Sebaceous neoplasia and Torre-Muir syndrome

Abstract

Sebaceous tumours include hyperplasia, adenoma, sebaceoma and carcinoma. Importantly, the latter three are potential markers of Torre-Muir syndrome; the hereditary association of sebaceous neoplasia and internal malignancy, most commonly colorectal carcinoma. The diagnostic features, differential diagnosis, molecular diagnostics and recent advances in pathogenesis of this rare group of tumours are discussed along with Torre-Muir syndrome and recommendations for screening for this important association.

Figure 1

Sebaceous hyperplasia shows superficial sebaceous lobules surrounding a central pore (A, B). Higher power reveals foamy eosinophilic cytoplasm in central cells and only two basaloid or germinative cell layers at the periphery (C). (D) While most of the lesion appears to be sebaceous hyperplasia, a few of the lobules have expanded basaloid areas, indicating that this lesion is best considered as sebaceous adenoma.

Figure 2

Ectopic sebaceous gland in an oesophageal mucosa biopsy. The left and right insets magnify the sebaceous lobule and sebaceous ductal structure (courtesy of Dr. Huamin Wang, UT MD Anderson Cancer Center, Houston, Texas, USA).

Figure 3

Sebaceous adenomas can be dermal or show extensive association with the overlying epidermis.

Figure 4

Sebaceous adenomas are well circumscribed and lobular (A, B). The higher magnification images highlight the expanded basal (germinative) cell layer (C, D).

Figure 5

Sebaceoma can be free in the dermis or show connection to the overlying epithelium (A, B). Squamous differentiation and sebaceous ducts are sometimes present (C, D).

Figure 6

Carcinoid-like or rippled pattern is infrequently encountered in sebaceoma and can cause diagnostic confusion.

Figure 7

Ocular sebaceous carcinoma with adjacent prominent meibomian (sebaceous) glands and carcinoma primarily involving the cutaneous portion of the eyelid (A). Extensive involvement of the epithelial and adnexal structures can be seen with associated intra-epithelial pagetoid migration (B). Carcinomas are infiltrative and can mimic basal cell carcinoma (C), but closer inspection reveals atypical hyperchromatic nuclei with focal intracytoplasmic lipid vesicles indicating sebaceous differentiation (D).

Figure 8

Non-ocular sebaceous carcinoma with polypoid appearance, an infiltrative architecture and areas of necrosis (A). Mature sebaceous differentiation can be focal in sebaceous carcinoma (B).

Figure 9

Naevus sebaceus (A) with a sebaceous tumour arising within it (B) that shows unusual architecture but is likely to be benign sebaceoma.

Figure 10

In ocular sebaceous carcinoma, when fresh tissue is available, oil red-O stain can vividly reveal intracytoplasmic lipid when findings are equivocal, particularly on frozen section (A, B). More recently, adipophilin has been demonstrated to detect sebaceous differentiation in permanent sections where lipid has been extracted during tissue processing (C, D) (courtesy of Dr. Fiona Roberts, Glasgow, UK).

Figure 11

Keratoacanthoma-like (A) or cystic (B) architecture can be seen in Torre–Muir syndrome, but is not an entirely specific or sensitive marker.

Figure 12

Microsatellite instability in sebaceous tumours can also be demonstrated by a polymerase-chain-reaction-based assay as seen here at the BAT-26 locus.

Figure 13

Portion of a sebaceous adenoma (A). Immunohistochemistry for DNA mismatch repair proteins revealed that the cells were deficient for MSH2 (B) while MLH1 (C) was intact. The overlying squamous epithelium provides a positive control. This patient also had a caecal colonic carcinoma deficient for MSH2 (D, inset).

Figure 14

The Wnt pathway leading to nuclear translocation of β-catenin is complex, but this greatly simplified figure shows that nuclear β-catenin is normally able to bind to Lef-1 and allow gene transcription (A), but cannot perform this function when Lef-1 is mutated (B). The dual mutations (E45K and S61P) in the N-terminal β-catenin interaction domain of Lef-1 demonstrated in a subset of sebaceous adenomas and sebaceomas blocks the interaction between these proteins and thus downstream gene transcription (C).

Figure 15

Stem cell model for sebaceous tumour development. Cutaneous multipotent stem cells can develop into follicular, interfollicular epidermal or sebaceous structures under a variety of signals (right side). Intense signalling through the Wnt pathway resulting in increased β-catenin and Lef-1 activation leads to a follicular fate, while less intense signalling allows a sebaceous fate and absence of signalling to an interfollicular epidermal fate. Regarding tumourigenesis (left side), activating mutations in β-catenin, presumably acting with Lef-1, leads to hair follicle tumours such as pilomatrixomas. Abrogation of the Lef-1 pathway, likely in combination with other events, leads to sebaceous tumourigenesis and perhaps keratoacanthoma-like lesions as well. The role of stem cells in this process is not well characterized, but this is an attractive model since stem cells persist for the life of the organisms and thus can more readily be the target of the multiple mutations likely required for tumourigenesis. SHH, sonic hedgehog; IHH, indian hedgehog; PTCH, patched.