Two histopathologic patterns of well-differentiated extraocular sebaceous carcinoma

Background: No previous reports on the variation in the histopathological patterns of well‐differentiated sebaceous carcinoma are yet to be published. Methods: We reviewed the histopathology of six examples of well‐differentiated extraocular sebaceous carcinoma. Results: Two distinct histopathological patterns of sebaceous carcinoma, namely a secretory pattern (N = 2) and a non‐secretory pattern (N = 4), were defined. The secretory pattern is typified by sebaceous lobular architecture with focal holocrine secretion, whereas the non‐secretory pattern lacks this organoid quality. Both carcinomas with the secretory pattern showed low‐grade cytological atypia, whereas the four carcinomas with the non‐secretory pattern included three lesions with high‐grade cytological atypia. A sebaceous adenoma‐like area was seen in both secretory pattern carcinomas, whereas a focus of intraepithelial sebaceous carcinoma (sebaceous carcinoma in situ) was seen in two of the non‐secretory pattern carcinomas. Conclusions: The clinicopathological significance of the two histopathological patterns remains unclear, because the number of reported cases is limited. It is possible that these two histopathological patterns of carcinoma have different histogenetic and prognostic implications, but no definitive conclusions can be made until further studies of a larger number of cases can be completed. Misago N, Toda S, Narisawa Y. Two histopathologic patterns of well‐differentiated extraocular sebaceous carcinoma.     

An updated review of the sebaceous gland and its role in health and diseases Part 1: Embryology,evolution, structure,and function of sebaceous glands

Sebaceous glands are sebum‐secreting components of pilosebaceous units. The embryological development of the sebaceous gland follows that of the hair follicle and epidermal tissue, beginning between weeks 13 and 16 of fetal development. New sebaceous glands do not normally develop following birth, but their size increases with age. Sebocytes express a multitude of hormone receptors and are heavily regulated to secrete sebum by androgens. There is a large increase of sebum excretion at birth and again at puberty, until approximately age 17. In adulthood, sebum production remains stable and declines to zero in postmenopausal women and in men aged 60‐70. Besides the production and release of sebum, sebaceous glands function to lubricate the skin and hair, provide thermoregulation, and exhibit antimicrobial activity. Research has shown sebaceous glands to possess the cellular capability to transcribe genes necessary for androgen metabolism. Dysfunction of the sebaceous gland can be seen primarily in steatocystoma simplex and multiplex, sebaceous gland hyperplasia, sebaceoma, sebaceous adenoma, sebaceous carcinoma, nevus sebaceus, and folliculosebaceous cystic hamartoma. Sebaceous glands are secondarily involved in acne vulgaris, seborrheic dermatitis, and androgenic alopecia.     

Nuclear factor XIIIa staining (clone AC‐1A1 mouse monoclonal) is a sensitive and specific marker to discriminate sebaceous proliferations from other cutaneous clear cell neoplasms

Sebaceous carcinoma is a rare but serious malignancy that may be difficult to diagnose when poorly differentiated. Other epithelial tumors with clear cell change may mimic sebaceous carcinoma. Few useful or specific immunohistochemical markers for sebaceous differentiation are available. Nuclear staining with factor XIIIa (clone AC‐1A1) was recently found to be a highly sensitive marker of sebaceous differentiation. We evaluated nuclear factor XIIIa (AC‐1A1) staining in sebaceous neoplasms vs. other cutaneous clear cell tumors. We stained 27 sebaceous proliferations: sebaceous hyperplasia (7), sebaceous adenoma (8), sebaceoma (5), sebaceous carcinoma (7). We also stained 67 tumors with clear cell change: basal cell carcinoma (8), squamous cell carcinoma (8), hidradenoma (7), desmoplastic trichilemmoma (2), trichilemmoma (10), trichilemmal carcinoma (3), clear cell acanthoma (9), atypical fibroxanthoma (1), syringoma (8), trichoepithelioma (1), metastatic renal cell carcinoma (2), and nevi with balloon cell change (8). Nuclear factor XIIIa (AC‐1A1) staining was present in 100% of sebaceous proliferations; 96% displayed strong staining. Non‐sebaceous clear cell tumors were negative or only weakly positive with factor XIIIa (AC‐1A1) in 95.5%; only 4.5% showed strong staining. This suggests that strong nuclear factor XIIIa (AC‐1A1) staining is a sensitive and specific marker of sebaceous neoplasms vs. other clear cell tumors.     

