Sweat-gland carcinoma with neuroendocrine differentiation (SCAND): a clinicopathologic study of 13 cases with genetic analysis.

Low-grade neuroendocrine carcinoma of the skin (LGNECS) was proposed in 2017 as a new primary cutaneous neoplasm with neuroendocrine differentiation; however, it is not yet well known due to its rarity. Herein, we perform a detailed clinicopathologic analysis of 13 cases as well as panel DNA sequencing in three cases. The study included 12 males and 1 female with a median age of 71 (43-85) years. All lesions occurred on the ventral trunk. The mean tumor size was 2.2 (0.8-11.0) cm. The histopathology resembled that of well-differentiated neuroendocrine tumors (NETs) in other organs, but intraepidermal pagetoid spreading was seen in 8 (61.5%) cases and stromal mucin deposits in 4 (30.8%). Immunoreactivity for CK7, CK19, EMA, BerEP4, CEA, chromogranin A, synaptophysin, INSM1, GCDFP15, GATA3, ER, and bcl-2 were present in varying degrees in all tested cases. PTEN c.165-1G>A splice site mutation was detected by panel sequencing in one case, and GATA3 P409fs*99 and SETD2 R1708fs*4 in another case. Lymph node metastasis was seen significantly in cases with tumor size >2.0 cm [8/8 (100%) vs. 1/5 (20%)]. All three cases with size >3.0 cm were in unresectable advanced-stage [3/3 (100%) vs. 1/10 (10%)], and two of the three patients succumbed to the disease. The two cases of death revealed mild nuclear atypia (mitosis: 1/10 HPFs) and moderate nuclear atypia (2/10 HPFs). Thus, tumor size would be a better prognostic factor than nuclear atypia, mitotic count, and Ki67 index, unlike in NETs. These clinicopathologic and immunohistochemical features would represent the characteristics as skin adnexal tumors with apocrine/eccrine differentiation rather than NETs; therefore, we rename it as sweat-gland carcinoma with neuroendocrine differentiation (SCAND).

Surgical management and lymph-node biopsy of rare malignant cutaneous adnexal carcinomas: a population-based analysis of 7591 patients.

OBJECTIVE: To analyze the prognosis of cutaneous adnexal malignancies, survival relative to surgical management, and utility of lymph-node biopsy. DESIGN: Population-based study of the SEER-18 database from 1975 to 2016. PARTICIPANTS: 7591 patients with sweat gland carcinoma, hidradenocarcinoma, spiradenocarcinoma, sclerosing sweat duct tumor/microcystic adnexal tumor (SSDT/MAC), porocarcinoma, eccrine adenocarcinoma, and sebaceous carcinoma RESULTS: Five-year OS ranged from 68.0 to 82.6%, while 5-year DSS ranged from 94.6 to 99.0%. The majority of patients were treated with narrow (42.4%) or wide local excision (16.9%). DSS at 5 years showed that patients with stage IV had significantly poorer survival (50.3%) than I, II, or III (99.3%, 97.8%, and 89.0% respectively). 5-year OS was significantly higher for narrow excision (excision with < 1 cm margin, 78.5%) than observation (65.0%), excisional biopsy (66.8%), or wide local excision (WLE, 73.2%). Lymph-node biopsy was performed in a minority of cases (8.1%) and patients showed no significant difference in survival based on nodal status. The sensitivity and specificity of lymph-node biopsy for all malignancies were 46% and 80%, respectively. The PPV and NPV for that group were 0.46 and 0.80, respectively. Invasion of deep extradermal structures was a poor predictor of nodal positivity. CONCLUSIONS: These malignancies have excellent DSS. Narrow excisions demonstrate better 5-year DSS and OS compared with WLE. Lymph-node biopsy is a poor predictor of survival in advanced stage disease and utility is limited.

Prognostic factors and survival outcomes for head and neck cutaneous adnexal cancers.

