Muir-Torre Syndrome A Case Associated with an Infrequent Gene Mutation

Alexandra Grob, DO; Christina Feser, DO; Steven Grekin, DO; Oakwood Healthcare System, Trenton, Michigan.

Disclosure: The authors report no relevant conflicts of interest.


Muir-Torre syndrome is a rare, autosomal dominant genodermatosis characterized by the presence of at least one sebaceous gland neoplasm, associated with an underlying visceral malignancy. Muir-Torre syndrome is believed to be a subtype of Lynch Syndrome. Affected individuals are found to have germline mutations predominantly in DNA mismatch repair gene MSH2, and much less frequently, MLH1. The authors report the case of a 55-year-old woman presenting with multiple cutaneous neoplasms including sebaceoma, basal cell carcinoma, and squamous cell carcinoma; personal history of colorectal and endometrial cancer; and family history of colorectal cancer; found to have a deletion at mismatch repair gene MLH1. It is important to recognize the role of these less common gene deletions in producing the Muir-Torre syndrome phenotype, and consider the correlation of cutaneous manifestations with internal disease. The authors discuss the clinical presentation of Muir-Torre syndrome, methods of diagnosis, and the importance of regular medical surveillance to detect and prevent disease progression in Muir-Torre syndrome patients and their family members. (J Clin Aesthet Dermatol. 2016;9(1):56–59.)

A 55-year-old woman with a history of colorectal and endometrial cancer status post-partial colectomy and total abdominal hysterectomy, squamous cell carcinoma (SCC), basal cell carcinoma (BCC), and hypertension presented to the clinic for evaluation of a nasal lesion. She was unsure of the total duration the lesion had been present, yet stated that the area had recently been changing in character with crusting and pain. The patient admitted to similar appearing lesions in the past, which had been biopsied, as well as treated with electrocautery and cyrotherapy. She had previously undergone Mohs micrographic surgery for SCC of the left breast, as well as BCC of the right nasal ala. Prior biopsy reports revealed history of two sebaceomas of the right nose for which no further intervention was performed. Family history was positive for visceral malignancy, as her mother was deceased at age 64, secondary to colon cancer. The patient could not recall a history of cutaneous lesions in her mother and had no known family history of skin cancer. A review of systems was otherwise negative.


Physical examination revealed a well-developed female in no apparent distress. Her face featured a 4mm non-tender, pearly papule on the right nasal tip along with multiple, scattered, 0.2 to 0.4cm, yellow, lobulated papules, most dense throughout the nose and bilateral cheeks. Chest was without evidence of recurrence or suspicious lesions. The back and extremities demonstrated multiple, scattered, brown, waxy papules and plaques, as well as uniform brown macules consistent with seborrheic keratoses and solar lentigos. At the time of examination, a 3mm shave biopsy was obtained of the lesion at the right nasal tip, which was suspicious for malignancy.


Microscopic examination revealed a well-circumscribed vertically oriented neoplasm composed of immature and mature sebocytes. Ductal structures with an eosinophilic, undulating cuticle were scattered throughout the lesion. No palisading nuclei were noted. Epidermal erosion with scale crust was seen. Overall findings were classified as sebaceoma (Figure 1A and Figure 1B). These findings were consistent with two prior biopsies of the right nose.

Course and Therapy

The patient’s clinical history, family history, and histopathology obtained were strongly suggestive of Muir- Torre syndrome (MTS). She was counseled regarding this diagnosis, and referred for further genetic testing. Tumor testing of previous endometrial cancer was microsatellite in-stability (MSI) high, with 5 of 5 markers showing MSI with absent staining of the MLH1 and PMS2 proteins. Additional germ-line analysis of the MLH1 gene was positive for a deletion, con-firming the diagnosis of MTS.

Current management of the patient is focused on surveil-lance and preventative measures. She is being monitored with skin exam-inations every six months to detect new or changing lesions. Biopsies will be ob-tained if any suspicion of malignancy. A multidisciplinary team will be involved for routine care and to monitor the patient for malignant transformation, with regular laboratory work, mammograms, pelvic examin-ations, pap smears, and colon-oscopies. Relatives have also been notified of her condition, with recommendations for genetic testing. There have been no additional diagnoses to date.


Muir-Torre syndrome is a rare autosomal dominant geno-dermatosis defined by the coincidence of at least one sebaceous gland neoplasm and one visceral malignancy. The sebaceous neoplasms encom-pass sebaceous adenomas, sebaceous epitheliomas (seb-aceoma), and sebaceous car-cinomas, as well as kerato-acanthomas with sebaceous differentiation.[1]

Muir-Torre syndrome patients show an increased risk of developing various internal malignancies, including colo-rectal, endometrial, ovarian, genitourinary, and small bowel cancers.[2] The most common of these is colorectal cancer, which accounts for about 50 percent of all primary cancers in MTS. Approximately 15 percent of female MTS patients develop endometrial cancer.[3]

Characteristic skin lesions may occur before, concurrently, or after the development of visceral malignancy. In 22 percent of patients, a sebaceous neoplasm is the first inclination to the diagnosis of MTS and precedes the diagnosis of visceral malignancy. However, more frequently, in up to 56 percent of reported cases, the diagnosis of a visceral malignancy is made prior to the discovery of a sebaceous neoplasm, while in six percent of cases, the diagnoses are made simultaneously.[4]