Sebaceous mantleoma (mantle adenoma): reappraisal of the myth of the problematic benign neoplasm with sebaceous mantle differentiation

Few cases of a true benign neoplasm with sebaceous mantle differentiation have been reported, and little is known about this tumor. Herein, we present a rare case of the neoplasm called sebaceous mantleoma, along with a comparison of the histology and immunoprofile with those of normal sebaceous mantles. A pedunculated polyp occurred on the scalp of a 51‐year‐old woman. Histopathologically, the tumor showed lobulated epithelial‐mesenchymal units that were separated from the normal dermis by clefts. The lesion was composed of cords and columns of basaloid cells containing a few mature sebocytes, with a focal connection to infundibulocystic structures as well as dense fibrotic or fibromyxoid stroma. Immunohistochemically, androgen receptor, estrogen receptor, and CD117 were partially positive for the tumor, and CD8 (C8/144B) and epithelial membrane antigen were focally positive. Additionally, cytokeratin 20‐positive Merkel cells were individually admixed in the tumor nests as well as in normal sebaceous mantles. This case report reveals the characteristic histology and immunoprofile of this problematic benign neoplasm and helps to understand this entity.     

Folliculosebaceous Cystic Hamartoma Associated with Rosacea

A case of folliculosebaceous cystic hamartoma associated with rosacea is presented. Clinically, a solid, 5-mm-sized nodule was observed on the nose which showed telangiectasia and a waxy appearance. Histologically, a large horn cyst was located in the dermis, and was continuous with the surface epidermis. It was associated with mature sebaceous glands and immature hair follicles. Folliculosebaceous cystic hamartoma and similar cases have recently been reported, but this is the first report accompanied by rosacea.     

Microcystic adnexal carcinoma with sebaceous differentiation: Three cases

Microcystic adnexal carcinoma (MAC) is a low‐grade malignant tumor of the skin. Histologically, this tumor shows a biphasic pattern, with cords and nests of basaloid cells, as well as keratin horn cysts. This biphasic histological appearance has been interpreted by some authors as a sign of double eccrine and folliculosebaceous‐apocrine differentiation, whereas some other authors defend a solely eccrine differentiation. In this context, sebaceous differentiation in MAC would support the first option. However, there are only 3 cases of MAC with sebaceous differentiation in the literature, and all of them were reported before adipophilin was available, which in the appropriate context (eg, testing clear cells for sebaceous vs eccrine differentiation) is very useful. In this study, we present 3 cases of MAC with focal sebaceous differentiation confirmed by immunoexpression of adipophilin in the sebaceous foci.     

Spatial analysis of p63, K5 and K7 defines two groups of progenitor cells that differentially contribute to the maintenance of normal sebaceous glands,extraocular sebaceous carcinoma and benign sebaceous tumors

The histogenesis of extraocular sebaceous carcinomas is – in contrast to ocular sebaceous carcinomas – unclear, and information about the exact cellular architecture of these lesions and even of the normal sebaceous gland is still scarce. This study attempts to elucidate the histogenesis of sebaceous tumors, using multicolor immunofluorescence stainings to analyze 21 cases of sebaceous tumors (six each of extraocular sebaceous carcinoma, sebaceous adenoma and sebaceoma, and three cases of steatocystomas) and eight cases of normal sebaceous glands for p63, several keratins, androgen receptor, adipophilin, epithelial membrane antigen (EMA) and Ki‐67. The data of this observational study provide evidence for the existence of two subpopulations of progenitors in normal sebaceous glands: (i) p63⁺ K5⁺ progenitors which generate the K10⁺ luminal cells of sebaceous ducts; and (ii) p63⁺ K5⁺ K7⁺ progenitors which finally generate K7⁺ adipophilin⁺ EMA⁺ sebocytes. Without exception, all types of sebaceous tumors contained p63⁺ K5⁺ cells. Furthermore, these tumors showed a cellular hierarchy and differentiation to adipophilin⁺ and/or EMA⁺ mature sebocytes and to K10⁺ ductal cells through intermediary cells. Notably, a considerable number of sebaceous tumors lack the K7 pathway of cell maintenance in the normal sebaceous lobule. Based on our data, we propose a cellular algorithmic model of the hierarchy of normal sebaceous glands and of sebocytic tumors in which p63⁺ K5⁺ cells play a major role.     

Epidermal growth factor receptor and the sebaceous gland

Side effects of EGFR inhibition do not include primary sebaceous gland changes. Dahlhoff et al. evaluated EGFR actions on the sebaceous glands in mutant mice with constitutively activated EGFR expression. Enlarged, hyperproliferative sebaceous glands and increased sebum levels were detected, and c‐myc levels were increased. These data indicate that EGFR‐induced sebocyte mechanisms are probably species‐specific. The detected SCD deregulation is compatible with previous reports, whereas SCD is a marker of sebaceous differentiation, and its expression is essential for lipogenesis. As SCD expression is upregulated by TLR2 activation, there is a link between SCD overexpression and sebaceous differentiation/lipogenesis with inflammation.     

