Mutant Lef1 controls Gata6 in sebaceous gland development and cancer.

Mutations in Lef1 occur in human and mouse sebaceous gland (SG) tumors, but their contribution to carcinogenesis remains unclear. Since Gata6 controls lineage identity in SG, we investigated the link between these two transcription factors. Here, we show that Gata6 is a ß-catenin-independent transcriptional target of mutant Lef1. During epidermal development, Gata6 is expressed in a subset of Sox9-positive Lef1-negative hair follicle progenitors that give rise to the upper SG Overexpression of Gata6 by in utero lentiviral injection is sufficient to induce ectopic sebaceous gland elements. In mice overexpressing mutant Lef1, Gata6 ablation increases the total number of skin tumors yet decreases the proportion of SG tumors. The increased tumor burden correlates with impaired DNA mismatch repair and decreased expression of Mlh1 and Msh2 genes, defects frequently observed in human sebaceous neoplasia. Gata6 specifically marks human SG tumors and also defines tumors with elements of sebaceous differentiation, including a subset of basal cell carcinomas. Our findings reveal that Gata6 controls sebaceous gland development and cancer.

HPV-associated Vulvar Intraepithelial Carcinoma With Sebaceous Differentiation: Report of 2 Cases.

Sebaceous carcinoma (SC) is a malignant neoplasm demonstrating sebocytic differentiation, commonly in the periocular area. Sebocytic differentiation is recognized by multivesicular cytoplasmic clearing with frequent nuclear scalloping. The vesicles can be highlighted by immunohistochemical stains against the perilipin family proteins including adipophilin. Extraocular SC is uncommon but well reported, often in the setting of Muir-Torre syndrome; however, vulvar SC is exceptionally rare. The literature review yielded only 12 prior cases of vulvar SC, all of which showed invasion. Here we report 2 additional similar cases from 2 different institutions of an intraepithelial carcinoma with sebaceous differentiation. Histologic examination of multiple specimens from both patients showed similar features: a multifocal intraepithelial basaloid nodular neoplasm sparing the basal layer with occasional pagetoid spread. The tumor cells demonstrated a high nuclear to cytoplasmic ratio, mitoses, variably foamy vacuolated cytoplasm, and nuclear indentation. Multiple specimens from both patients showed evidence of sebaceous differentiation (substantiated by adipophilin positivity in a membranous vesicular pattern in case 1 and by androgen receptor and epithelial membrane antigen positivity in case 2), and squamous differentiation (substantiated by p63/p40 and weak CK 5/6 expression), as well as human papillomavirus (HPV) association (substantiated by p16 block positivity and detection of high-risk HPV by in situ hybridization). One case was a true in situ lesion without evidence of invasion, and the other case was predominantly an in situ carcinoma with prominent adnexal extension and focal superficial invasion of <1 mm seen in one of multiple specimens. To our knowledge, these 2 cases are the first to show a vulvar SC/carcinoma with sebaceous differentiation that is predominantly limited to the epidermis, and the first documentation of HPV infection in vulvar sebaceous neoplasms. Vulvar intraepithelial carcinoma with sebaceous differentiation is the umbrella term we chose for this entity. Whether this is a true SC in situ that is HPV positive/driven, or a vulvar intraepithelial neoplasia with sebaceous differentiation, is not entirely clear. We emphasize the importance of looking for this morphology to avoid misclassification. Due to the rarity of cases, optimal treatment at this site has not been established.

Upregulated MYC expression and p53 mutations may contribute to the oncogenesis of canine Meibomian gland carcinomas.

Sebaceous carcinomas of the human ocular adnexa commonly exhibit pagetoid spread, mutations in tumor-suppressor genes, and protooncogene copy number gain. Sebaceous carcinomas are rarely reported in other species, and while the Meibomian gland (MG) represents the most common ocular adnexal structure of the canine eyelid to develop neoplasia, most are clinically and histologically benign. The objective of this study was to compare molecular features of canine MG carcinomas and adenomas. Two retrospectively identified MG carcinomas were subject to immunohistochemistry and qPCR. When compared with normal glands, MYC was upregulated in benign and malignant MG neoplasms. Aberrant p53 expression was restricted to the nuclei of intraepithelial neoplastic cells in MG carcinomas. Adipophilin expression was diminished in MG neoplasms compared with the normal MG. Our findings, if confirmed in a larger cohort of cases, could suggest that MG oncogenesis in a dog may exhibit similar molecular features as their human counterparts.

