TdT expression in normal and neoplastic sebaceous cells.

AIMS: Terminal deoxynucleotidyl transferase (TdT) is a DNA polymerase expressed in immature, normal and neoplastic, lymphoid or haematopoietic cells and in neuroendocrine carcinomas, such as Merkel cell carcinoma and small-cell carcinoma. It has not yet been described in cells of epithelial origin. After observing TdT immunoreactivity in normal sebaceous glands, we analysed its spectrum of expression in cases of sebaceous cell hyperplasia (SGH) and sebaceous cell neoplasm. METHODS AND RESULTS: Twelve cases of SGH and three cases of other benign lesions, namely sebaceoma, sebaceous adenoma, and sebaceous naevus, along with four archived cases of sebaceous cell carcinoma (SC) were collected and stained with TdT antibody. In addition, tissue microarrays were constructed from 11 cases of basal cell carcinoma (BCC) and 10 cases of squamous cell carcinoma (SCC), which had nine evaluable cases each, and, after carcinoma type confirmation with immunostaining for epithelial membrane antigen, TdT immunohistochemistry was performed. All cases of SGH and sebaceous cell neoplasm were positive for TdT. The staining intensity was variable, being often weak to moderate in a significant proportion of cells, apart from one case of SC and the case of sebaceous naevus, which were only focally positive. No BCCs and only one SCC showed immunoreactivity. CONCLUSIONS: TdT protein can be found in cells of epithelial origin and specifically sebaceous cells, both benign and malignant. It can be hypothesized that this expression is due to sebaceous cell differentiation as a prelude to apoptosis and holocrine secretion. Additional studies are needed to further elucidate its biological role.

Cutaneous Sebaceous Lesions in a Patient With MUTYH-Associated Polyposis Mimicking Muir-Torre Syndrome.

A 76-year-old white male with a history of adenocarcinoma of the rectosigmoideum and multiple colonic polyps removed at the age of 38 and 39 years by an abdominoperitoneal amputation and total colectomy, respectively, presented with multiple whitish and yellowish papules on the face and a verrucous lesion on the trunk. The lesions were surgically removed during the next 3 years and a total of 13 lesions were investigated histologically. The diagnoses included 11 sebaceous adenomas, 1 low-grade sebaceous carcinoma, and 1 squamous cell carcinoma. In some sebaceous lesions, squamous metaplasia, intratumoral heterogeneity, mucinous changes, and peritumoral lymphocytes as sometimes seen in sebaceous lesions in Muir-Torre syndrome were noted. Mutation analysis of the peripheral blood revealed a germline mutation c.692G>A,p.(Arg231His) in exon 9 and c.1145G>A, p.(Gly382Asp) in exon 13 of the MUTYH gene. A KRAS mutation G12C (c.34G>T, p.Gly12Cys) was detected in 1 sebaceous adenoma and a NRAS mutation Q61K (c.181C>A, p.Gln61Lys) was found in 2 other sebaceous adenomas. No germline mutations in MLH1, MSH2, MSH6 and PMS2 genes, no microsatellite instability, no aberrant methylation of MLH1 promoter, and no somatic mutations in MSH2 and MSH6 were found. An identical MUTYH germline mutation was found in the patient's daughter. Despite striking clinicopathological similarities with Muir-Torre syndrome, the molecular biologic testing confirmed the final diagnosis of MUTYH-associated polyposis.

Expression of Malic Enzymes in Sebaceous Lesions.

Malic enzymes (MEs) are involved in fatty acid biosynthesis and lipid accumulation, and their expression in sebocytes and sebaceous lesions has not been investigated. The aims of this study were to examine ME1 and ME2 expression in normal skin and sebaceous lesions. A total of 68 cases including 5 specimens of normal skin, 12 facial lesions showing sebaceous hyperplasia, 18 sebaceous adenomas, 10 sebaceomas, 13 steatocystomas, and 10 sebaceous carcinomas were examined for the expression of ME1 and ME2. All benign and malignant sebaceous lesions showed ME1 in clear cells and ME2 in nonclear cells, respectively. ME1/ME2 phenotype is seen in basal sebocytes, basal keratinocytes, sweat glands, and outer root sheath cells and hence not specific. This study demonstrates that ME1/ME2 expression phenotype may have a potential to be a valuable marker for sebaceous differentiation. It is necessary to perform large-scale studies including skin tumors with a clear cell morphology that may mimic sebaceous differentiation.