Bonbon toffee sign: a new dermatoscopic feature for sebaceous hyperplasia

Introduction Sebaceous hyperplasia is a benign proliferation of the sebaceous gland. In this study, we tried to define the dermatoscopic features of sebaceous hyperplasia, which will help to minimize misdiagnoses. Material and method Seventeen patients with 30 sebaceous hyperplasia lesions were included in the study. All the lesions were evaluated dermatoscopically. Results Cumulus sign, crown vessels, and milia‐like cysts were detected in 100%, 86.6%, 53.3% of the lesions, respectively. In 80% of the lesions, the bonbon toffee sign was detected. Conclusion During this study, we observed a feature with central umbilication surrounded by cumulus sign in 80% of our cases, and we named this entity as the ‘Bonbon toffee sign’, which resembled us ‘bonbon toffee’. We think the ‘bonbon toffee sign’ is a simple and easily recognizable phrase, and it can be used as a new terminology in dermatoscopic diagnosis of sebaceous hyperplasia.     

Photodynamic therapy of facial nevus sebaceous

A 29‐year‐old man visited our department with an orange‐colored patch on his right cheek. A skin biopsy confirmed the diagnosis of nevus sebaceous. As surgical excision was considered too destructive, photodynamic therapy (PDT) was proposed. Sixteen sessions of PDT was performed in total. There was a definitive but transient decrease in sebum production and destruction of the sebaceous glands. Overall, we were not able to achieve long‐lasting clinical improvement after PDT.     

Fifty years of the asebia mouse: origins,insights and contemporary developments

First described as an alopecic spontaneous mutant mouse line lacking sebaceous glands in a publication in Science in 1965 by Allen H. Gates and Marvin Karasek, asebia mice soon became a popular tool for rodent sebaceous gland research. In addition to the study of sebaceous lipids, the original asebia mice and subsequent allelic mutations were widely employed to examine the influence of the sebaceous gland on hair growth, epidermal proliferation, dermal inflammation and skin carcinogenesis, among other aspects. With the identification of Scd1 gene mutations as the genetic basis of the asebia phenotype and with the advent of more refined methods for manipulating the mouse genome, asebia mice progressively lost importance. However, they contributed to, or even provided the initial spark for, several current research topics. These include the role of the sebaceous gland in hair shaft–sheath interaction and its significance for cicatricial alopecia, and the antimicrobial activity of sebum. Furthermore, mice with skin‐specific deletion of SCD1, which have increased energy expenditure and are protected from high fat diet‐induced obesity, provided novel insights into the crosstalk between the skin and peripheral tissues in maintaining energy homeostasis. In briefly reviewing its story, this commentary pays tribute to asebia mice and to the original publication in its golden anniversary year.     

Reticulated acanthoma with sebaceous differentiation: another sebaceous neoplasm associated with Muir–Torre syndrome?

Reticulated acanthoma with sebaceous differentiation (RASD) represents a rare benign cutaneous epithelial neoplasm with sebaceous differentiation. There has been much speculation about the relationship between RASD and Muir–Torre syndrome (MTS). We report a 53 year‐old man who presented with RASD in addition to a prior history of sebaceous adenomas. Immunohistochemically, the tumour cells in the RASD and sebaceous adenomas showed a significantly reduced MSH6 protein expression, whereas there was no loss of MLH1, MSH2 and PMS2. This benign neoplasm, which can be mistaken for various other cutaneous lesions with sebaceous differentiation, deserves wider recognition for its possible association with MTS.     

Zileuton prevents the activation of the leukotriene pathway and reduces sebaceous lipogenesis

Please cite this paper as: Zileuton prevents the activation of the leukotriene pathway and reduces sebaceous lipogenesis. Experimental Dermatology 2010; 19: 148–150. Abstract: Arachidonic acid (AA) activates the 5‐lipoxygenase, induces leukotriene‐B₄ (LTB₄) synthesis, enhances interleukin‐6 (IL‐6) release and increases intracellular neutral lipids in human sebocytes. Moreover, the enzymes of LTB₄ biosynthesis are activated in acne‐involved sebaceous glands. Zileuton a 5‐lipoxygenase inhibitor, reduces the number of inflammatory acne lesions and lipogenesis in patients with acne. In this study, we investigated the activity of zileuton on LTB₄ generation, lipid content and IL‐6 and ‐8 release from human SZ95 sebocytes in vitro. Pretreatment with zileuton partially prevented the AA‐induced LTB₄ and IL‐6 release and increased neutral lipid content. IL‐6 release and neutral lipid content were also reduced under long‐term zileuton treatment. In conclusion, zileuton prevents the activation of the leukotriene pathway and enhancement of lipogenesis by AA in human sebocytes in vitro.     

