demonstrate microsatellite instability. The MTS II subtype represents approximately 35% of tumors and, in contrast to MTS I, is associated with the MYH1 gene and displays autosomal recessive inheritance (Table 1). Initial testing for MTS involves evaluation of a tumor with immunohistochemistry staining for lack of expression of MMR genes or for microsatellite instability. However, testing sebaceous neoplasms in this way is prone to false positive results at a rate of about 56%. It is therefore recommended to evaluate colon or endometrial tumors instead, which have a much great specificity with immunohistochemistry. If this is not possible, genetic testing for germline mutations may be performed instead.

Table 1.

Lynch syndrome subtypes

Subtype	Defining characteristics	Associated germline mutations	Inheritance	Presence of microsatellite instability
Lynch Syndrome	Early onset and/or multiple malignancies: Colorectal, endometrial, ovarian, GU, and other GI cancers	MSH2, MLH1, MSH6, PMS2	Autosomal dominant	Yes
Muir-Torre Syndrome (type I)	Visceral primary malignancy (same as those of Lynch Syndrome) plus Sebaceous neoplasms	Same as Lynch Syndrome	Autosomal dominant	Yes
Muir-Torre Syndrome (type II)	Same as MTS I	MYH1	Autosomal recessive	No
Turcot Syndrome (more commonly a subtype of familial adenomatous polyposis (FAP))	Colorectal carcinoma plus Brain tumors: Gliomas or medulloblastomas)	Same as Lynch Syndrome APC (when occurring as a subtype of FAP)	Autosomal dominant	Yes (in Lynch subtype) No (in FAP subtype)

Currently, no staging system or practice guidelines exist to guide the management of extraocular sebaceous carcinomas, although the American Joint Committee on Cancer tumor, node, metastasis (TNM) staging guidelines for cutaneous squamous cell carcinomas and other cutaneous carcinomas can be applied. Imaging for the purpose of staging is not of conclusive benefit, as no studies have been performed to evaluate its role. Computed tomography (CT) with or without positron emission tomography (PET) has been suggested for patients with aggressive tumors, palpable regional lymphadenopathy, or biopsy proven nodal metastases.

The treatment of choice for sebaceous carcinoma is wide local excision with 5 – 6 mm margins using pathology confirmation of adequate margins. The authors note that in the case presented, the margins achieved were less than what is recommend however, this is acceptable only when a lesion in is an aesthetically sensitive area, as was our case. The use of Mohs micrographic surgery has also been reported. While sebaceous carcinoma tends toward a more indolent course when associated with MTS, its presence should prompt an evaluation for suspicious lymph nodes. However, given that the rate of regional metastasis is only 1.4% in extraocular sebaceous carcinoma, it is not recommended that sentinel node biopsy be routinely performed. Radiation is not typically necessary but may be used in cases of recurrence, metastasis, or for palliation. Additionally, there is no role for chemotherapy in treating these lesions. Ten-year survival is 57.02% in extraocular cases of sebaceous carcinoma in the setting of MTS.⁴

Extraocular sebaceous carcinomas may be the initial clinical manifestation of the Lynch variant, MTS. Yet, little has been reported in the literature regarding this. This case adds to the literature and highlights the importance of obtaining a thorough history and keeping a broad differential when evaluating skin lesions. In patients diagnosed with MTS, vigilance is required to screen for associated neoplasms. In addition to screening for colorectal cancer by colonoscopy every 2 years beginning at age 20 -25, a multi-society task force has issued guidelines recommending other screening be offered to those at risk. These screens include annual pelvic exams and endometrial sampling, annual transvaginal ultrasound, esophagogastroduodenoscopy (EGD) every 2 - 3 years, and annual urinalysis all beginning at age 30 - 35. Any diagnosis of MTS or Lynch syndrome in an individual should prompt screening and possibly genetic testing in first-degree family members as well.