PD-L1 expression in sebaceous carcinomas.

BACKGROUND: Traditional systemic treatments for unresectable, recurrent, and/or advanced sebaceous carcinoma (SC) are ineffective. Tumoral immune microenvironment characterization is essential for considering immune checkpoint inhibitors as a treatment option. METHODS: A total of 173 resected SCs were reviewed. Clinical information, lesion size, and location were collected. Microscopic examination documented histopathologic features and expression of immunohistochemical markers PD-L1 and CD8. PD-L1 percentage was assessed amongst tumor (PD-L1 + Tu) and immune infiltrating cells (PD-L1 + Inf). Each case was attributed a combined positive score (CPS) following Head and Neck squamous cell carcinoma recommendations. PD-L1 expression was evaluated according to clinicopathologic parameters. Human Papilloma Virus presence (HPV) was analyzed using PCR microarray scanning. RESULTS: A therapeutically relevant CPS was seen in 51.4% of cases. Higher PD-L1 + Tu, PD-L1 + Inf, and CPSs were positively associated with greater lesion size and an extraocular location. No association was seen with patient age or gender. 9.2% of SCs showed PD-L1 + Tu ≥ 1, while 52.0% showed PD-L1 + Inf ≥ 1. A higher CD8 + T-lymphocyte density was significantly associated with a higher CPS, PD-L1 + Tu, and PD-L1 + Inf. Tumor-associated T-cell infiltrate's density was higher along tumor periphery. HPV-16, HPV-43, HPV-52, and HPV-66 were detected in 8.4% of SCs. There was no significant association between HPV status, PD-L1 expression, and CPS. A significant number of SCs express PD-L1 at therapeutic levels. Nevertheless, PD-L1 expression shows a higher intertumoral heterogeneity, in extraocular than in biologically distinct periocular cases. CONCLUSION: Our data support the need for large-scale prospective studies evaluating anti-PD-L1 immunotherapy mainly in extraocular SC treatment.

Histopathological study of canine sebaceous tumors and their association with PCNA expression by immunohistochemistry / Estudo histopatológico de tumores sebáceos caninos e sua associação com a expressão de PCNA por imuno-histoquímica

Sebaceous tumors are common in dogs and include benign and malignant lesions. The increase in immunohistochemical evaluation of sebaceous tumors aggregates information regarding the origin and degree of malignancy of the lesions. The objective of this study was to evaluate PCNA immunohistochemical expression of  sebaceous tumors in dogs. Sixty-one samples include normal skin and sebaceous tumors were selected from dogs of various breeds and ages, no gender predilection, sent to the Veterinary Pathology Service of Universidade Federal Fluminense, Niterói/RJ, Brazil. Samples passed through histological processing, routine staining and immunostaining from PCNA. Descriptive statistical analysis, Wilcoxon-Mann-Whitney and Fishers exact test were performed. The mean age of the affected animals was 10.56 years. There was no sexual predilection. Breeds more frequently affected were: Poodles, mixed-breed dogs and Cocker Spaniels. Most of the tumors were neoplasms (67.27%), and 75.67% of those were benign. Sebaceous adenoma was the most frequent neoplasm (56.75%). PCNA immunoexpression was present in hyperplasia, benign and malignant tumors. No previous studies were found using PCNA antibody in sebaceous tumors of dogs. Thus, more studies are needed to provide greater clarity regarding the role of these markers on normal skin and sebaceous tumors of dogs, as well as their use as prognos