Considerations on the performance of immunohistochemistry for mismatch repair gene proteins in cases of sebaceous neoplasms and keratoacanthomas with reference to Muir-Torre syndrome.

Cutaneous sebaceous tumors, as well as keratoacanthomas, are associated with Muir-Torre syndrome (MTS). Visceral neoplasias are a feature of this syndrome; thus, early detection using a cutaneous biopsy is very important in dermatopathology. A dermatopathologist can apply different techniques in such cases, including immunohistochemistry for several mismatch repair proteins or molecular studies for microsatellites instability. However, in a world where economic resources play an increasing role, how discriminative the dermatopathologist should be in investigating cutaneous lesions that may indicate MTS is not a trivial matter. Although previous reports have presented algorithms on MTS focusing on a multidisciplinary approach, our report emphasizes the role of the dermatopathologist and tries to answer several questions that could arise when facing a cutaneous tumor that may indicate MTS.

Reduction of Pten dose leads to neoplastic development in multiple organs of Pten (shRNA) mice.

To address the impact of partial reduction of Pten on tumor initiation, we generated PtenshRNA mice, in which PTEN expression was reduced below normal levels in various tissues. PtenshRNA mice frequently developed lymphoid and prostatic hyperplasia, splenomegaly, and sebaceous adenomas. Our observations support the notion that partial reduction of the dose of Pten with shRNA is sufficient to induce neoplastic disease in multiple organ systems.

Expression of alpha-methylacyl-CoA racemase (P504S) in sebaceous neoplasms.

BACKGROUND: Alpha-methylacyl-CoA racemase (AMACR), also known as P504S, is a protein that plays an important role in mitochondrial and peroxisomal beta-oxidation of branched-chain fatty acid and bile acid intermediates. AMACR has been established as a valuable diagnostic marker for prostate cancer and has recently been shown to be useful in the diagnosis of colorectal carcinoma. Despite the importance of lipid metabolism in sebum production by sebaceous glands of the skin, there are no studies evaluating the expression of AMACR in sebaceous neoplasms. METHODS: Five samples of normal sebaceous glands as well as five cases each of sebaceous hyperplasia (SH), sebaceous adenoma (SA), basal cell carcinoma (BCC) with sebaceous differentiation and extraocular sebaceous carcinoma (SC) were evaluated for immunohistochemical (IHC) expression of AMACR. Each case was reviewed by a single dermatopathologist and graded using a semi-objective grading schema. RESULTS: Normal sebaceous glands showed strong (4+) expression of AMACR. Among sebaceous neoplasms, SH showed the highest expression (4+), SA and BCC with sebaceous differentiation showed varied expression (2+ and 1+, respectively), and extraocular SC showed no expression of AMACR. CONCLUSIONS: The expression of AMACR is increased in benign sebaceous glands and SH; with decreasing AMACR expression in tumors with less sebaceous differentiation (i.e. SA and SC). These findings provide insight into the potential pathogenesis of sebaceous neoplasms while assisting in the microscopic distinction of SA from SC.

Telomerase expression in sebaceous carcinoma of the eyelid.