Sebaceous adenoma occurring within an intracranial dermoid cyst.

Among intracranial cystic lesions, dermoid cysts and epidermoid cysts are relatively common benign tumors. In a small number of these tumors, it is known that squamous cell carcinomas arise in the lining epithelium of the cysts. Among tumors derived from the appendage, only one case of hidradenoma within a dermoid cyst and no cases of sebaceous tumor have been reported previously. In the present case, a protruding lesion was present in the cystic wall, and it was composed of two cell types: sebaceous cells (sebocytes) and basaloid/germinated cells, being characteristic of this tumor. It is essential to distinguish it from other sebaceous lesions such as hyperplasia, sebaceoma, sebaceous carcinoma, and basal cell carcinoma with sebaceous differentiation derived from the epidermis. The critical distinguishing points in making a differential diagnosis among these lesions are the ratio of the two cell types and the presence or absence of other components such as hair sacs, invasion or cellular atypia. Immunohistochemical examination revealed that the tumor cells were positive for the epithelial markers, such as cytokeratin (CK)14, p63, p40, high-molecular CK, and adipophilin; these findings are peculiar to sebaceous adenoma. Although there have been several similar case reports of sebaceous tumors associated with dermmoid cysts in the ovaries, most of the intracranial lesions were squamous cell carcinomas that developed within the cysts, and there has been no precedent showing an association with a sebaceous tumor. The present report describes the first case of sebaceous adenoma that occurred in an intracranial dermoid cyst.

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.

Desmoplastic Trichoepithelioma With Pseudocarcinomatous Hyperplasia: A Folliculosebaceous Neoplasm in Young Persons.

ABSTRACT: Pseudocarcinomatous desmoplastic trichoepithelioma (PDTE) features verrucous squamous epidermal hyperplasia with a jagged undersurface overlying cords of follicular germinative cells in a fibrotic stroma. To date, only 5 cases have been reported. We identified 7 new PDTEs from 2 institutions and reviewed their clinical manifestations and immunohistochemical profile. The median age was 14 years (range 8-34 years). New findings included vacuolization of the basal layer of the pseudocarcinomatous surface epithelium, and the frequent presence of singly distributed sebocytes within the cords of basaloid cells. The immunohistochemical profile resembles desmoplastic trichoepithelioma, with expression of TDAG51, CK15, and Ber-Ep4. Colonizing CK20+ Merkel cells were present in all cases. PDTE needs to be differentiated from malignant neoplasms such as squamous cell carcinoma, morphoeic basal cell carcinoma, and microcystic adnexal carcinoma. Recognizing the features of this sclerosing folliculosebaceous neoplasm facilitates accurate diagnosis and avoids overtreatment.

Glioma-Associated Oncogene-1 Expression in Basal Cell Carcinoma and Its Histologic Mimics.