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.     

Presenile diffuse familial sebaceous hyperplasia successfully treated with low‐dose isotretinoin: A report of two cases and review of the published work

Presenile diffuse familial sebaceous hyperplasia (PDFSH) presents as extensive yellowish papules with central umbilication on the face without involvement of periorificial regions and occurs in adolescents or young adults with a positive family history. Thirteen cases of PDFSH have been reported in the English‐language published work, 10 of which responded to oral isotretinoin from 0.5 to 1 mg/kg per day but recurrences were often observed. Herein, we report two cases of PDFSH, which were successfully managed without recurrence with prolonged low‐dose isotretinoin (0.2 mg/kg per day, a cumulative dose of 41 and 64 mg/kg, respectively). Treatment protocols among different published works were reviewed to verify the efficacy of isotretinoin.     

Ten cases of sebaceous carcinoma arising in nevus sebaceus

Although nevus sebaceus is known to develop various types of secondary neoplasms, it rarely causes carcinoma and only 14 cases of secondary sebaceous carcinoma have been reported. In this study, 10 cases of sebaceous carcinoma arising in nevus sebaceus were collected. The clinicopathological features and results of immunohistochemical examinations with adipophilin, perilipin and p53 were summarized. Sebaceous carcinoma arising in nevus sebaceous predominantly occurred on the scalp (8/10) of elderly women (mean age, 67.7 years). No case was associated with Muir–Torre syndrome. We found several pathological features of sebaceous carcinoma; that is, made up mainly of germinative cells, moderate nuclear atypia without pleomorphism and many mitoses (4–28/10 high‐power field). Adipophilin and perilipin antibodies highlighted lipid drops in the cytoplasm of the malignant cells in all cases. Overexpression of p53 was seen in all cases. In two cases there were coexisting benign‐looking sebaceous lesions at the periphery of the main cancer nodule, and in these lesions p53 showed low positivity compared with the clearly malignant area. There was co‐occurrence of another neoplasm in three cases with trichoblastoma, sebaceoma and syringocystadenoma papilliferum, respectively. All cases were treated by excision of the malignant lesion, with or without inclusion of the nevus sebaceus. In a follow‐up period of 1–7 years, there was no case of recurrence, lymph node metastases or distant metastases. With these specific pathological and immunohistochemical findings using adipophilin, perilipin and p53, we have to consider the possibility that there is a tendency to underdiagnose secondary sebaceous carcinomas in nevus sebaceus. These clinicopathological features of sebaceous carcinomas developing in the nevus sebaceus seem to indicate different biological entities from de novo sebaceous carcinoma.     

Sebaceous Epithelioma

An 83-year-old woman had developed an asymptomatic, yellowish, dome-shaped skin tumor on her scalp which had enlarged for a period of 60 years to 10 times 10 times 10 mm in size. Histopathologically, the tumor consisted of undifferentiated basaloid cells, differentiated sebaceous cells and transitional cells. Although the basaloid cells resembled those of basal cell epithelioma (BCE), the tumor was distinct from BCE in the following points; existence of cystic spaces, no peripheral palisading, no proliferation of connective tissue stroma, and no tendency toward local invasion. Immunohistochemical studies using antikeratin monoclonal antibodies revealed that the tumor contained both the keratin types of BCE and of sebaceous glands. Electron microscopically, the tumor cells contained lipid droplets and keratohyaline granules in their cytoplasm. It is suggested that “sebaceous epithelioma” is a benign skin tumor which may be distinguished cytologically from BCE.     

Histochemical detection of burn-induced lipid peroxidation in sebaceous glands of rat skin.

Increased lipid peroxide levels both in skin and serum have been reported after cutaneous thermal injury. However, it still remains unclear where lipid peroxides are produced at the site of burned skin. In the present study, a histochemical method using cold Schiff's reagent was applied in order to detect the localization of lipid peroxide. Schiff positivity was detected in sebaceous glands, and the extent of positivity seemed to correlate with the serum lipid peroxide levels. These results may suggest that lipid peroxides produced in sebaceous glands after thermal injury enter the blood stream and are partially responsible for the elevated serum lipid peroxide levels.