Sebaceous adenoma is considered the most specific tumor marker of MTS, with a reported association ranging from 25 to 60 percent. The incidence of sebaceoma in patients with MTS, however, varies anywhere from 31 to 86 percent.[5] Clinically, sebaceous adenomas appear as tan, pink, or yellow nodules or papules, usually about 5mm in greatest dimension, and are most commonly found on the head and neck. Sebaceomas appear similar, although larger in size, ranging from 5mm to 3cm with a fleshy yellow to orange color. These lesions can range from few in number to hundreds.[2],[6] Although adenomas and sebaceomas are considered two ends in a spectrum of benign sebaceous neoplasia, it is important to recognize these lesions as potential markers of MTS, and their presence should therefore prompt a screening for visceral malignancy.[7]

Proper histological identification is important for diagnosis, treatment, and prognosis. An increase in the number of germinative cells is a key discriminator between the relatively benign sebaceous hyperplasia versus a potentially concerning sebaceous neoplasm. Sebaceous adenomas for example, show variably expanded basaloid cells with more than the normal two layers seen in usual sebaceous glands and sebaceous hyperplasia, but comprise less than 50 percent of tumor cell volume. Sebaceomas appear similar, although with germinative basaloid cells predominating over mature sebocytes in greater than 50 percent of tumor cell volume. Sebaceomas also differ, in that prominent populations of mature sebocytes typically appear in haphazard arrangement, lacking the central maturation often seen in sebaceous adenoma.[2]

Several studies have shown that the spectrum of internal malignancies observed in patients with MTS is similar to that observed in hereditary nonpolyposis colorectal cancer (HNPCC), or Lynch Syndrome, raising the possibility that MTS or one of its subtypes represents a phenotypic variant of HNPCC.[3],[5],[8],[9] Deleterious germline mutations within the DNA mismatch repair (MMR) pathway are the genetic anomaly responsible for HNPCC. This includes at least one mutation in MMR genes MSH2, MLH1, MSH6, PMS1, or PMS2.[3],[10] MMR gene mutations are also implicated in MTS, most commonly affecting MSH2, followed by MLH1.[11]

A significantly greater incidence of MSH2 mutations, from 61 to 93 percent, has been reported in MTS patients, in contrast to just 7 to 10 percent reported to have MLH1 mutations. This suggests a geno-phenotype correlation where MSH2 mutations are the predominant causative factor in MTS.8,10,12 Although MLH1 mutations are thought to be associated less with MTS then MSH2 mutations, it has been argued that both genes have an equal etiopathological role in visceral tumorigenesis, and their involvement in MTS patients should always be investigated together.11

Such mutations in these DNA repair genes result in microsatellite instability (MSI). In one study of unselected sebaceous neoplasms by Kruse et al,[13] MSI was detected in 60 percent of sebaceous adenomas, sebaceomas, and sebaceous carcinomas collectively, as compared to only three percent of sebaceous hyperplasia.[13] Further evidence has indicated that lesional tissue from both cutaneous and visceral neoplasms in patients with MTS often exhibit MSI secondary to defects in MMR genes.[4]

Immunohistochemistry (IHC) analysis of tumor tissue shows loss of one or more MMR proteins in sporadic sebaceous neoplasms, including those associated with MTS. Increasing evidence suggests the use of IHC as the initial screening test, as suggested by ease of methodology, sensitivity in detecting the involved MMR protein, and good correlation between results from IHC and MSI analyses.[5],[14]

The combination of a thorough family and past medical history, along with physical exam, can aid in identifying most cases of MTS. A diagnosis should be considered in a patient with at least one sebaceous neoplasm and one primary visceral malignancy. Without a sebaceous neoplasm, the diagnosis can be obtained by the presence of multiple keratoacanthomas and visceral malignancies, along with a known family history of MTS. After the clinical criteria are met, immunohistochemical stains for MSH2 and MLH1 can be used to confirm a diagnosis.[4]

Early detection of malignancy is crucial in implementing proper treatment regimes for these patients. Strong indicators of MTS include multiple sebaceous neoplasms, yet only a single tumor can represent the syndrome. Evaluation of patients with just one sebaceous neoplasm of any type for colonic adenocarcinoma is recommended.[1] Diagnosis of MTS is essential for both the patient and his or her extended family, as surveillance and preventative measures can be utilized to increase life expectancy in those genetically predisposed to malignancy.

Recommended screening guidelines for MTS patients and their first-degree relatives are listed in Table 1.[15]

In addition to annual pelvic exams, transvaginal ultrasonography and endometrial biopsy are also recommended in female patients with an associated gene mutation, for those aged 25 and above.[15] Some suggest hysterectomy and bilateral salpingo-oophorectomy in women 35 years or older who do not want any more children.[16] Gastroscopy and renal ultrasonography can be considered every 1 to 2 years in families with a history of gastric or renal tract cancer. Finally, prophylactic colectomy may also be considered.[15]


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