Tumores sebáceos são comuns em cães. Tais tumores incluem lesões benignas e malignas. A avaliação imunohistoquímica desses tumores pode agregar informações sobre a origem e o grau de malignidade das lesões. Para este fim, sessenta e uma amostras, incluindo pele normal e tumores sebáceos foram selecionadas de cães de várias raças e idades, sem predileção por sexo, do arquivo do Serviço de Patologia Veterinária da Universidade Federal Fluminense, Niterói/RJ, Brasil. As amostras passaram por processamento histológico, coloração de rotina e imuno-histoquímica com anti-PCNA (proliferating cell nuclear antigen). Foram realizadas análises estatísticas descritivas além dos testes de Wilcoxon-Mann-Whitney para comparar a distribuição da marcação de anti-PCNA entre grupos de variáveis. Para variáveis com mais de dois grupos, aplicou-se a Análise de Variância (ANOVA). A idade média dos animais afetados foi de 10.56 anos. As raças mais afetadas foram Caniches e Cocker Spaniel, e ainda animais sem raça definida. Houve imunomarcação de PCNA em tumores benignos, malignos, e ainda em lesões hiperplásicas com intensidade variada. A maioria dos tumores eram neoplásicos representando 67.92% do total; destes, 75.00% eram benignos. O adenoma sebáceo foi a neoplasia mais frequente (37.74%). Não foram encontradas diferenças significativas nas distribuições de anti-PCNA entre os grupos das variáveis sexo, idade, status reprodutivo, localização e tamanho do tumor e diagnóstico histopatológico. Embora não haja estudos com anti-PCNA em tumores sebáceos caninos, numerosas publicações apontam seu valor preditivo em outras neoplasias. Com isso, a finalidade deste estudo foi avaliar a expressão de anti-PCNA em tumores sebáceos caninos e sua possível associação com a malignidade das lesões.

Resolution of Benign and Malignant Sebaceous Neoplasms, in a Renal Transplant Patient Treated With Everolimus.

Nonmelanoma skin cancers are the most common malignancies in transplant recipients under immunosuppression; nevertheless, appendage tumors also may appear. The onset of several cutaneous neoplasms in transplant patients can cause deterioration in quality of life of these patients. A 62-year-old white woman patient developed several malignant and benign sebaceous neoplasms during an immunosuppressive treatment for a renal transplant. The genetic study showed a mutation in MSH6-eson 1 (c116G>A), without mutations in MLH1 gene and MSH2. A final diagnosis of multiple sebaceous tumors in an immunosuppressed patient without Muir -Torre syndrome was made. The spreading of further cutaneous neoplasms led to a change in immunosuppression: namely, that clinicians suspended tacrolimus and add everolimus. After 2 months, all tumor lesions on the face and on the limbs have disappeared, and no further lesions occurred. Everolimus could represent a valid therapeutical treatment for transplant patients at high risk for cutaneous tumors. A genetic consult and a consequent study of the genetic profile should be performed on each of these patients, to avoid risks of recurrent cutaneous tumors and negative effects on the quality of life.

Sebaceous carcinoma in patients receiving long-term immunosuppresive treatment: case report and literature review.

BACKGROUND: Sebaceous carcinoma (SC) is a very rare and aggressive malignant skin cancer that appears to occur with a greater frequency in the clinical setting of chronic immunosuppression; however, it is not reported in the literature as frequently as is squamous cell carcinoma (SCC). We report 2 cases of SC in organ transplant patients from clinical and histopathological points of view. METHODS: A 48-year-old patient after 3 renal transplantations (1986, 1986, and 1998) was presented to the Dermatology Department in 1999 because of a papillomatous lesion along her right upper eyelid. The lesion was excised. Histopathologically, it was diagnosed as a SC. There was no lymphovascular invasion and no metastasis; therefore no other treatment was included. No symptoms of recurrent disease were present 14 years since diagnosis. An 87-year-old patient after a renal transplantation in 1989 was referred to dermatologist in 1993 because of the lesion on his right temple. The lesion was excised; histopathologically, it was diagnosed as SC. Because of metastatic disease, he had a course of radiotherapy to the right side of the neck. The immunosuppressive drugs azathioprine and cyclosporine A were reduced. The patient died of metastatic disease 1 year later (3 years since diagnosis). Both patients had very high cumulative UV exposition during their lifetimes, and many skin cancers were diagnosed, especially SCC. RESULTS: It is necessary to realize that this cancer occurs more frequently in organ transplant patients, and its correct diagnosis is an essential issue because it has significantly more aggressive behavior than does SCC. In the 2 presented patients, we observed very rapid progression of disease. Despite aggressive treatment and reduction of immunosuppressive drugs, the second patient died 3 years after diagnosis. CONCLUSIONS: Regular dermatological follow-up is required in the population of organ transplant patients to identify all skin tumors in the early stage.

