Periocular intraepithelial sebaceous neoplasia: critical appraisal of nomenclature and prognostic importance.

Intraepithelial sebaceous neoplasia in the forms (or subclassification) of pagetoid spread and carcinoma in situ is a common feature of periocular sebaceous carcinoma and is associated with less favourable outcomes. Seminal studies of periocular sebaceous carcinoma in the 1980s indicated that the two patterns of intraepithelial spread had differing influences on prognosis with pagetoid invasion being worse. Later studies reported conflicting results, but careful inspection of those studies revealed considerable variation in what was meant by pagetoid invasion. Different interpretations of pagetoid spread continue, leading to ambiguous results in clinical studies and miscommunication with potential unintended decisions affecting clinical management. This paper reviews the background leading to the frequent interchangeable use of pagetoid spread with in situ sebaceous carcinoma and how this problem confounds interpretation of clinical studies. The author recommends that for effective communication, all morphological patterns of in situ spread of sebaceous carcinoma fall under the term intraepithelial sebaceous neoplasia, which can be accompanied by subclassification whenever desired.

Cytologic Grading of Cutaneous Sebaceous Neoplasms: Does it Help to Differentiate Benign From Malignant?

Both architectural and cytologic characteristics are used to distinguish benign from malignant sebaceous neoplasms; however, specific cytopathologic features of sebocytes have not been well defined. The authors assessed architectural and cytological features of 63 sebaceous neoplasms [15 sebaceous hyperplasias, 12 sebaceomas, 16 sebaceous adenomas (SA), 14 sebaceous carcinomas (SC), and 6 ocular sebaceous carcinoma (OSC)] to investigate whether cytological grading may facilitate classification of lesions. Among other criteria, nuclear pleomorphism (size, nucleolar appearance, membrane irregularity, crowding, mitoses, and chromatin pattern) was assessed and 3 theoretical nuclear grades established. Immunohistochemistry for CK10, p16, adipophilin and ki67 was performed on 7 cases of each type of tumor. Most sebaceous neoplasms, except OSC, showed a bland architectural silhouette. However, SA, SC, and OSC revealed larger nuclei (≥14 µm in ≥50% of cases), evident to multiple nucleoli, membrane irregularity, coarse to clumped chromatin, and nuclear grade ≥2 (latter in ≥56% of cases); by contrast, sebaceous hyperplasia and sebaceomas showed smaller nuclei (≤10 µm in ≥50% of cases), smooth borders, inconspicuous nucleoli, fine chromatin, and grade 1 nuclei (latter in 100% of cases). In the setting of a well-circumscribed architecture, cytologic features gain importance in the classification of sebaceous neoplasms. Interestingly, cytologic similarities found in SA and SC may indicate a close relationship of both neoplasms.

Cell of origin and mutation pattern define three clinically distinct classes of sebaceous carcinoma.

Sebaceous carcinomas (SeC) are cutaneous malignancies that, in rare cases, metastasize and prove fatal. Here we report whole-exome sequencing on 32 SeC, revealing distinct mutational classes that explain both cancer ontogeny and clinical course. A UV-damage signature predominates in 10/32 samples, while nine show microsatellite instability (MSI) profiles. UV-damage SeC exhibited poorly differentiated, infiltrative histopathology compared to MSI signature SeC (p = 0.003), features previously associated with dissemination. Moreover, UV-damage SeC transcriptomes and anatomic distribution closely resemble those of cutaneous squamous cell carcinomas (SCC), implicating sun-exposed keratinocytes as a cell of origin. Like SCC, this UV-damage subclass harbors a high somatic mutation burden with >50 mutations per Mb, predicting immunotherapeutic response. In contrast, ocular SeC acquires far fewer mutations without a dominant signature, but show frequent truncations in the ZNF750 epidermal differentiation regulator. Our data exemplify how different mutational processes convergently drive histopathologically related but clinically distinct cancers.

Topics in histopathology of sweat gland and sebaceous neoplasms.