OBJECTIVES: Malignant cutaneous adnexal tumors (MCAT) are rare and comprise a heterogeneous group of cancers. There have been several studies reviewing prognostic factors of these tumors, but no studies focusing on the head and neck. This study aimed to review a large population based database to evaluate prognostic factors that could impact survival. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was utilized to identify patients with MCAT of the head and neck. Both overall and disease specific survival were the main outcome measures for the study. Univariate and multivariate analyses were performed to evaluate the association of suspected prognostic factors with survival. RESULTS: The five-year OS and DSS were 72.6 and 95.5%, respectively. A favorable factor for OS was surgical resection ([HR] 0.324; P = 0.001), while unfavorable factors for OS include older age (1.051; P < 0.001), higher tumor grade (1.254; P = 0.049), larger tumor size (1.293; P = 0.003), and positive nodal involvement (3.323; P = 0.002). A favorable factor for DSS was surgical resection (0.026; P < 0.001). Unfavorable factors for DSS include older age (1.058; P = 0.046), larger tumor size (2.528; 1.565-4.085; P < 0.001), and positive nodal involvement (4.761; P = 0.022). CONCLUSION: Review of the SEER database shows good 5-year OS and DSS rates, similar to those cited in other studies. We identified several prognostic factors associated with survival, while histologic sub-type does not seem to be associated with survival. Surgical resection is the mainstay of treatment.

Loss of periostin/OSF-2 in ErbB2/Neu-driven tumors results in androgen receptor-positive molecular apocrine-like tumors with reduced Notch1 activity.

INTRODUCTION: Periostin (Postn) is a secreted cell adhesion protein that activates signaling pathways to promote cancer cell survival, angiogenesis, invasion, and metastasis. Interestingly, Postn is frequently overexpressed in numerous human cancers, including breast, lung, colon, pancreatic, and ovarian cancer. METHODS: Using transgenic mice expressing the Neu oncogene in the mammary epithelium crossed into Postn-deficient animals, we have assessed the effect of Postn gene deletion on Neu-driven mammary tumorigenesis. RESULTS: Although Postn is exclusively expressed in the stromal fibroblasts of the mammary gland, Postn deletion does not affect mammary gland outgrowth during development or pregnancy. Furthermore, we find that loss of Postn in the mammary epithelium does not alter breast tumor initiation or growth in mouse mammary tumor virus (MMTV)-Neu expressing mice but results in an apocrine-like tumor phenotype. Surprisingly, we find that tumors derived from Postn-null animals express low levels of Notch protein and Hey1 mRNA but increased expression of androgen receptor (AR) and AR target genes. We show that tumor cells derived from wild-type animals do not proliferate when transplanted in a Postn-null environment but that this growth defect is rescued by the overexpression of active Notch or the AR target gene prolactin-induced protein (PIP/GCDFP-15). CONCLUSIONS: Together our data suggest that loss of Postn in an ErbB2/Neu/HER2 overexpression model results in apocrine-like tumors that activate an AR-dependent pathway. This may have important implications for the treatment of breast cancers involving the therapeutic targeting of periostin or Notch signaling.

[Primary eccrine porocarcinoma: a clinicopathological study of 50 cases]. / Étude clinique et histopronostique de 50 cas de porocarcinome eccrine.