Muir-Torre syndrome or phenocopy? The value of the immunohistochemical expression of mismatch repair proteins in sebaceous tumors of immunocompromised patients.

Primary and secondary immunodepressive conditions are associated with an increased incidence of sebaceous tumors. Microsatellite instability (MSI) and lack of expression of mismatch repair (MMR) proteins, typical markers of Muir-Torre/Lynch heredo-familial settings, can be recognized also in immunocompromised patients. We aimed to carry on a systematic examination of clinical, immunohistochemical, biomolecular features of sebaceous tumors arising in immunocompromised and immunocompetent patients between 1986 and 2012. Microsatellite screening, immunohistochemical analysis and genetic testing were performed for hMLH1, hMSH2 and hMSH6. Methylation status of MMR genes was checked in cases with immunohistochemistry (IHC) loss of MMR proteins expression and no germline mutations. Fifteen patients had a personal history of visceral carcinomas fulfilling diagnostic criteria for Muir-Torre syndrome. In this cohort, IHC analysis, MSI status and genetic testing were in agreement, showing eight MSH2 and two MLH1 germline mutations. Five patients were immunosuppressed and their sebaceous tumors showed a lack of MSH2/MSH6 expression, although just one case with positive family history for visceral cancer harbored a germline mutation. In immunosuppressed patients, loss of IHC for MMR proteins is not necessarily secondary to MMR germline mutations. IHC false positives are probably due to epigenetic alterations. MSI and lack of expression of MMR proteins can be recognized also in immunocompromised patients without MMR germline mutations.

New pharmaceutical concepts for sebaceous gland diseases: implementing today's pre-clinical data into tomorrow's daily clinical practice.

The human sebaceous gland is a microscopic branched type multiacinar gland been present everywhere on the body except on the palms and soles, whereas they are sparsely located on the dorsum of hands and feet. Several medical conditions are related with sebaceous gland pathology, such as acne, sebaceous hyperplasia, sebaceous adenoma and sebaceous carcinoma. Acne is a common, complex, chronic disorder of the human pilosebaceous unit that mostly occurs in adolescence and young adulthood. The sebaceous gland plays an exquisite role in the initiation of the disease. The multifactorial nature of the pathogenesis of acne includes increased sebum production, alteration of the quality of sebum lipids, inflammatory processes, interaction with neuropeptides and dysregulation of the hormone microenvironment, follicular hyperkeratinization and inflammation maintained by Propionbacterium acnes products within the follicle. On the other hand, the sebaceous gland, as a major and critical compartment of human skin, is also affected through ageing, both intrinsic and extrinsic, which lead to distinct clinical and histological changes. Intrinsic ageing of the sebaceous gland is determined primarily by genetic factors and hormonal status, with androgens playing a major role. A clinical manifestation associated with intrinsic ageing changes is skin xerosis. Extrinsic ageing of human sebaceous gland is mainly caused by accumulating UV irradiation, especially UVA. Photoageing of sebaceous gland is expressed with a wide spectrum of benign and malignant sebaceous tumours, such as sebaceous hyperplasia, sebaceous carcinoma and Muir-Torre syndrome. This review will focus on the pathogenesis of the most common sebaceous gland diseases and their molecular pathways which may represent future pharmaceutical targets.

Sebaceous carcinoma and the T-antigen.