ABSTRACT: Basal cell carcinoma (BCC) is the most common skin cancer, and it has numerous histologic mimics with variable prognoses and treatments. Although some immunohistochemical stains can be used for the differential diagnosis of BCC, variability and overlap in results can complicate their interpretation. Immunohistochemical staining for glioma-associated oncogene-1 (Gli-1) was performed on 26 nodular BCCs, 22 infiltrative BCCs, 9 basaloid squamous cell carcinomas, 12 desmoplastic trichoepitheliomas, 19 Merkel cell carcinomas, 11 sebaceous carcinomas, 10 cylindromas, 14 spiradenomas, 12 adenoid cystic carcinomas (AdCC), and 1 solitary trichoepithelioma. Strength of staining was scored as 0, 1+, 2+, or 3+, and distribution of staining was categorized as diffuse, multifocal, or focal. Strong, diffuse Gli-1 expression was seen in all tumors with basal epidermal-type differentiation, including BCC, trichoepithelioma, and basaloid squamous cell carcinoma. All examples of Merkel cell carcinoma were negative for cytoplasmic expression. Seven out of 11 sebaceous carcinomas were negative for Gli-1, and the remaining 4 showed 1+ expression. Cylindroma, spiradenoma, and AdCC, each an adnexal skin tumor, showed the most variable staining, but with cylindroma and spiradenoma demonstrating comparable labeling patterns. Overall, although Gli-1 may not distinguish between basal epidermal-type tumors, it may have a role in separating that group from lesions with adnexal differentiation, particularly sebaceous carcinoma, but also cylindroma, spiradenoma, and AdCC. Any cytoplasmic staining seems to exclude the diagnosis of Merkel cell carcinoma.

Sebaceous Tumors of the Skin: A Study of 145 Lesions From 136 Patients Correlating Pathologic Features and DNA Mismatch Repair Staining Pattern.

ABSTRACT: Sebaceous neoplasms occur sporadically or in the setting of Muir-Torre syndrome. The data regarding the correlation of pathologic features and DNA mismatch repair (MMR) staining pattern in sebaceous tumors of the skin are very scanty and based on relatively small series of patients. The goal of this study was to correlate MMR staining pattern with selected morphological features in a series of 145 sebaceous neoplasms (sebaceous adenoma, sebaceoma, and extraocular sebaceous carcinoma) from 136 patients. Cystic change, intratumoral mucin deposits, squamous metaplasia in the absence of keratoacanthoma-like changes, ulceration, intratumoral and peritumoral lymphocytes (in cases without epidermal ulceration), and intertumoral heterogeneity proved to be significantly associated with MMR deficiency. Identification of any of these changes, alone or in combination, should prompt further investigation of the patient to exclude Muir-Torre Syndrome. Our study also confirms the previously published observation that the diagnosis and tumor location are significantly associated with MMR deficiency.

Clear Cell Proliferations of the Skin: A Histopathologic Review.

ABSTRACT: Cutaneous clear cell proliferations encompass a heterogenous group of several primary cutaneous neoplasms and metastatic tumors with different histogenesis. Many of these clear cell proliferations may seem strikingly similar under the microscope resulting in challenging diagnosis. In many of these clear cell lesions, the reason for the clear or pale appearance of proliferating cells is unknown, whereas in other ones, this clear cell appearance is due to intracytoplasmic accumulation of glycogen, mucin, or lipid. Artifacts of tissue processing and degenerative phenomenon may also be responsible for the clear cell appearance of proliferating cells. Awareness of the histopathologic findings as well as histochemical and immunohistochemical techniques are crucial to the accurate diagnosis. This review details the histopathologic features of clear cell cutaneous proliferations, classifying them according their type of differentiation and paying special attention to the histopathologic differential diagnosis among them.

CDKN2A, CDK1, and CCNE1 overexpression in sebaceous gland carcinoma of eyelid.

PURPOSE: To investigate the overexpression of genes in sebaceous gland carcinoma (SGC) of the eyelid compared to sebaceous adenoma of the eyelid in order to elucidate the molecular mechanism underlying pathogenesis. METHODS: We performed histopathological examination of eyelid tissues surgically removed from four patients diagnosed with SGC (cases 1-3) and sebaceous adenoma (case 4) of the eyelid. Next, we performed global gene expression analysis of surgical tissue samples using a GeneChip® system and the Ingenuity Pathways Knowledge Base. The results of the GeneChip® analysis were explored with quantitative real-time polymerase chain reaction (qRT-PCR) analysis. RESULTS: In the SGC samples, we found that 211, 199, and 199 genes, respectively, showed ≥ 2.0-fold higher expression than those in the sebaceous adenoma sample (case 4); 194 genes were common to all three SGC samples. For the 194 genes with upregulated expression, functional category analysis showed that SGC of the eyelid employed a unique gene network, including cyclin-dependent kinase inhibitor 2A (CDKN2A), cyclin-dependent kinase 1 (CDK1), and cyclin E1 (CCNE1), which are related to cell cycle progression, incidence of tumor, and cell viability. Furthermore, qRT-PCR analysis showed that the expression levels of CDKN2A, CDK1, and CCNE1 were significantly upregulated in all SGC cases compared to those in the sebaceous adenoma case. These data were similar to the results of microarray analysis. CONCLUSION: Overexpression of cell cycle-related genes CDKN2A, CDK1, CCNE1, and their gene network may help elucidate the pathogenic pathway of SGC of the eyelid at the molecular level.