BACKGROUND: Eccrine porocarcinoma is a rare cutaneous tumor arising from the intra-epidermal portion of eccrine sweat glands, the acrosyringium. Histoprognostic studies in large series are rare. Herein, we report a retrospective study of 50 cases. PATIENTS AND METHODS: Fifty cases of porocarcinoma were retrieved from a histopathological register. Each histopathological sample was evaluated for the following criteria: presence or absence of dermal invasion, pattern of the infiltrative component (pushing or infiltrative), tumor thickness, lymphovascular emboli, perineural invasion and mitotic index. Clinical data and outcome were also retrieved for each patient. RESULTS: Mean patient age was 77 years (range: 43-99 years). The mean duration of progression prior to diagnosis was 4 years and 5 months. The 2 most common skin locations were the head (38%) and lower limbs (20%). The lesions showed no specific distinctive clinical features. Six cases were in situ, and 44 were invasive (23 with limited infiltration and 20 with scattered infiltration). Mean tumor thickness was 4.37 mm (range: 0.5 to 20 mm). Neighboring or remote epidermal involvement was noted in 7 cases. Lymphovascular emboli were observed in 3 cases. No cases of neurotropism were observed. The average mitotic index was 6.5 mitoses/high power (×400) field. A mean follow-up of 24.3 months was available for 48 patients. Local recurrence was noted in 5 patients, 4 of whom died from visceral metastases. These 5 cases showed no distinctive clinical features, a scattered pattern of the invasive component, cuticular cells, significant tumor thickness (mean 12.8 mm, range 9-20 mm), and an elevated mitotic index. Two histopathological criteria were significantly associated with a metastatic outcome: scattered pattern of the dermal invasive component (P=0.04) and significant tumor thickness, above 10mm (P<0.01). CONCLUSION: Porocarcinoma is a tumor without any particular clinical criteria to distinguish it from squamous cell carcinoma. The architecture of the invasive component and tumor thickness constitute 2 important histoprognostic criteria.

Survival after resection of cutaneous adnexal carcinomas with eccrine differentiation: risk factors and trends in outcomes.

BACKGROUND: Current staging systems do not specifically address cutaneous adnexal carcinomas with eccrine differentiation. Due to their rarity, prognosis and management strategies are not well established. A population-based study was performed to determine prognostic factors and survival. METHODS: Patients diagnosed with cutaneous adnexal carcinomas with eccrine differentiation were identified using the surveillance, epidemiology, and end results population-based cancer registry. Associations between risk factors, treatment modalities, and survival were calculated using logistical regression, Kaplan-Meier estimates and log-rank analysis. RESULTS: The incidence of distinct eccrine subtypes was determined within 1,045 patients with cutaneous adnexal tumors containing eccrine differentiation. All-cause 5-year survival (OS) was 82%, while age-adjusted survival was 94%. Patients with microcystic adnexal carcinoma had improved OS (90%) compared to patients with hidradenocarcinoma (74%), spiradenocarcinoma (77%), porocarcinoma (79%), and eccrine adenocarcinoma (81%). The majority of patients were treated with surgical excision and a small subset with surgery plus radiation, with similar OS. Patients with well-to-moderately differentiated tumors demonstrated improved OS compared to those with poorly differentiated/anaplastic disease. CONCLUSIONS: Histological subtype and grade were associated with survival, and should be specified in biopsies and excised specimens. Surgical excision is appropriate, and the addition of adjuvant radiation may not be associated with survival. These results highlight survival data and high-risk prognostic factors that warrant prospective validation, and may augment current staging systems.

Cutaneous digital papillary adenocarcinoma: a clinicopathologic study of 31 cases of a rare neoplasm with new observations.

Aggressive digital papillary adenocarcinoma is a rare tumor predominantly involving the distal end of digits. We examined 31 cases of this distinctive tumor for clinicopathologic, immunohistochemical, and follow-up data where available. Males were predominantly affected (n=29), with a mean age of 43 years (range, 14 to 67 y). Three lesions were reported in patients below the age of 20 years. All cases involved a finger (n=26) or a toe (n=5), with most involving the distal portion of the digit (n=29). Two lesions involved the base of the digit/webspace. Histopathologically, all tumors involved the dermis with subcutaneous extension in 14 cases. The lesions demonstrated a multinodular solid and/or cystic pattern, with focally infiltrative architecture in 21 cases. Papillary projections were: prominent (n=10), focal (n=15), or not identified (n=6). Within the solid component, tubular structures were present at least focally in all cases. Cytologic atypia ranged from mild (n=8) to moderate (n=20), but was focally severe in 3 cases. Mitotic count ranged from <1 to 18 per mm. Focal necrosis was seen in 6 cases. Immunohistochemically stained sections were available for review in 8 cases. Tumor cells were diffusely positive for MNF116 (3 of 3). Carcinoembryonic antigen and epithelial membrane antigen highlighted the luminal border of tubules (8 of 8). Smooth muscle actin (5 of 6) and calponin (6 of 6) highlighted a myoepithelial layer around tubular/glandular structures, as did p63 (2 of 2) and podoplanin (5 of 5). Follow-up after excision or amputation (n=23; range, 2 mo- to 21 y) revealed local recurrence (n=5) and metastatic disease (n=6; lymph node in 1, lungs in 4, and both lymph node and lung in 1). Metastases were noted at presentation in 2 cases (lymph node in 1 and lung in 1), but presented as late as 14 and 20 years in lymph node and lung, respectively. Only 1 patient died of metastatic disease 6 years after initial diagnosis, after multiple recurrences and lung metastases. Three patients were alive with progressive disease up to 24 months after developing lung metastases. Histopathologic features were not found to be predictive of outcome. The presence of tumor-associated myoepithelial cells histologically and immunohistochemically was not synonymous with benignity. Wide excision and partial digit amputation significantly reduced recurrence and metastatic rates. Delayed occurrence of metastases and a protracted course despite metastatic disease, necessitates long-term follow-up. As the name implies a malignant neoplasm, the rubric "aggressive" is unnecessary.