Carcinomas of sebaceous glands are uncommon. They are traditionally classified into ocular and extraocular sebaceous carcinomas (SC). Ocular SC tend to be more common and more aggressive than extraocular SC. However, the latter can occasionally follow a fatal course. Histologically, SC should be classified into 1) SC in situ; 2) SC, infiltrating, low-grade with or without pagetoid spread; 3) SC, infiltrating, high-grade, with or without pagetoid spread; and 4) SC with extraocular and extracutaneous involvement, including metastases. Immunohistochemistry plays a minor role in the diagnosis of SC. Thomsen-Friedenreich (T) antigen can be a helpful tool in differentiating SC (strong T-antigen reactivity in basaloid cells) from other mimicking neoplasms (basaloid cells are T-antigen negative). The histologic differential diagnosis, pathogenesis, and management of SC are reviewed.

Thomsen-Friedenreich (T) antigen: a possible tool for differentiating sebaceous carcinoma from its simulators.

The Thomsen-Friedenreich (T) antigen is a cryptic glycoprotein, referred to as tumor antigen or cancer-associated antigen because it is absent or masked by some carbohydrates in normal tissues, but present in many human cancers. The latter include gastrointestinal, lung, pancreatic, mammary, and some ovarian carcinomas. Cancer cells frequently undergo incomplete glycosylation resulting in the appearance of precursor structures that normally would be absent like the case with the T antigen. T antigen can be detected by several different reagents including monoclonal antibodies and several plant lectins-e.g., Arachis hypogea (peanut agglutinin). The aim of the current study was to evaluate the expression of T antigen in sebaceous carcinoma and to compare it with its simulators. The authors studied the immunohistochemical expression of T antigen in 45 skin biopsy and excisional specimens obtained from the archives of their dermatopathology laboratories, including 8 cases of sebaceous carcinoma, 15 cases of sebaceous adenoma, 9 cases of sebaceoma, 1 case of basal cell carcinoma with sebaceous differentiation, and 12 cases of basal cell carcinoma with cytologic atypia. Sebaceous carcinoma was unique in expressing a strong, diffuse cytoplasmic T antigen reactivity (7 of 8 cases) along the immature basaloid cells and the intermediate cells. However, sebaceous adenoma, sebaceoma, and basal cell carcinomas expressed negative reaction in the basaloid cells and mild reactivity in the intermediate cells. Mature sebocytes showed a strong reaction in all cases. The authors concluded that T antigen expression may be a helpful tool in differentiating sebaceous carcinoma from other sebaceous lesions that may simulate it histologically.

Thomsen-Friedenreich and its precursor (Tn) antigen expression in normal skin and in benign cutaneous tumours: a marker for sebaceous differentiation.

The Thomsen-Friedenreich (T) antigen is the core disaccharide of cancer-associated carbohydrates, whose expression allegedly correlates with the prognosis of some carcinomas. We studied the expression of the T antigen and its precursor (Tn) with monoclonal antibodies in formalin-fixed specimens of normal skin and various benign cutaneous tumours and inflammatory lesions (n: 105). In normal skin, both antigens were consistently expressed within the cytoplasm of mature sebocytes and rarely over the luminal surface of secretory sweat gland cells. All (21/21) sebaceous tumours showed strong T/Tn positivity; several (9/16) sweat-gland tumours were also immunoreactive, although more weakly. Pilar (n = 11), non-adnexal tumours (n = 45) and inflammatory lesions (n = 12) were as a rule unreactive. These results suggest that the T antigen is a sensitive marker of sebaceous differentiation that can be used for the study of adnexal skin tumours in routinely processed tissue specimens.

A histochemical and immunohistochemical study of extra-ocular sebaceous carcinoma.

