Muir-Torre syndrome is a rare cancer predisposition syndrome characterized by unusual cutaneous tumors and internal malignancy.1,2 The cutaneous tumors associated with Muir-Torre syndrome include mainly sebaceous gland neoplasms (sebaceous adenoma and sebaceous carcinoma), keratoacanthoma, and basal cell carcinoma.1- 3 Colorectal and genitourinary carcinoma are the common types of internal malignancies that occur in Muir-Torre syndrome.3 Although Muir-Torre syndrome is characterized by autosomal dominant inheritance, sporadic cases are known to occur. Significant variation can occur in the phenotypic manifestations of Muir-Torre syndrome, and in some cases Muir-Torre syndrome may resemble hereditary nonpolyposis colorectal carcinoma.4,5 Recent investigations into the molecular genetics of Muir-Torre syndrome have revealed genomic replication errors, known as microsatellite instabilities, due to mutations in the mismatch repair genes, hMSH2 and hMLH1.6 In this report, we present the clinical and histologic features of a patient with Muir-Torre syndrome who had multiple facial lesions, some of which involved the eyelid, in association with an internal malignancy.
A 59-year-old man sought care in July 2003 for a progressively enlarging exophytic lesion that involved the left upper eyelid for the last 6 months. He had a history of biopsy-proven basal cell carcinoma of the right temple region, which had been treated with external beam radiotherapy in 1996. He had also been treated for biopsy-proven advanced rectal adenocarcinoma with preoperative combined chemoradiotherapy followed by an abdominoperineal resection and sigmoid colostomy in 1996. He was free of local tumor recurrence or metastasis. There was no family history of any ocular disease or malignancy.
On examination, the patient’s corrected visual acuity was 20/20 OU. External examination revealed an 8 × 5 × 4-mm, yellowish-pink, warty growth of the left upper eyelid close to the margin (Figure 1A). The surface of the lesion had fine papillary projections without vascularity, crusting, or ulceration, and no surrounding induration was present. Numerous yellow-white, slightly raised lesions that ranged in size from 3 to 10 mm were distributed on the face in the central forehead region, nose, and adjacent cheek area (Figure 1B). Each lesion appeared to be a conglomeration of many smaller nodular lesions. The results of anterior segment examination and fundus evaluation of both eyes were unremarkable. The eyelid lesion and one of the facial lesions were excised and submitted for histopathologic evaluation.
Sebaceous adenomas on the face in a patient with Muir-Torre syndrome. A, External appearance of the left eye. Note a yellowish-pink warty growth arising from the anterior lamella of the left upper eyelid. B, Multiple yellow nodular lesions involving the central forehead, nose, and adjacent cheek area (arrow).
Macroscopically, the eyelid lesion was composed of a 10 × 8 × 5-mm pentagonal piece of skin, with a 5 × 4-mm, firm, yellow exophytic nodule. The facial lesion was composed of a 10 × 6 × 3-mm elliptical-shaped piece of skin with a 6 × 4 × 3-mm, central yellow nodule.
Microscopy of the eyelid lesion demonstrated an exophytic neoplasm situated principally within the cutaneous compartment that was composed of multiple, irregularly shaped, closely packed, circumscribed sebaceous lobules, separated by compressed, dermal connective tissue septa (Figure 2A). The lobules communicated with the epidermal surface via several openings. Each lobule was composed of a peripheral, mitotically active basaloid germinative layer, which exhibited moderate cytologic atypia maturing to vacuolated sebocytes centrally, with transitional forms seen (Figure 2B). The mature, central sebocytes comprised most of the lesional tissue. Variable eosinophilic holocrine degeneration was seen. No convincing cystic change was identified. There was no evidence of an infiltrative growth pattern, pagetoid lesions, mitotic figures, or lymphovascular space invasion. The eyelid tissue adjacent to the lesion exhibited patchy, focal lipogranulomatous inflammation, constituting secondary chalazion formation. The cheek lesion demonstrated histologic features identical to those described herein (Figure 2A and 2B). The circumscription, mature sebaceous phenotype, lack of infiltrative borders, absence of aberrant mitotic figures, and necrosis of both lesions supported the diagnosis of benign sebaceous adenomas.
Histopathologic features of Muir-Torre syndrome. A, Eyelid (upper panel) and face (lower panel) sebaceous adenomas (original magnification ×10). B, Higher-power images of the eyelid (upper panel) and face (lower panel) sebaceous adenomas, demonstrating the mitotically active, cytologically atypical basaloid germinative cells layer (arrows) with adjacent mature vacuolated sebocytes (arrowheads) (original magnification ×100). C, Rectal adenocarcinoma. Note the malignant glandular profiles with a surrounding desmoplastic response (original magnification ×50). D, Sebaceous adenoma stained immunohistochemically with an antibody to the MLH1 protein. Note the presence of brown nuclear staining (original magnification ×50). E, Sebaceous adenoma stained immunohistochemically with an antibody to the MSH2 protein. Note the absence of nuclear staining (original magnification ×50). F, Normal sebaceous lobules adjacent to the sebaceous adenoma stained immunohistochemically with an antibody to the MSH2 protein. Note the presence of brown nuclear staining (original magnification ×50).