Cutaneous apocrine adenocarcinoma: defining epidemiology, outcomes, and optimal therapy for a rare neoplasm.

BACKGROUND AND OBJECTIVES: Apocrine adenocarcinoma is a rare neoplasm. There is a paucity of data on demographics and survival with no clear consensus on management of at risk lymph nodes, therefore, we analyzed a large cohort of patients identified via a national tumor registry. METHODS: Patients ages 17-91 from 1973 to 2006 were identified in the SEER registry and excluded breast and non-cutaneous neoplasms. Data analyzed included basic demographics, survival, surgical therapy, and stage. RESULTS: A total of 186 patients with apocrine adenocarcinoma were identified. The median age was 67 years, 76% were white and there was an equal distribution of males and females. The most common site was trunk (53%) followed by head and neck (35%). Surgery was performed on most patients (96%), either excision (50%) or wide excision (30%). Lymph node metastases were present in 69% patients undergoing node surgery. Median overall survival was 51.5 months. Positive lymph node status (P = 0.006) and metastatic disease (P < 0.001) were associated with diminished overall survival. CONCLUSIONS: Cutaneous apocrine adenocarcinoma is a rare neoplasm. Excision is standard treatment. The most important predictor of survival in localized disease is lymph node status; therefore, sentinel lymph node biopsy could be considered in management of this disease.

Rare tumors through the looking glass: an examination of malignant cutaneous adnexal tumors.

OBJECTIVE: To identify prognostic factors related to malignant cutaneous adnexal tumors. DESIGN: Population-based study using the Surveillance, Epidemiology, and End Results database from January 1, 1988, through December 31, 2006. SETTING: Seventeen population-based cancer registries. PARTICIPANTS: A total of 4032 patients with malignant cutaneous adnexal tumors. MAIN OUTCOME MEASURES: Overall survival (OS) and disease-specific survival (DSS). RESULTS: Ten-year OS and DSS rates were 54% and 97%, respectively. Unfavorable factors for OS were increasing age (hazard ratio [HR] 1.08; 95% confidence interval [CI], 1.07-1.09; P < .001), distant metastases (3.26; 2.34-4.53; P < .001), no surgical procedure (1.27; 1.01-1.59; P = .04), grade IV tumors (1.97; 1.18-3.28; P = .009), nodal metastases (2.19; 1.40-3.43; P = .001), and T3 tumors (1.37; 1.00-1.87; P = .04). Favorable factors for OS were a wide surgical excision (HR, 0.78; 95% CI, 0.68-0.89; P < .001), female sex (0.73; 0.65-0.82; P < .001), malignant eccrine spiradenoma (0.72; 0.53-0.99; P = .04), and histologic findings of sweat duct carcinoma (0.63; 0.44-0.90; P = .01). Unfavorable factors for DSS included N1 status (HR, 6.77; 95% CI, 2.11-21.68; P < .001), distant metastases (12.24; 6.03-24.85; P < .001), histologic findings of malignant eccrine spiradenoma (5.62; 1.25-25.34; P = .02), and no surgical procedure (2.81; 1.09-7.23; P = .03). Favorable factors for DSS included female sex (HR, 0.52; 95% CI, 0.30-0.91; P = .02). CONCLUSIONS: Five-year survival among patients with malignant cutaneous adnexal tumors is good in the absence of distant metastases. Wide resection may be preferable to less aggressive excision. The prognostic importance of lymph node metastases warrants consideration of lymph node basin staging.