BACKGROUND: In humans telomerase is expressed in most cancers and immortal cell lines, and activation of telomerase may play important roles in tumorigenesis and immortalization. This study was to investigate the roles of telomerase activity (TA) and human telomerase RNA (hTR) in sebaceous carcinoma of the eyelid. METHODS: The telomerase repeated amplification protocol (TRAP) was used to demonstrate telomerase activity in 12 cases of sebaceous carcinoma of the eyelid. In situ hybridization (ISH) was used to demonstrate the expression of hTR in 55 cases of paraffin-embedded sebaceous carcinoma of the eyelid, and the results were compared with the proliferative index determined by Mib-1 immuno-labeling, histological patterns and recurrence of the tumor. RESULTS: Different telomerase activity was shown in the 12 cases of sebaceous carcinoma of the eyelid. The positive expression of hTR was 85.5% (47/55) in tumor cells, but not in the adjacent tissues. The positive expression of hTR was correlated with the proliferative activity (as assessed by Mib-1 immunolabelling, r = 0.942, P < 0.001) and the differentiation of sebaceous carcinoma of the eyelid (chi(2) = 17.621, P < 0.001), but not significantly related to tumor recurrence. The level of hTR expression increased with the decrease of differentiation of sebaceous carcinoma of the eyelid. CONCLUSIONS: The results suggest that the up-regulation of telomerase expression plays some roles in tarsal gland carcinogenesis, and the expression of hTR is a useful marker for malignant degree of sebaceous carcinoma of the eyelid.

15-Lipoxygenase-2 expression in benign and neoplastic sebaceous glands and other cutaneous adnexa.

15-Lipoxygenase-2 has a limited tissue distribution in epithelial tissues, with mRNA detected in skin, cornea, lung, and prostate. It was originally cloned from human hair rootlets. In this study the distribution of 15-lipoxygenase-2 was characterized in human skin using immunohistochemistry and in situ hybridization. Strong uniform 15-lipoxygenase-2 in situ hybridization (n = 6) and immunostaining (n = 16) were observed in benign cutaneous sebaceous glands, with expression in differentiated secretory cells. Strong 15-lipoxygenase-2 immunostaining was also observed in secretory cells of apocrine and eccrine glands. Variable reduced immunostaining was observed in skin-derived sebaceous neoplasms (n = 8). In the eyelid, Meibomian glands were uniformly negative for 15-lipoxygenase-2 in all cases examined (n = 9), and sebaceous carcinomas apparently derived from Meibomian glands were also negative (n = 12). The mechanisms responsible for differential expression in cutaneous sebaceous vs eyelid Meibomian glands remain to be established. In epidermis, positive immunostaining was observed in the basal cell layer in normal skin, whereas five examined basal cell carcinomas were negative. Thus, the strongest 15-lipoxygenase-2 expression is in the androgen regulated secretory cells of sebaceous, apocrine, and eccrine glands. This compares with the prostate, in which 15-lipoxygenase-2 is expressed in differentiated prostate secretory cells (and reduced in the majority of prostate adenocarcinomas). The product of 15-lipoxygenase-2, 15-hydroxyeicosatetraenoic acid, may be a ligand for the nuclear receptor peroxisome proliferator activated receptor-gamma, which is expressed in sebocytes, and contribute to secretory differentiation in androgen regulated tissues such as prostate and sebaceous glands.

Immunohistochemical study of carbonic anhydrase in mixed tumours and adenomas of sweat and sebaceous glands.

Immunohistochemical distribution of carbonic anhydrase II (CA) in mixed tumours and adenomas of sweat gland origin and in sebaceous adenomas was demonstrated by the PAP method. Normal sweat glands, both eccrine and apocrine, clear cells of the secretory coils, and ductal epithelial cells all showed conspicuous staining for CA, and sebaceous glands were also positive. Mixed tumours of the skin indicated strongly positive staining for CA in the luminal cells of tubular and duct-like or cystic structures, while most of the other tumour cells were negative. In solid or massive foci, CA positive cells were found scattered among the cellular mass. Sebaceous adenomas were usually moderately positive for CA throughout the tumour.

Wax ester synthesis in the mouse preputial gland tumour.

The microsomal fraction from the mouse preputial gland tumour contains an acyltransferase which catalyzes the synthesis of wax esters. The enzyme is inhibited by moderate concentrations of free fatty acids (40 muM or more) but the inhibition is relieved by the addition of bovine serum albumin. The specific activity of the enzyme increases markedly between the 20th and 30th days of tumor growth. A number of other lipid synthesizing enzymes show similar trends for specific activity as related to tumour age.