The rectal biopsy results from 1996 were reviewed, and a diagnosis of primary adenocarcinoma was confirmed (Figure 2C). The sebaceous adenoma and rectal adenocarcinoma underwent immunohistochemical analysis with antibodies directed at MLH1 (PharMingen, Oxford, England) and MSH2 (Cambridge Bioscience Ltd, Cambridge, England) proteins, using a conventional diaminobenzidine detection method, with a brown chromogen. The sebaceous adenoma (Figure 2D) exhibited consistent nuclear positivity for MLH1 but was negative for MSH2 (Figure 2E). As an internal control, the normal background sebaceous lobules showed positive nuclear staining for both MLH1 and MSH2 proteins (Figure 2F).
Various eyelid and adnexal tumors are known to be markers of benign and malignant visceral tumors. Some of the well-recognized entities include neurofibromatosis type 1,7 Gardner syndrome,8 Gorlin syndrome,9 Cowden syndrome,10 Carney complex,11 multiple endocrine neoplasia type 2B,12 and Muir-Torre syndrome (Table).3 Other tumor predisposition syndromes are xeroderma pigmentosa, Bazex-Dupré-Christol syndrome, Rombo syndrome, dysplastic nevus syndrome, and epidermodysplasia verruciformis.13 In general, these disorders are characterized by eyelid and adnexal tumors that have the hallmarks of inherited cancer predisposition, such as early onset compared with sporadic cases, multifocal involvement, phenotypic abnormalities, familial tendency, and autosomal dominant inheritance.14 In such a setting, eyelid and adnexal tumors are markers of genetic predisposition to develop benign or malignant visceral tumors.
Cutaneous sebaceous glands may undergo hyperplasia or neoplasia. Sebaceous hyperplasia consists of mature sebaceous lobules grouped around a single central dilated duct, which is often filled with debris. Sebaceous adenoma shows irregularly shaped, closely packed sebaceous glands that communicate with 1 or more dilated infundibula or directly to the surface. There are more basaloid germinative cells than normal sebaceous glands, together with transitional forms, but there still tends to be a majority of mature vacuolated sebocytes, as described in the lesions in this case report. Sebaceous carcinoma is usually asymmetric, infiltrative, and composed of lobules, nests, and sheets of principally basaloid cells with variable sebaceous differentiation. The cells are often highly pleomorphic, and necrosis is usually present. The ocular variant commonly shows an in situ component.15
Sebaceous adenoma associated with Muir-Torre syndrome can undergo cystic change, whereas those of sporadic type do not exhibit this feature.16 Meibomian glands and Zeis glands of the eyelids are modified sebaceous glands and can undergo similar histopathologic changes.
Sebaceous gland tumors, especially adenomas, occur rarely. Solitary or multiple sebaceous adenomas appear as yellow nodules, typically on the face, and are considered one of the diagnostic criteria of Muir-Torre syndrome.3 Sebaceous hyperplasia seen in elderly individuals is not associated with Muir-Torre syndrome. Although sebaceous gland carcinoma of the eyelid and extraocular sites17 has been reported in patients with Muir-Torre syndrome, such patients also had sebaceous adenomas.18 Sebaceous gland carcinoma of the eyelid by itself is not suggestive of Muir-Torre syndrome.19,20 Similarly, keratoacanthoma and basal cell carcinoma without sebaceous adenoma are not diagnostic of Muir-Torre syndrome.
In a review of 120 patients with Muir-Torre syndrome, sebaceous tumors were diagnosed before the internal malignancy in almost 40% of the patients.3 Almost half of patients with Muir-Torre syndrome develop colorectal adenocarcinoma, and one fourth develop genitourinary tumors. Adenocarcinoma of the colon in the setting of Muir-Torre syndrome and other genetic predispositions such as Gardner syndrome tends to occur almost a decade earlier than the sporadic cases.3 The adenocarcinoma tends to be multifocal and arises from the proximal colon in genetically predisposed cases compared with unifocal involvement of the distal aspect of the colon in sporadic cases.21 Diagnosis of solitary or multiple sebaceous adenomas should raise a strong suspicion of Muir-Torre syndrome. Such patients and their first-degree relatives should be encouraged to undergo detailed systemic evaluation to exclude gastrointestinal and genitourinary malignancy according to published protocols.3 Because systemic malignancy may occur many years after the onset of sebaceous adenoma, continued long-term surveillance is necessary.
The principal genetic aberrations in Muir-Torre syndrome are mutations in the mismatch repair genes, hMLH1 and hMSH2, leading to microsatellite instability.6 Microsatellite testing requires the services of a molecular diagnostic laboratory, but tumors that exhibit microsatellite instability can be detected with immunohistochemical staining. The absence of hMLH1 and hMSH2 nuclear expression identifies tumors with mismatch repair deficiencies.22 Application of this technique to cutaneous sebaceous neoplasms has proved to be a reliable screening method, with high predictive value for the diagnosis of DNA mismatch repair–deficient Muir-Torre syndrome.23,24 In this study, the sebaceous adenoma did not express MSH2 protein but expressed MLH1 protein; the same pattern was seen in the rectal adenocarcinoma. The overall findings indicate mutations in the hMSH2 gene and, coupled with the clinical findings, are highly suggestive of Muir-Torre syndrome.
Correspondence: Dr Singh, Department of Ophthalmic Oncology, Cole Eye Institute (i3-129), Cleveland Clinic Foundation, Cleveland, OH 44195 (firstname.lastname@example.org).
Financial Disclosure: None.
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