A histochemical and immunohistochemical study of five cases of extra-ocular sebaceous carcinoma was performed using formalin-fixed and paraffin-embedded tissue specimens. Histochemically, the clear cells of sebaceous carcinomas were negative with periodic acid-Schiff and alcian blue staining. Immunohistochemically, the tumour cells of sebaceous carcinomas showed positive reactions for epithelial membrane antigen, human milk fat globules subclass 1, human milk fat globules subclass 2 and Leu M1, but did not express carcinoembryonic antigen, breast carcinoma associated antigen, S-100 protein, gross cystic disease fluid protein-15 or Dako M1. These histochemical and immunohistochemical findings were compared with those of other skin cancers which must be distinguished histopathologically from sebaceous carcinoma. We conclude that sebaceous carcinoma can be distinguished from eccrine porocarcinoma, malignant clear cell hidradenoma, extramammary Paget's disease, malignant trichilemmoma, squamous cell carcinoma and basal cell carcinoma by histochemical and immunohistochemical techniques using formalin-fixed and paraffin-embedded tissue specimens.

Reactivity of monoclonal antibody OKM5 with sebaceous carcinoma.

Two cases of sebaceous carcinoma (SC), as well as epithelial tumours, melanoma, and lymphoma, were examined using immunoperoxidase and a panel of monoclonal antibodies on cryostat sections. The results showed that, whereas all SC cells in both cases reacted strongly with monoclonal antibody OKM5, other tumour cells (except juvenile xanthogranuloma cells) did not. The pagetoid cells within the epidermis of SC also reacted with OKM5 antibody. Although the nature of the phenomenon merits further study, this reactivity, or cross-reactivity, might possibly aid diagnosis of SC.

Immunohistochemical staining of sebaceous cell carcinoma of the eyelid.

We characterized the inflammatory infiltrate of two sebaceous cell carcinomas of the eyelid with immunohistochemical staining to determine the functional class of the mononuclear cells associated with the tumor. The results were compared with the inflammatory infiltrate associated with basal cell carcinomas. The subepithelial spaces and the area immediately surrounding the sebaceous cell neoplasms were free of mononuclear inflammatory cells, in contrast to the basal cell tumors, which had large numbers of subepithelial inflammatory cells and inflammatory cells in intimate contact with the neoplastic cells as previously reported. Inflammatory reaction in the sebaceous cell tumor was limited to a T-cell infiltrate surrounding the vessels adjacent to the tumor. The predominant mononuclear inflammatory cell in both the sebaceous cell and the basal cell carcinomas was the T helper cell. The apparent difference in mononuclear cell infiltrate may be a significant factor in the clinical behavior of the tumors.

Torre's syndrome: exacerbation of cutaneous manifestations with immunosuppression.

Torre's syndrome is characterized by the association of sebaceous neoplasms and keratoacanthomas with visceral malignancies. We report on a patient in whom the cutaneous manifestations of Torre's syndrome dramatically increased following immunosuppression.

Epithelial markers in primary skin cancer: an immunoperoxidase study of the distribution of epithelial membrane antigen (EMA) and carcinoembryonic antigen (CEA) in 65 primary skin carcinomas.

Sixty-five primary malignant skin tumours have been stained for carcinoembryonic antigen (CEA) and epithelial membrane antigen (EMA) using rabbit polyclonal affinity-purified antibodies and an indirect immunoperoxidase technique. The tumours consisted of 15 invasive squamous carcinomas, 23 basal cell carcinomas, 16 malignant eccrine poromas (porocarcinomas), and 11 sebaceous carcinomas. The basal cell carcinomas were negative for CEA and EMA except where there was keratotic or sebaceous differentiation. All the sebaceous and squamous carcinomas and 15/16 porocarcinomas contained EMA. 12/15 squamous carcinomas were positive for CEA. The malignant poromas were negative for CEA except on the ulcerated surface of two. In tumours classified as sebaceous carcinomas there was positive staining for CEA in some cells, cyst contents and/or keratotic foci. These findings have implications for the use of immunoperoxidase localization of epithelial markers in the differential diagnosis of primary and metastatic skin cancer.