Loss of ZNF750 in ocular and cutaneous sebaceous carcinoma.

BACKGROUND: Sebaceous carcinoma (SeC) is an uncommon malignancy arising from sebaceous glands of the conjunctiva and skin. Recurrent mutations in the ZNF750 were recently identified in ocular SeC. We assessed whether ZNF750 loss is a specific feature of ocular SeC or a general feature of sebaceous tumors. METHODS: Immunostaining for ZNF750 expression was performed in 54 benign and malignant sebocytic proliferations. Staining for ZNF750 was scored on a three-tier scale: positive (>75%), partially positive (5%-74%), and negative (<5%). RESULTS: ZNF750 expression was negative in 4/11 ocular SeC, and partially positive in 4/11 ocular SeC and 6/13 cutaneous SeC. No extraocular tumors were negative. No loss was found in sebaceous adenoma or sebaceous hyperplasia. In nine previously sequenced ocular SeCs, two lacked detectable somatic mutations in ZNF750, but showed complete loss of staining, indicating non-mutational inactivation of ZNF750. CONCLUSION: We show complete loss of the ZNF750 epidermal differentiation regulator in about half of ocular SeC, highlighting the most common genetic defect in this cancer type. Loss of ZNF750 expression is seen even in tumors without truncating mutations and reduced in many of the remaining ocular and cutaneous SeC. In contrast, no ZNF750 loss was detected in benign sebaceous proliferations.

Clinico-pathological predictors of mismatch repair deficiency in sebaceous neoplasia: A large case series from a single Australian private pathology service.

BACKGROUND/OBJECTIVES: Loss of expression of mismatch repair (MMR) proteins is frequently observed in sebaceous skin lesions and can be a herald for Lynch syndrome. The aim of this study was to identify clinico-pathological predictors of MMR deficiency in sebaceous neoplasia that could aid dermatologists and pathologists in determining which sebaceous lesions should undergo MMR immunohistochemistry (IHC). METHODS: An audit of sebaceous skin lesions (excluding hyperplasia) where pathologist-initiated MMR IHC was performed between January 2009 to December 2016 was undertaken from a single pathology practice identifying 928 lesions from 882 individuals. Lesions were further analysed for differences in gender, age at diagnosis, lesion type and anatomic location, stratified by MMR status. RESULTS: The 882 individuals (67.7% male) had a mean (SD) age of diagnosis of 68.4 ± 13.3 years. Nearly two-thirds of the lesions were sebaceous adenomas, with 82.6% of all lesions occurring on the head and neck. MMR deficiency, observed in 282 of the 919 lesions (30.7%), was most common in sebaceous adenomas (210/282; 74.5%). MMR-deficient lesions occurred predominantly on the trunk or limbs (64.7%), compared with 23.2% in head or neck (P < 0.001). Loss of MSH2 and MSH6 protein expression was most frequent pattern of loss (187/281; 66.5%). The highest AUC for discriminating MMR-deficient sebaceous lesions from MMR-proficient lesions was observed for the ROC curve based on subgroups defined by type and anatomic location of the sebaceous lesion (AUC = 0.68). CONCLUSION: The best combination of measured clinico-pathological features achieved only modest positive predictive values, sensitivity and specificity for identifying MMR-deficient sebaceous skin lesions.

Clinicopathological features of considerable reduction in androgen receptor expression in sebaceous gland carcinoma of the eyelid.

