Endocrine mucin‐producing sweat gland carcinoma occurring on extra‐facial site: a case report

Cutaneous endocrine mucin‐producing sweat gland carcinoma (EMPSGC) is a very rare low‐grade malignant neoplasm analogous to the mammary solid‐papillary carcinoma. It frequently expresses neuroendocrine markers and may show mucinous differentiation. Although the nodules are circumscribed, myoepithelial cells cannot be showed in most cases and about half of the cases are associated with invasive mucinous carcinoma. Hence, it has been suggested to be invasive and the precursor lesion of some primary cutaneous mucinous carcinomas. After being recognized as a distinct entity, all cases reported to date occurred either in the periocular region or on the cheek. Two thirds of the patients were female. Herein we present an unusual case of in situ EMPSGC on the chest wall skin of a middle‐aged man.     

PTH‐independent hypercalcaemia and non‐melanoma skin cancer

Background Recently, it became more evident that skin is a target for neuroendocrine signals. Aims (1) To evaluate the relationship between tumour aggressiveness and hypercalcaemia in patients with non‐melanoma skin cancer; (2) to identify clinical, functional, biological alterations caused by this setting; (3) calcium redistribution from extracellular fluids to intracellular compartments; (4) to describe several molecular aspects of hypercalcaemia development. Materials and methods This study was conducted between January 2000 and May 2009 in Dermatoveneorological Center, Bucharest. From the 1232 cases that were investigated, there were 32 patients with keratoachantoma, 468 patients with basal cell carcinoma, 412 patients with squamous cell carcinoma and 320 healthy volunteers. All the patients were screened by clinical and paraclinical examinations (haematology, biochemistry, immunology). After biochemical confirmation of hypercalcaemia, patients had endocrine tests, electrocardiography and imagistic approaches. Total serum calcium was measured in extracellular fluids (serum, urine) by spectrophotometric methods. Ionized calcium was calculated depending on total serum calcium and total proteins. Corrected serum total calcium (cTCa) levels were calculated using albumin and total serum calcium levels. In tumour tissues and intact skin, calcium was assayed by physical methods of analysis: Instrumental Neutron Activation Analysis (INAA), Proton‐Induced X‐ray Emission (PIXE). Intact PTH was measured by ELISA. Results PTH‐independent hypercalcaemia prevalence is low in SCC patients (1.21%). Hypercalcaemia manifestations are multiple including: digestive, renal, neuromuscular, and cardiovascular abnormalities. In these patients, intact PTH (iPTH) is normal, urinary calcium is decreased, serum albumin is reduced, and calcium concentration in tumour tissue is significantly increased compared to healthy tissue. Conclusions PTH‐independent hypercalcaemia has a low prevalence in SCC patients. Hypercalcaemia is correlated with susceptibility to develop metastases in SCC. A possible mechanism is PTHrp hypersecretion by malignant keratinocytes.     

Bazex‐Dupré‐Christol syndrome: review of clinical and molecular aspects

Bazex‐Dupré‐Christol syndrome is a rare genodermatosis that manifests with the classical triad of basal cell carcinoma, follicular atrophoderma, and hypotrichosis; yet it may be accompanied by milia, ichthyosis, neurological symptoms, and visceral malignancies. Symptom onset is nonsimultaneous, and hence the diagnosis is often made late and the opportunity of counseling and following up is missed. This article aims toward providing a comprehensive review of the clinical perspective of Bazex‐Dupré‐Christol syndrome, highlighting the major clinical variants to facilitate reaching a prompt diagnosis. In addition, the molecular aspects are discussed. Though the gene responsible for this syndrome is yet nonspecified, it is confirmed to be localized to the long arm of chromosome X.     

