Synonyms: None
Etiology: Mutations in MLH1 and/or MSH2
Associations: Visceral malignancies (mainly gastrointestinal)
Clinical: Asymptomatic yellow papule/nodule
Histology: Lobules of sebocytes surrounded by basaloid keratinocytes
IHC repertoire: EMA+
Staging: N/A
Prognosis: 100% benign
Adverse variables: Visceral malignancies
Treatment: Careful screening
11
Muir-Torre Syndrome
Sebaceous adenomas are benign adnexal tumors that have no malignant potential. They are of no clinical signifi - cance in isolation, but may be indicators of internal malig- nancy when occurring as part of the Muir-Torre syndrome.
Sebaceous adenomas grow as exophytic, yellowish papules and nodules. In most cases, these lesions are less than 1 cm in diameter (1). While they may occur at any body site, they are most common on the face. They usually appear in middle age. Ulceration is not a common feature.
Muir-Torre is inherited in an autosomal dominant manner (2). It has a high degree of penetrance and vari- able expression. The syndrome is twice as common in men as in women. It usually manifests in middle age, with the sixth decade the most common time of onset. In some studies, as many as 61% of afflicted families will have a family history of visceral malignancy (3). The syndrome is defined as the presence of at least one sebaceous neoplasm (excluding sebaceous hyperplasia and nevus sebaceous of Jadassohn) or keratoacanthoma with sebaceous differentiation, and one visceral cancer.
Alternatively, a patient with multiple keratoacanthomas, multiple visceral malignancies and a family history of Muir-Torre syndrome can be so classified (2). In most cases, however, multiple cutaneous neoplasms are present (Figure 11.1). In one review, the cutaneous tumors preceded the development of the visceral cancers in 22%
of cases, occurred concurrently in an additional 6%, and presented after the internal malignancy in 56%. No
temporal relationship was established in the other cases (4).
An inherited mutation of the mismatch DNA repair gene MSH2 has been reported in many patients with Muir-Torre syndrome (5). Others have reported germ- line mutations in the MLH1 mismatch repair gene (6).
Sebaceous adenomas may occur as part of the Muir- Torre syndrome. Multiple sebaceous neoplasms, kerato- acanthomas, and visceral carcinomas characterize this syndrome (Table 11.1) (2). The sebaceous tumors include sebaceous adenomas, epitheliomas, sebaceomas, and seb- aceous carcinomas. Most investigators do not include sebaceous hyperplasia as a criterion for the syndrome, as the vast majority of these lesions are unrelated to a systemic process. The cutaneous neoplasms tend to be indolent. Even the sebaceous carcinomas, which can behave aggressively when isolated, do not usually met astasize in patients with the Muir-Torre syndrome.
Keratoacanthomas also occur most frequently outside of the syndrome, but when multipled, may suggest visceral malignancy. Gastrointestinal, and more specifically, colonic adenocarcinomas are the most common visceral malignancies experienced by patients with the Muir Torre syndrome (Table 11.2). The colonic adenocarcino- mas occur a decade earlier than in the general population and are more frequently located proximal to the splenic flexure. They tend to behave in a relatively indolent fashion.
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54 Deadly Dermatologic Diseases
Table 11.1. Tumors Associated with Muir-Torre Syndrome (Expressed as Percentage of Affected Patients)
Tumor Percentage of Patients with MTS
Sebaceous adenoma >90
Sebaceous carcinoma 24
Other sebaceous neoplasms
Keratoacanthoma 22
Colonic polyps 48
2–3 Visceral neoplasms 37
>3 Visceral neoplasms 10
Table 11.2. Visceral Tumors Associated with Muir-Torre Syndrome (Expressed as Percentage of Total Tumors)
Colonic Adenocarcinoma 50
Genitourinary carcinoma 24
Breast 5
Non-Hodgkin’s lymphoma 2
Head and neck squamous cell carcinoma 3.9 Small intestinal adenocarcinoma 3.9
Lung carcinoma 1.5
FIGURE 11.1. Multiple tan umbilicated papules representing sebaceous adenoma and sebaceous hyperplasia in patient with Muir-Torre syndrome.
Some investigators believe these to be indistinguishable from basal cell carcinomas with sebaceous differentiation.
There is some overlap between sebaceous epithelioma and the more recently described tumor known as sebaceoma (7). The distinction from sebaceous adenoma is academic, as the prognosis for each of these neoplasms is invariably benign.
Sebaceous carcinomas are most prevalent, arising from the meibomian glands in the eyelids. However, they can occur in any hair-bearing body site. Eyelid lesions occur primarily in elderly patients, whereas extraocular neoplasms are more common in middle-aged men.