PURPOSE: This study aimed to evaluate the relationships between androgen receptor (AR) expression and clinicopathologic features of sebaceous gland carcinoma (SGC) of the eyelid. METHODS: AR expression was evaluated via immunohistochemistry analysis of surgically derived samples from 11 patients with SGC of the eyelid. RESULTS: The expression of AR was evident in 9 of 11 patients (82%). We divided patients into high AR (7 patients) and low AR (4 patients: 2 patients with low expression and 2 patients with no expression) groups. The low AR group showed significantly greater progression than the high AR group with regard to T category and exhibited a lower grade of differentiation. CONCLUSION: In patients with SGC of the eyelid, a marked decrease in AR expression may be associated with a poor prognosis. AR may be a prognostic factor and a potential therapeutic target in cases of SGC of the eyelid.

Analysis of hedgehog signaling in periocular sebaceous carcinoma.

PURPOSE: Sebaceous carcinoma (SC) is a clinical masquerader of benign conditions resulting in significant eye morbidity, sometimes leading to extensive surgical treatment including exenteration, and even mortality. Little is known about the genetic or molecular basis of SC. This study identifies the involvement of Hedgehog (Hh) signaling in periocular SC. METHODS: Fifteen patients with periocular SC patients were compared to 15 patients with eyelid nodular basal cell carcinoma (nBCC; a known Hh tumor), alongside four normal individuals as a control for physiological Hh expression. Expression of Patched 1 (PTCH1), Smoothened (SMO), and glioma-associated zinc transcription factors (Gli1 and Gli2) were assessed in histological sections using immunohistochemistry and immunofluorescence (IF) techniques. Antibody specificity was verified using Western-blot analysis of a Gli1 over-expressed cancer cell line, LNCaP-Gli1. Semi-quantification compared tumors and control tissue using IF analysis by ImageJ software. RESULTS: Expression of the Hh pathway was observed in SC for all four major components of the pathway. PTCH1, SMO, and Gli2 were more significantly upregulated in SC (P < 0.01) compared to nBCC. Stromal expression of PTCH1 and Gli2 was observed in SC (P < 0.01). In contrast, stromal expression of these proteins in nBCC was similar or down-regulated compared to physiological Hh controls. CONCLUSIONS: The Hh signaling pathway is significantly more upregulated in periocular SC compared to nBCC, a known aberrant Hh pathway tumor. Furthermore, the stroma of the SC demonstrated Hh upregulation, in particular Gli2, compared to nBCC. Targeting of this pathway may be a potential treatment strategy for SC.

Microcystic adnexal carcinoma of the orbit mimicking pagetoid sebaceous gland carcinoma.

Microcystic adnexal carcinoma (MAC) is a rare malignancy of sweat glands that has been reported most often on the face in the form of a cutaneous lesion, with the potential for deeper invasion. The synonyms of MAC include sclerosing sweat duct carcinoma, syringomatous carcinoma, and malignant syringoma. Clinically, MAC in the periocular area has been misdiagnosed as basal cell carcinoma, squamous cell carcinoma, or even chalazia. We report a case of MAC presenting clinically as sebaceous gland carcinoma with pagetoid spread for the first time in literature.

Sebaceous gland carcinoma of the ocular adnexa - variability in clinical and histological appearance with analysis of immunohistochemical staining patterns.