Deaths from non-melanoma skin cancer in Western Australia.

OBJECTIVES: Non-melanoma skin cancer (NMSC) is common, slow growing, and rarely metastasizes. However, there are still nearly 400 deaths from NMSC in Australia annually. We aimed to investigate the accuracy of NMSC death coding and to describe the characteristics of these deaths and the potential for prevention. METHODS: Histology reports for all deaths coded as NMSC (ICD-10 C44.0-C44.9) by the Western Australian Cancer Registry for the years 1996-2005 were reviewed for type of cancer, body site (primary tumor and metastases), and level of available documentation. RESULTS: Of 368 deaths recorded as being due to NMSC only 3 were found to be miscoded. An additional 53 deaths contained inadequate information to confirm NMSC as the cause of death. Of the confirmed cases, 219 were due to squamous cell carcinoma, 53 to Merkel cell carcinomas, and 40 to other skin cancers. Cases were mainly males and were elderly. Most of the primary squamous and Merkel cell carcinomas were in areas of maximum sun exposure (face, ears, and hands, and scalp in males). CONCLUSIONS: Misclassification of NMSC deaths in WA was minimal. The majority of NMSC deaths were due to squamous cell carcinomas; had primary sites associated with significant sun exposure; and occurred in older men.

Primary cutaneous apocrine carcinoma: a clinico-pathologic analysis of 24 cases.

Primary cutaneous apocrine carcinoma is a rare malignancy. This study of 24 examples suggests that the prognosis is not always poor and that grading criteria devised for breast carcinoma may have utility in this group of malignancies. Furthermore, steroid receptor expression should be investigated in these tumors, particularly if a tumor is unlikely to be controlled by surgery alone.

Sweat-gland tumours: a clinical review of cases in one centre over 20 years.

AIMS: Sweat-gland tumours (SGTs) are uncommon, but malignant varieties are very rare. We have added our data on 30 new cases seen at the Royal Marsden NHS Foundation Trust to the published literature, particularly concentrating on clinical issues. We include a literature review. MATERIALS AND METHODS: The Royal Marsden NHS Foundation Trust database was searched for cases of SGT from 1972. Data were collected on all cases, including patient demographics and tumour characteristics, treatment and outcome. RESULTS: Thirty cases were confirmed histologically to be SGTs. Fourteen were malignant, 15 benign and the degree of malignancy in one was histologically indistinguishable. Mean age was 55 years (64 for malignant, 47 for benign tumours). The 15 patients with benign tumours were almost all treated with complete excision. Those with local relapse underwent successful re-excision. Their 5-year disease-free survival was 78% and cause-specific survival was 100%. Twelve of the 14 malignant tumours had localised disease at diagnosis, one had nodal disease and one had metastatic tumour nodules. All except one were treated with wide local excision. The patient with nodal involvement also had a lymph-node dissection. Two received adjuvant radiotherapy to the tumour bed. One received a melphalan limb perfusion. Eight of the 14 had no relapse. Six had locoregional relapse, and four of these also developed distant metastases. Visceral disease was always fatal. Radiotherapy and chemotherapy at relapse were unsuccessful. Five-year disease-free survival was 45%, and cause-specific survival was 57%. CONCLUSION: These rare tumours should be treated initially with complete wide local excision. In malignant tumours, lymph-node involvement is a poor prognostic sign. Wide local excision remains the primary treatment. Adjuvant radiotherapy may be useful in high-risk cases.