This article reviews several topics regarding sweat gland and sebaceous neoplasms. First, the clinicopathological characteristics of poroid neoplasms are summarized. It was recently reported that one-fourth of poroid neoplasms are composite tumors and one-fourth are apocrine type lesions. Recent progress in the immunohistochemical diagnosis of sweat gland neoplasms is also reviewed. CD117 can help to distinguish sweat gland or sebaceous tumors from other non-Merkel cell epithelial tumors of the skin. For immunohistochemical differential diagnosis between sweat gland carcinoma (SGC) other than primary cutanesous apocrine carcinoma and skin metastasis of breast carcinoma (SMBC), a panel of antibodies may be useful, including p63 (SGC+ , SMBC- ), CK5/6 (SGC+ , SMBC- ), podoplanin (SGC+ , SMBC- ) and mammaglobin (SGC- , SMBC+ ). Comparison of antibodies used for immunohistochemical diagnosis of sebaceous carcinoma (SC) suggests that adipophilin has the highest sensitivity and specificity. Some authors have found that immunostaining for survivin, androgen receptor and ZEB2/SIP1 has prognostic value for ocular SC, but not extraocular SC. In situ SC is rare, especially extraocular SC, but there have been several recent reports that actinic keratosis and Bowen's disease are the source of invasive SC. Finally, based on recent reports, classification of sebaceous neoplasms into three categories is proposed, which are sebaceoma (a benign neoplasm with well-defined architecture and no atypia), borderline sebaceous neoplasm (low-grade SC; an intermediate tumor with well-defined architecture and nuclear atypia) and SC (a malignant tumor with invasive growth and evident nuclear atypia).

Extraocular Sebaceous Carcinoma-A Clinicopathologic Reassessment.

Sebaceous carcinoma is an aggressive adnexal neoplasm with sebaceous differentiation. Few reports have described the histopathologic characteristics of the sebaceous carcinoma occurring extraocularly. Seventy-two cases of extraocular sebaceous carcinoma were identified from the database of a Dermatopathology Laboratory from January 1, 2007 to May 31, 2013. More cases occurred in men (60%), with a mean age at diagnosis of 65.8 years (range 39-99 years). Neoplasms were histopathologically classified as well-differentiated (22%), moderately differentiated (67%), and poorly differentiated (11%). Sixty-seven percent (67%) of cases demonstrated a squamoid growth pattern and thirty-three percent (33%) demonstrated a basaloid growth pattern. A majority of the neoplasms histopathologically classified as well-differentiated (94%) and moderately differentiated (65%) demonstrated a squamoid growth pattern. Ten percent (10%) of cases exhibited cystic histopathologic changes. The histopathological features reported in this study aid in the understanding of extraocular sebaceous carcinoma and its eventual diagnosis and classification.

Proposal of a Provisional Classification of Sebaceous Carcinoma Based on Hormone Receptor Expression and HER2 Status.

Despite recent progress in comprehensive genetic analysis, little is known about the molecular pathogenesis of sebaceous carcinoma. On the basis of the ontogenic proximity of sebaceous and mammary glands, we designed an intrinsic classification for sebaceous carcinoma adapted from that of breast cancer and evaluated its clinical significance. We investigated 42 cases of sebaceous carcinoma, including 32 ocular and 10 extraocular cases. Immunohistochemical analyses for estrogen receptor (ER), progesterone receptor (PR), androgen receptor (AR), HER2, Ki67, and CK5/6 and fluorescence in situ hybridization for the HER2 gene were performed. The immunohistochemistry for ER, PR, and AR showed positivity in 18 (42.9%), 11 (26.2%), and 34 (81.0%) cases, respectively. Expression of the HER2 protein was found in 10 (33.8%) cases, whereas extra copies were found in 3 (7.1%). According to our system, there were 16 (38.1%) cases of the luminal 1 subtype, 4 (9.5%) of the luminal 2 subtype, and 7 (16.7%) of the HER2 subtype, respectively. Fifteen cases (35.7%) belonged to the triple-negative group. In univariable analysis, loss of AR was significantly associated with shorter disease-free survival (P=0.020), whereas the expression of HER2 was associated with a better outcome with borderline significance (P=0.060). The luminal 2 subtype showed the best survival, and the all-negative subtype showed the worst (P=0.001). In multivariable analysis, negativity of PR or AR, low CK5/6, and female sex were independent poor prognostic factors (all P<0.05). This is the first study to categorize sebaceous carcinoma on the basis of the possible link between its molecular pathogenesis and future therapeutic applications.

Prognosis of eyelid sebaceous gland carcinoma based on the tumor (T) category of the American Joint Committee on Cancer (AJCC) classification.