PURPOSE: The purpose of the study was to evaluate the characteristics of sebaceous gland carcinoma (SGC) of the ocular adnexae, which is due to a high variability in clinical, histological and immunohistochemical characteristics often challenging to diagnose. METHODS: Records of six patients with SGC were reviewed, who underwent surgical excision and who were histologically diagnosed with SGC. For comparison, there were specimens from four patients with basal cell carcinoma (BCC) and four patients with squamous cell carcinoma (SCC). Histological and immunohistochemical analysis included stains for HE, cytokeratins (CKpan, Cam5.2), epithelial membrane antigen (EMA), androgen receptor (AR441), perforin and adipophilin. RESULTS: SGC's were located in the upper (n = 2) or lower (n = 4) eyelid and were associated with various presenting clinical signs including chalazion-like lesions with pyogenic granuloma (n = 1), papillomatous conjunctival tumors (n = 3), a hyperkeratotic exophytic neoplasm (n = 1) and an ulcerating crusted lesion resembling chronic blepharitis (n = 1). The treatment was tumor resection, followed (if necessary) by adjuvant therapy with topical Mitomycin C (n = 2). Histologic characteristics included basophilic pleomorphic cells with vacuolated cytoplasm, prominent nucleoli, mitotic figures and in some cases pagetoid spread (n = 2). CKpan, EMA and Cam5.2 showed strong positive immunoreactivity in all specimens (SGC, BCC, SCC). Perforin immunostaining showed a varying, but overall weak, non-specific cytoplasmatic staining reaction in all lesions. AR441 positivity was noted with variable intensity in almost all lesions and in particular in pagetoid spread in contrast to non-tumor cells. Adipophilin showed an annular staining of lipid granules in immature sebaceous cells in SGC in contrast to a more granular staining pattern in BCC and SCC. CONCLUSION: SGCs display a variety of clinical signs and may mimic many other lesions. Tumor resection, followed by histological and immunohistochemical analysis, leads to the diagnosis and initiation of the proper treatment regimen. Herein, immunohistochemistry showed an unequivocal profile in SGC and did not allow for an exact differentiation from BCC and SCC by immunohistochemical means only. An extended evaluation of HE stains remains essential. However, immunohistochemistry can make relevant contributions to the diagnosis of SGC, especially in cases of inconclusive histology, by positive staining for adipophilin in immature sebaceous cells or by AR441 labeling in cases of pagetoid spread.

Clinical relevance of cyclooxygenase 2 and peroxisome proliferator-activated receptor γ in eyelid sebaceous gland carcinoma.

AIMS: Sebaceous gland carcinoma (SGC) is a malignancy associated with the pilosebaceous unit, and occurs at ocular or non-ocular sites. Cyclooxygenases (COXs) are enzymes that are crucial for lipid metabolism. COX-2 is overexpressed in various cancers, and its inhibition by non-steroidal anti-inflammatory drugs is known to reduce the risk of many cancers. Peroxisome proliferator-activated receptor (PPAR)-γ is a transcription factor involved in adipogenesis. PPAR-γ is a potential therapeutic target for the treatment of malignant tumours, including colon carcinoma. The aim of this study was to explore the status of COX-2 and PPAR-γ as prognostic markers in human eyelid SGC. METHODS AND RESULTS: The immunohistochemical expression of COX-2 and PPAR-γ was evaluated in 31 SGC cases. Cytoplasmic expression of COX-2 was detected in 80% of the SGC cases, and nuclear expression of PPAR-γ in 87%. There were significant correlations of PPAR-γ expression with well-differentiated SGC [19/21 (90%)] and of COX-2 overexpression with reduced disease-free survival (P = 0.0441, log rank analysis). COX-2 expression [odds ratio (OR) 3.82, 95% confidence interval (CI) 1.02-14.33, P = 0.046] and lymph node metastasis (OR 0.17, 95% CI 0.04-0.65, P = 0.009) emerged as significant risk factors in the univariate analysis. However, COX-2 expression did not emerge as a significant independent prognostic factor in multivariate analysis. CONCLUSIONS: COX-2 is a potential marker for identifying high-risk SGC patients. Expression of PPAR-γ in eyelid SGC cases reflects terminal sebaceous differentiation. Inhibitors of COX-2 signalling and PPAR-γ agonists are both prospective novel therapeutic targets in the management of eyelid SGC patients.

Expression of epidermal stem cell markers in skin and adnexal malignancies.