A retrospective study of 44 canine apocrine sweat gland adenocarcinomas.

Apocrine sweat gland adenocarcinomas (AACs) are relatively uncommon skin tumors in dogs. Little prognostic or behavioral information has been published for these tumors. In this retrospective study, 44 AACs from diagnostic archives were reexamined and clinical postexcisional follow-ups for 25 of the 44 cases were obtained by a survey. There were 28 out of 44 (65.9%) AACs that invaded the capsule, stroma, or both, 5 of 44 (11.4%) invaded blood vessels and stroma, and 1 out of 25 (4%) had distant metastases. The presence or absence of stromal and vascular invasion was predicted by clinical examination with more than 80% accuracy. Postexcisional median survival of dogs with AACs was 30 mo at the time of survey. Determination of a correlation between histological features and malignant behavior of AACs was compromised by the low number of cases with clinical AAC-related problems; however, it appears that intravascular invasion is an important indicator of potential systemic metastases.

Sweat gland carcinoma: a clinicopathologic analysis of an expanded series in a single institution.

Primary adenocarcinoma of sweat glands is a rare tumor; approximately 220 cases have been reported in the last 30 years. We reviewed the charts of patients with primary diagnosis of this tumor treated at the Mayo Clinic between 1935 and 1995. We included only cases with initial histology slides available for re-examination. Tumors were classified into five recognizable histologic patterns (solid, ductal, mucinous, microcystic adnexal, and adenocystic carcinoma) and graded by the Broder system. Statistical analysis consisted of Kaplan-Meier product limit method and Cox multiple regression test. In total, 55 patients were identified, and age ranged from 13 to 85 years (mean 59 years). Thirty-six patients (65 percent) presented to the Mayo Clinic for initial treatment; all except one had disease limited to the primary site. Microcystic adnexal carcinoma was the most frequent type, and more than 50 percent were grade 2 tumors. Among these 36 patients, 4 had some type of recurrence. Patients who developed metastasis had a high-grade tumor in the initial biopsy. Nineteen patients were referred with recurrence; 13 had local recurrence, 4 had regional diseases, and 2 had distant metastases. The histologic distribution showed 47 percent solid tumors, and 37 percent of them were grade 3. Multiple regression analysis did not show a difference in recurrence or survival when gender, age, tumor location, or histologic pattern was evaluated. In addition, there was no difference in the outcome between wide surgical resection and micrographic surgery. The only predictive factor for distant metastases and/or death (p < 0.003) was histologic grade. Overall 10-year survival rate was 86 and 60 percent for primary and referred patients, respectively. We conclude that histologic diagnosis of sweat gland carcinoma must be complemented by clinical examination to evaluate metastases. Clinical behavior depends on the histologic type of tumor, degree of differentiation, and clinical stage. On recurrence, the likelihood of further recurrences and mortality increases dramatically. Aggressive initial local ablation with tumor-free margins is recommended. In high-grade tumors, prophylactic regional lymph node dissection may further characterize tumor aggressiveness and may justify adjuvant radiotherapy as part of the primary treatment.

Human papillomavirus DNA in adenosquamous carcinoma and squamous cell carcinoma of the vulva.

The tissues from 16 cases of adenosquamous carcinoma (pseudoglandular squamous cell carcinoma or adenoacanthoma of the sweat glands of Lever) and 26 cases of invasive squamous cell carcinoma of the vulva were studied for the presence of human papillomavirus (HPV) genomes using Southern blot hybridization on fresh tissues. Types 1, 2, 3, 4, 5, 6, 16, and 18 HPV DNA probes and in situ hybridization were used on formalin-fixed paraffin sections using type 2, 6, 16, and 18 HPV DNA probes. Only one case of adenosquamous carcinoma contained an undetermined type of HPV DNA, whereas five cases of squamous cell carcinoma contained HPV DNA. Three of these five cases contained type 16, one type 6 HPV, and two an undetermined type. These results demonstrate HPV DNA associations with malignancy of the vulva that are similar to those observed elsewhere in the genital tract.