The purpose of this study was to evaluate the clinical features and prognosis of eyelid sebaceous gland carcinoma (SGC) based on the T category of the American Joint Committee on Cancer (AJCC) classification (7th edition). This is a retrospective interventional case series study. Based on the T category of the AJCC classification, 191 patients with eyelid sebaceous gland carcinoma were classified as T1 (n = 1, 1 %), T2 (n = 111, 58 %), T3 (n = 76, 40 %), and T4 (n = 3, 2 %). Based on multivariate analysis, the factors predictive of regional lymph node metastasis included duration of symptoms >6 months (p = 0.04) and orbital tumor extension (p < 0.001). The factors predictive of systemic metastasis included orbital tumor extension (p < 0.001) and perivascular invasion (p = 0.007). The factor predictive of death due to systemic metastasis included orbital tumor extension (p < 0.001). Kaplan-Meier estimates of regional lymph node metastasis at 5 and 10 years, respectively, were 0 and 0 % for T1, 11 and 11 % for T2, 44 and 59 % for T3, and 100 and 100 % for T4 (p < 0.001). Kaplan-Meier estimates of systemic metastasis at 5 and 10 years, respectively, were 0 and 0 % for T1, 6 and 6 % for T2, 35 and 35 % for T3, and 100 and 100 % for T4 (p < 0.001). Kaplan-Meier estimates of death due to metastasis at 5 and 10 years, respectively, were 0 and 0 % for T1, 3 and 3 % for T2, 30 and 50 % for T3, and 100 and 100 % for T4 (p < 0.001). Primary tumor (T) category of the AJCC classification predicts the prognosis of patients with eyelid SGC. The risk of systemic metastasis and death increases with increasing tumor category.

[Differential diagnostics of sebaceous tumors]. / Differenzialdiagnostik der Talgdrüsentumoren.

Sebaceous tumors are epithelial tumors with a differentiation towards sebaceous adnexal structures of the skin. They imitate the epithelial cells of mature sebaceous glands, sebaceous ducts, immature (embryonic) sebaceous structures or sebaceous glands that are not stimulated by hormones (mantle structures). This article explains the classification of sebaceous tumors on the basis of the normal histology of sebaceous glands. Clinical and histopathological criteria are given for the most important sebaceous tumors. The differential diagnosis of sebaceoma, sebaceous adenoma and various types of sebaceous carcinoma is emphasized. The importance of a specific diagnosis of adnexal tumors is demonstrated by tumor-associated syndromes with involvement of other organs (e.g., Muir-Torre syndrome and Birt-Hogg-Dubé syndrome). Furthermore, conceptional controversies, problems in differential diagnosis and the impact of immunohistochemical staining in the assessment of sebaceous tumors are considered.

Prognostic value of clinical and pathologic T stages defined by the American Joint Committee on Cancer for eyelid sebaceous carcinoma in Korea.

PURPOSE: To investigate whether the clinical and pathologic T category classification, as defined by the American Joint Committee on Cancer (AJCC), is associated with lymph nodes (LN) or distant metastasis in patients with eyelid sebaceous carcinoma. METHODS: Forty patients treated for eyelid sebaceous carcinoma at Seoul National University Hospital between March 1999 and December 2011 were retrospectively staged according to the AJCC 7th edition criteria. Three different primary tumor classifications-(1) clinical tumor size at presentation; (2) clinical AJCC T stage (cT) at presentation based not only on size, but also on the extent of involvement and (3) pathologic AJCC T stage (pT) based on histopathological examination-were compared and evaluated with regard to their association with LN or distant metastasis. RESULTS: In univariate analysis, the AJCC cT (p = 0.005) and pT (p = 0.029) categories were significantly associated with metastasis, but clinical tumor size alone did not correlate with metastasis (p = 0.093). Clinical and pathologic AJCC stage T2b or higher tumors were significantly associated with metastasis compared to stage T1 or T2a tumors [odds ratio cT, 8.00 (p = 0.025); pT, 6.91 (p = 0.028)]. CONCLUSIONS: The clinical and pathologic AJCC T category has predictive value for LN or distant metastasis in eyelid sebaceous carcinoma. However, the clinically assessed largest tumor dimension alone is not an effective predictive factor. Clinicians should be aware of the increased risk of metastasis in patients with tumors of stage T2b or higher at initial presentation.

American Joint Committee on Cancer T category for eyelid sebaceous carcinoma correlates with nodal metastasis and survival.