Occupational exposure to non‐artificial UV‐light and non‐melanocytic skin cancer – a systematic review concerning a new occupational disease

Background: Although UV exposure is the most important risk factor for cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), a systematic review analyzing the risk of occupational UV exposure is missing. Methods: Based on a systematic literature search in PubMed (until 05/2009) supplemented by hand search, the association between occupational UV exposure and SCC and BCC was analyzed. Literature search and data abstraction was done independently by 2 reviewers. The association between occupational UV exposure and cancer risk is presented as odds ratios (OR). Results: We identified 25 relevant epidemiologic studies (5 cohort studies, 17 case‐control studies, 3 cross‐sectional studies). 12 studies described a positive association between occupational UV exposure and risk of SCC with OR > 3 in 6 studies and OR 1.5–2.0 in another 6 studies. 3 studies did not find a relevant association (OR: 1.0–1.4). A significant positive association between occupational UV exposure and BCC was reported in 5 studies; 11 studies did not find a significant association. Conclusions: The association between occupational UV exposure and SCC is well and consistently documented epidemiologically (approximately 2‐fold increased risk), so that the criteria for a new occupational disease are fulfilled. The association with BCC is unclear due to significant methodological limitations in the published studies.     

Case–control study of chronic low‐level exposure of inorganic arsenic species and non‐melanoma skin cancer

A significant relationship between arsenic exposure and non‐melanoma skin cancer (NMSC) is well known. The toxicity of arsenics which develop NMSC is dependent on their species. Accordingly, total arsenic levels are unreliable for risk assessment of NMSC. However, there are few studies on quantitative exposure assessment of arsenic species in NMSC patients. To validate the contribution of each arsenic species to NMSC, we compared the creatinine‐adjusted urinary concentration of arsenic species in NMSC patients and community controls. A total of 124 biopsy‐proven NMSC cases and 125 age‐ and sex‐matched community controls, drinking tap water with low‐level arsenic concentration (<5 μg/L), were included in the study. High‐performance liquid chromatography and inductively coupled plasma mass spectrometry were used for the measurement. The NMSC group was found to have significantly higher levels of total inorganic arsenic, trivalent and pentavalent arsenic and monomethylarsonic acid than the control group. Total arsenic, organic arsenic and dimethylarsonic acid levels were lower in the NMSC group. We suggest that inorganic arsenic species, trivalent arsenic and pentavalent arsenic may influence the prevalence of NMSC, in spite of these levels being lower than the Agency for Toxic Substances and Disease Registry‐recommended standard or the levels reported by other highly contaminated areas and neighboring countries in East Asia. Furthermore, it also suggests that total arsenic level cannot represent the risk of NMSC.     

UV‐Hauttumoren

In this review the epidemiology and pathogenetic aspects of UV‐induced malignant skin tumours (basal cell carcinoma, squamous cell carcinoma and melanoma) are discussed with regard to current literature. Whereas present knowledge, in particular, gained from experimental data, permits substantial conclusions about the development of squamous cell carcinoma, the situation for basal cell carcinoma and melanoma does not appear to be unequivocally clear. One reason for this can be explained by the fact that there exist no adequate animal models for these tumours that could exactly reflect the biological behaviour in man. Although there is no doubt about a causal role of sun exposure, this relationship is based on mere epidemiological facts.     

Primary signet‐ring cell carcinoma of the axilla

Primary cutaneous histiocytoid or signet‐ring cell carcinoma represents an extremely rare adnexal neoplasm that most frequently presents on the eyelid but more rarely may present in the axilla. As this tumor can resemble metastatic carcinoma with signet‐ring cells, especially lobular carcinoma of the breast, it can often present a diagnostic challenge. We present a case of cutaneous signet‐ring cell carcinoma presenting in the axilla and outline the challenges of diagnosing this rare malignancy.     

Intravesicular taxane‐induced dermatotoxicity in a 78‐year‐old man with urothelial carcinoma and primary cutaneous anaplastic large cell lymphoma

Patients treated with intravesical bacillus Calmette‐Guérin therapy for urothelial carcinoma often become refractory and experience recurrent disease, thus necessitating alternative intravesical treatment modalities if the patient is to be spared the morbidities associated with radical cystectomy. Intravesical treatment with taxane‐based chemotherapy, such as docetaxel, has gained traction in urologic oncology, proving to be an effective salvage therapy in such patients. Systemic taxane‐based chemotherapeutic regimens have long been used in several advanced malignancies, and their systemic side‐effects and associated histologic correlates have been extensively documented. In contrast to adverse effects associated with systemic administration, intravesical taxane administration has thus far proven to be well‐tolerated, with little to no systemic absorption. To our knowledge, features of taxane‐induced systemic effects have not been reported in this setting. Herein, we report a case of a patient with recurrent urothelial carcinoma treated with intravesical docetaxel, along with primary cutaneous anaplastic large cell lymphoma, who developed characteristic dermatotoxic histologic findings associated with intravenous taxane administration. As such histopathologic findings often represent close mimickers of neoplastic and infectious etiologies, knowledge of the potential for systemic manifestations of taxane therapy in patients treated topically may prevent potentially costly diagnostic pitfalls.     