BACKGROUND: Epidermal stem cells are multipotent cells that maintain the skin epidermis. Potential markers for stem cells have been identified in mammalian skin from mouse experiments; however, it is unclear if stem cells also contribute to tumour formation in human skin. OBJECTIVES: To investigate the expression of potential stem cell markers, such as leucine-rich repeat-containing G protein-coupled receptor (Lgr) 5, Lgr6, leucine-rich repeats and immunoglobulin-like domain protein 1 (Lrig1) and cytokeratin 15 (CK15) in basal cell carcinomas and tumours of the skin appendages. METHODS: We tested 45 human basal cell carcinomas (BCCs), including superficial, nodular, adenoid, infiltrating and sclerosing types, and 38 human tumours of skin appendages, including 13 sebaceous adenomas and carcinomas, 20 eccrine sweat gland tumours and five pilomatricomas, for the expression of hair follicle stem cell markers such as Lgr5, Lrig1, CK15, ß-catenin and SRY (sex determining region Y)-box 9 (SOX9), and compared these findings with those of healthy age-matched human epidermis. RESULTS: We detected the expression of stem cell markers in all tumours tested. Regarding Lgr5, Lrig1, CK15 and SOX9, expression seemed to be lower in more aggressive tumour types, such as in the most advanced parts of infiltrating BCC, in sebaceous carcinoma and late-stage porocarcinoma, compared with less aggressive superficial or nodular BCC or early-stage porocarcinoma and sebaceous gland tumours. In aggressive, sclerosing BCC, Lrig1 and Lgr5 were downregulated but CK15, SOX9 and nuclear ß-catenin were upregulated. CONCLUSIONS: Expression of potential stem cell markers of the epidermis and hair follicles was observed in skin tumours of appendages and BCCs. However, during tumour progression, many of these markers seemed to be downregulated.

Intraepidermal benign sebaceous neoplasm: apocrine poroma (hidroacanthoma simplex type) with extensive sebaceous differentiation with sebaceoma-like features.

We herein report a patient who clinically presented with a yellowish, flat plaque that histopathologically showed a benign lesion mainly composed of intraepidermal basaloid nests with sebaceous differentiation. This lesion was considered to be fundamentally apocrine poroma (hidroacanthoma simplex type) with sebaceous differentiation. Nests composed of typical poroid cells were seen, and the results of immunostaining for lumican supported this diagnosis and excluded the possibility of clonal seborrheic keratosis. The sebaceous differentiation in apocrine poromas mostly occurs in Pinkus type lesions, and is usually seen in only part of the lesions, as solitary, mature sebocytes within the poroma nests. However, our apocrine poroma case was unique not only in that sebaceous differentiation occurred in the hidroacanthoma simplex type, but also in that it was observed extensively (approximately 60% of the nests). We therefore called this lesion an 'intraepidermal benign sebaceous neoplasm'. Although it may be hard to differentiate sebaceous germinative cells (seen in sebaceoma) from poroid cells, in this case, some poroma nests could be judged to neighbor or contain the sebaceoma-like areas. Therefore, the presented apocrine poroma was considered to have some features of (intraepidermal and dermal) sebaceoma.

Sebaceous carcinoma within rippled/carcinoid pattern sebaceoma.

Although the histogenesis of sebaceous carcinomas remains unclear, the occurrence of intraepidermal or intraepithelial sebaceous carcinoma in the epidermis or conjunctiva may suggest de novo histogenesis. This report describes a case of sebaceous carcinoma within preexisting rippled/carcinoid pattern sebaceoma. This lesion was composed of two (benign and malignant) components, and the benign component of the lesion showed the typical features of a rippled/carcinoid pattern sebaceoma. Although evidence of trauma as well as a vertical orientation was seen in this lesion, the malignant component of the lesion showed histopathological evidence of malignancy (sebaceous carcinoma), such as the aggregations with irregular and infiltrated borders, a sheet-like growth pattern, and the cytopathological findings of the neoplastic cells, showing a high-grade of malignancy (a high mitotic index and abnormal mitotic figures). The immunohistochemical staining for p53, Ki-67 and D2-40 also favored this diagnosis. This sebaceous carcinoma component was considered to be the incipient stage of carcinoma within preexisting sebaceoma, therefore, it was still considered to be a vertically oriented lesion. This case shows the possibility that abnormal (malignant) sebaceous germinative cells may originate within a sebaceoma, thereby suggesting that some sebaceous carcinomas may develop from preexisting sebaceomas.