PURPOSE: To determine whether T category of the American Joint Committee on Cancer (AJCC) TNM staging system for eyelid carcinoma, 7th edition, correlates with lymph node metastasis, distant metastasis, and survival in patients with sebaceous carcinoma of the eyelid. DESIGN: Retrospective, cohort study. PARTICIPANTS: Fifty consecutive patients treated by 1 author (BE) for eyelid sebaceous carcinoma between May 1999 and August 2010. METHODS: Each tumor was staged according to the AJCC 7th edition TNM criteria. The Kaplan-Meier method was used to determine associations between disease-specific survival and (1) T category at presentation, (2) lymph node metastasis, and (3) distant metastasis. MAIN OUTCOME MEASURES: T category at presentation, nodal metastasis, survival. RESULTS: The study included 37 women and 13 men (median age, 68.5 years; range, 44-86 years). Forty-four patients were white, 5 were Hispanic, and 1 was Asian. TNM designations were TXN0M0, 7 patients; T1N0M0, 4 patients; T2aN0M0, 12 patients; T2bN0M0, 11 patients; T2bN1M0, 2 patients; T2bN1M1, 1 patient; T3aN0M0, 2 patients; T3aN1M0, 5 patients; T3bN0M0, 1 patient; T3bN1M0, 1 patient; T3bN0M1, 2 patients; T4N0M0, 1 patient; and T4N0M1, 1 patient. T category at presentation was significantly associated with lymph node metastasis (P = 0.0079). No tumors with T category better than T2b or smaller than 9 mm in greatest dimension were associated with nodal metastasis. Five patients (10%) died of disease during follow-up. Their TNM designations were T2bN1M1, 1 patient; T3bN0M1, 2 patients; T4N0M0, 1 patient; and T4N0M1, 1 patient. No tumors smaller than 12 mm in greatest dimension were associated with distant metastasis or death. T category was significantly associated with disease-specific survival (P = 0.0009). Disease-specific survival was poorer among patients with T category of T3a or worse (P = 0.035). CONCLUSIONS: T category in the 7th edition of the AJCC TNM staging system for eyelid carcinoma correlates with outcomes in patients with sebaceous carcinoma of eyelid. On the basis of the present findings, it seems reasonable to recommend sentinel lymph node biopsy or at least strict regional lymph node surveillance for patients with eyelid sebaceous carcinoma with tumors of T category T2b or worse or 10 mm or more in greatest dimension.

Sebaceous neoplasms in Siriraj Hospital, Mahidol University: a 9-year-retrospective study.

BACKGROUND: Sebaceous neoplasms are adnexal neoplasms that contain a varying number ofsebocytes, i.e. large cells with lipid-laden vacuolated cytoplasm, soap-bubble in appearance, and crenate nuclei. They are uncommon compared to other adnexal neoplasms. Various sebaceous neoplasms with complex histopathologic features and varying degree ofsebaceous cells differentiation have been described in the literature. OBJECTIVES: To study the prevalence of sebaceous neoplasms, i.e., nevus sebaceus, sebaceous hyperplasia, sebaceous adenoma, sebaceoma, sebaceous epithelioma, superficial epithelioma with sebaceous differentiation, and sebaceous carcinoma diagnosed in the Department of Pathology, Siriraj Hospital, Mahidol University during the 9-year-period between 1997 and 2005. To study the prevalence of tumor transformation that occurs in nevus sebaceus. MATERIAL AND METHOD: A retrospective study of all sebaceous neoplasms including Nevus sebaceous, sebaceous hyperplasia, sebaceous adenoma, sebaceoma, sebaceous epithelioma, superficial epithelioma with sebaceous differentiation, sebaceous carcinoma, and all neoplasms containing the term "sebaceous" was performed. All slides were re-analyzed and re-diagnosed, without knowledge of the previous diagnosis or any clinical data, according to the criteria described in the standard textbooks of dermatopathology by Elder, McKee. Comparison between the previous diagnoses and the reviewed diagnoses was performed to assess the initial accuracy of all sebaceous neoplasms diagnosed. Small-sized biopsies or biopsies that possess incomplete sebaceous differentiation, in which the sebocytes were few and subtle, sometimes are difFicult to diagnose. In these instances, the clinical correlation was needed for positive diagnosis. Afterwards, these reviewed diagnoses were recorded and classified according to the patient's age, gender, and localization. RESULTS: Two hundred seven sebaceous neoplasms (2.34%) from the 8819 skin biopsies that were taken in the Department of Pathology, Siriraj Hospital during the 9-year-period, were included After exclusion of some authentically non-sebaceous neoplasms, 182 sebaceous neoplasms were found Nevus sebaceus (n=85, 46.7%) and sebaceous hyperplasia (n=64, 35.1%) were the two most common benign lesions. The others were sebaceoma (n=3, 1.6%), sebaceous adenoma (n=2, 1.1%), sebaceous epithelioma (n=1, 0.5%), sebaceous carcinoma (n=26, 14.3%), and one unclassified sebaceous lesion that could not be considered a neoplasm. Tumor degeneration was found in 14 nevus sebaceus in which 21 neoplasms existed, namely, trichilemmoma (wart)-like lesion (n=4), primitive follicular induction (n=7), syringocystadenoma papilliferum (n=3), trichoblastoma (n=3), and one of each of trichoepithelioma, sebaceous adenoma, tumor of follicular infundiculum, and mucoepidermoid carcinoma. CONCLUSION: Twenty-six sebaceous carcinomas out of 182 sebaceous neoplasms, occurring mostly on the patients'eyelids, were found The most common sebaceous neoplasm was nevus sebaceus (n=85); the prophylactic excision of this lesion was recommended as tumor degeneration was frequent (14 out of 85 cases). Epithelial membrane antigen (EMA) usually decorated both normal and abnormal sebocytes. It was very helpful in the detection of sebocytes in basaloid cells in sebaceous neoplasms and among lymphoid cells within metastasized lymph nodes and a discriminant between sebaceous and nonsebaceous neoplasms.