Sebaceous carcinomas unassociated with the Muir Torre syndrome have a relatively high rate of metastasis, but this appears to be much lower when occurring in conjunction with the syndrome. These tumors dem- onstrate the characteristics of malignant neoplasms (Figure 11.4A and 11.4B). They are characterized by cells with greatly increased nucleus: cytoplasm ratios, high mitotic activity, abundant individual cell necrosis, and marked nuclear pleomorphism. Sebaceous differentiation may be difficult to detect. Immunostains with epithelial Sebaceous adenomas are neoplasms that are centered in
the mid-reticular dermis. In some cases, they arise from follicular epithelium that is connected to the epidermis, while in other cases, the epidermal connection may not be apparent. Lobules of mature sebocytes with abundant clear cytoplasm are surrounded by a collarette of more basaloid-appearing cells. The basal layer palisades around the outside of the lobules and the cells within demonstrate progressive maturation as they move toward the middle of the lobules (Figures 11.2A and 11.2B). Mitoses may be seen in small numbers, but no atypical forms are present.
Cytologic atypia is minimal and necrosis is not a common feature.
Sebaceous epitheliomas differ from sebaceous adeno- mas in having a larger percentage of basaloid cells and smaller percentage of mature sebocytes (Figure 11.3).
FIGURE 11.2. (A) Low power photo micrograph depicting lobular architecture of seba- ceous adenoma. (B) High power photomicrograph depicting lobules of sebocytes. Note central mature sebocytes with clear-foamy cytoplasm and more immature basaloid cells at periphery.
A
B
56 Deadly Dermatologic Diseases
FIGURE 11.3. Predominance of basaloid cells in sebaceous epithelioma.
FIGURE 11.4. (A) Medium power photomicrograph of sebaceous car- cinoma. Note the predominance of basaloid cells and the cellularity of the neoplasm.
membrane antigen may be helpful in isolating the intra- cytoplasmic microvesiculation frequently seen in sebo- cytic differentiation.
Keratoacanthoma is a controversial entity that is con- sidered by many to represent a rapidly growing yet indo-
lent variant of cutaneous squamous cell carcinoma (8).
The discussion of the etiology of these neoplasms is outside the purview of this volume. The histologic features of keratoacanthoma are best detected at low magnification.
These tumors demonstrate a cup-shaped, invaginated
A
FIGURE11.4. (B) High power pho- tomicrograph depicting the close apposition of the cells producing the cellularity of sebaceous carci- noma. Note the hyperchromatic nuclei of sebaceous carcinoma.
growth pattern. The central dell is filled with abundant keratin that is often orthokeratotic. Beneath the invagina- tion, sheets of keratinocytes with abundant, often pale-staining cytoplasm extend into the dermis. These cells may demonstrate nuclear atypia, pleomorphism, and a high mitotic rate (Figure 11.5A and 11.5B). In many
cases, there is a brisk underlying host response and in resolving lesions, dermal fibrosis may signify the regress- ing phase of the lesion.
Distinction between keratoacanthoma and other types of cutaneous squamous cell carcinoma is not always possible.
FIGURE 11.5. (A) Low power photomicrograph depicting the cup-shaped architecture of keratoacanthoma.
B
A
58 Deadly Dermatologic Diseases
FIGURE 11.5. (B) Medium power photomicrograph depicting the irregular infiltrating islands of neoplastic keratinocytes typical of invasive well-differentiated squa- mous cell carcinoma.
References
1. Rulon DB, Helwig EB. Cutaneous sebaceous neoplasms.
Cancer 1974; 33: 82–102.
2. Schartz RA. The Muir-Torre syndrome: A 25-year retrospective. J Am Acad Dermatol 1995; 33: 90–104.
3. Cohen PR, Kohn SR, Kurzrock R. Association of sebaceous gland tumors and internal malignancy: The Muir-Torre syndrome. Am J Med 1991; 90: 606–613.
4. Akhtar S, Oza KK, Khan SA, Wright J. Muir-Torre syndrome:
Case report of a patient with concurrent jejunal and ureteral cancer and a review of the literature. J Am Acad Dermatol 1999; 41: 681–686.
5. Nystrom-Lahti M, Parsons R, Sistonen P, Pylkkanen L, Aaltonen LA, Leach FS, Hamilton SR, Watson P, Bronsen E., Fusar, R, et al. Mismatch repair genes on chromosomes 2p
and 3p account for a major share of hereditary nonpolyposis colorectal cancer families evaluable by linkage. Am J Human Genet 1994; 55: 659–665.
6. Mathiak M, Rutten A, Mangold E, Fischer H-P, Ruzicka T, Friedl W, Propping P, Kruse R. Loss of DNA mismatch repair proteins in skin tumors from patients with Muir-Torre syndrome and MSH2 or MLH1 germline mutations: Establishment of immunohistochemical analysis as a screening test. Am J Surg Pathol 2002; 26: 338–
343.
7. Troy JL, Ackerman AB. Sebaceoma. A distinctive benign neoplasm of adnexal epithelium differentiating toward sebaceous cells. Am J Dermatopathol 1984; 6: 7–13.
8. Hodek E, Jones RE, Ackerman AB. Solitary keratoacanthoma is a squamous-cell carcinoma: Three examples with metastases. Am J Dermatopathol 1993; 15: 332–342.
B