Sebaceous lesions and their associated syndromes: part I.

Sebaceous neoplasms have long been a source of confusion to dermatologists and pathologists alike. Disagreements regarding nomenclature, classification, and management have been longstanding. Sebaceous lesions represent a broad spectrum of interesting entities that range from hamartomas, hyperplasias, and benign tumors to highly malignant neoplasms. This article discusses the clinical and pathologic features of sebaceous hyperplasia, nevus sebaceous of Jadassohn, sebaceous adenoma, seboacanthoma, sebaceous epithelioma, sebaceoma, mantleoma, basal cell carcinoma with sebaceous differentiation, sebomatricoma (sebomatrixoma), and sebaceous carcinoma. Controversies regarding these lesions will be explored, and any relationship with Muir-Torre syndrome will be discussed.

Discordant architectural and cytological features in cutaneous sebaceous neoplasms--a classification dilemma: report of 5 cases.

The authors present a series of 5 cases of cutaneous sebaceous neoplasms having "benign" architectural features (symmetry, sharp circumscription, smooth borders, pseudoencapsulation) but which simultaneously displayed atypical cytology including abnormal mitoses, high mitotic rates, and moderate-to-striking pleomorphism including bizarre cells. The patients included 4 females and 1 male, ranging in age at diagnosis from 49 to 72 years. All presented with a small solitary nodule (6-9 mm) on the forehead (2), chest wall (1), occiput (1), and shoulder (1). The lesions were surgically excised. There were no recurrences on follow-up ranging from 16 to 148 months (average 77 months). In none of the patients was there a history of internal malignancy before or after diagnosis of the cutaneous neoplasms. Of 3 tumors assessed immunohistochemically for the expression of DNA mismatch repair gene proteins, only one showed loss of MLH1 expression. This was the only tumor to contain numerous tumor-infiltrating lymphocytes. Our report emphasizes the existence of rare sebaceous tumors that, despite a deceptively bland architectural appearance, discordantly exhibit a range of atypical cytological features more characteristic of either low-grade or even high-grade carcinomas. Whether such tumors should be classified as sebaceomas with atypia or sebaceous carcinomas is unclear at present. Further studies are needed to confirm their seemingly benign course as identified in this report, as are further investigations to clarify their association with Muir-Torre syndrome.

Sebaceoma and related neoplasms with sebaceous differentiation: a clinicopathologic study of 30 cases.

The classification of benign sebaceous neoplasms has been challenged both by the assertion that sebaceous adenomas are really carcinomas and by difficulties in drawing the boundaries between sebaceomas and other lesions. We performed a clinicopathologic study of 30 cases of basaloid neoplasms with sebaceous differentiation, excluding cases of definite sebaceous carcinoma with severe nuclear atypia invading deep within the subcutaneous tissue and those of ocular sebaceous carcinoma. We tried to classify sebaceous neoplasms in six categories with defined histopathologic criteria. All the neoplasms were characterized by aggregations of basaloid cells admixed with sebocytes and sebaceous duct-like structures located in the dermis with or without connection to the epidermis. The categories were 1) sebaceoma (14 cases); 2) trichoblastoma with sebaceous differentiation (3 cases); 3) apocrine poroma with sebaceous differentiation (2 cases); 4) low-grade sebaceous carcinoma (6 cases); 5) sebaceous carcinoma (4 cases); and 6) basal cell carcinoma with sebaceous differentiation (1 case). The sebaceoma was further subclassified as classic type (12 cases) or verruca/seborrheic keratosis type (2 cases). Although most sebaceomas can be distinguished from other lesions, there are problematic cases. We discuss the histopathologic diagnostic problems associated with sebaceoma and also argue in favor of the concept of sebaceous adenoma.