Vergleich und Bewertung der aktuellen Staging‐Systeme des Karzinoms der Haut

Background: Recently the “Union for International Cancer Control” (UICC) and the “American Joint Committee on Cancer” (AJCC) changed their TNM (tumor, node, metastasis) classification of cutaneous carcinomas. Methods: We compared these classifications, tested their practicability with 615 prospectively collected, unselected, primary cutaneous squamous cell carcinomas, and introduced additional classification criteria. Results: Neither classification contains information about prognosis. Non‐metastasizing types of cutaneous carcinoma should be excluded. The vermilion border of the lower lip and the eyelids should be included. Both systems have been improved, but in part they are irreproducible. The AJCC has introduced six “high‐risk features” to differentiate between T1 and T2. However, this does not seem reasonable. Only rare cases are classified as T4. Both systems have different N classifications. A clinical cT classification based on tumor size 2 cm seems reasonable but not sufficient. It should be complemented by a postoperative p (pathologic) T classification based on tumor thickness: “no risk”≤ 2 mm thickness (0% risk of metastasis), “low risk” > 2 mm to 6 mm thickness (4% risk of metastasis), and “high risk” > 6 mm thickness (16% risk of metastasis). Immune suppression, poor differentiation/desmoplasia, and the ear as tumor site are additional risk factors for metastasis, currently not evaluable. Conclusions: The classifications are unsuitable for a realistic estimate of the risk of metastasis which is possible using a combination of tumor size and thickness. The N staging system should consider histopathologic findings.     

UV‐induced Skin Cancer: Similarities – Variations

Skin cancer, the most common cancer world wide, encompasses different tumor entities, the keratinocyte‐derived basal cell carcinoma (BCC), and squamous cell carcinoma (SCC) as well as the neuroectodermal malignant melanoma (MM) and the neuroendocrine Merkel cell carcinomas (MCC). While knowledge is significantly increasing about genetic changes contributing to BCCs and MMs, our understanding for the development and progression of SCCs and MCCs is still fragmentary. This review, thus, aims, on the one hand to summarize the present knowledge without claiming completeness and, on the other hand, to provide information on the HaCaT in vitro skin carcinogenesis model that is used to evaluate the functional consequence of genetic aberrations believed to play a role in skin cancer development and progression.     

Dermoscopy‐guided surgery in basal cell carcinoma

Background In basal cell carcinoma (BCC), excision margins between 3 and 10 mm, according to site, size, borders, previous treatment and histology, can allow for radical excision in at least 95% of cases. Objective The objective was to ascertain whether dermoscopy can detect more accurately the lateral borders in BCCs than clinical examination alone, and allow us to obtain radical excision in more than 95% of cases with only 2‐mm excision margins. Methods A prospective study was performed of 200 consecutive BCCs of the head and neck removed with 2‐mm dermoscopically detected excision margins. Morpheaform BCC, deeply recurrent BCC, BCC in Gorlin‐Goltz syndrome, BCC located in sites not accessible through dermoscopy and superficial multifocal BCC were excluded. All cases of excised BCC were submitted to a uniform method of histological examination of the whole specimen with serial parallel sections at 2‐mm intervals. Results In only three cases did surgical excision with 2‐mm margins prove to be inadequate; in the remaining 197 cases, the excision margins were tumour‐free. The comparison of clinical and dermoscopic extension measurement showed concordance in 131 cases (65.5%). In 69 cases (34.5%), dermoscopic evaluation showed a larger peripheral extension. Conclusions These results indicate that 2‐mm dermoscopically detected excision margins can achieve histologically confirmed complete excisions in 98.5% of cases.     

Update on the anti‐programmed cell death‐1 receptor antibodies in advanced cutaneous squamous‐cell carcinoma

Regarding the rising incidence and the not negligible mortality, the treatment of cutaneous squamous‐cell carcinoma (cSCC) has a high clinical relevance. Immune checkpoint inhibitors (ICI), especially anti‐programmed cell death‐1 receptor (anti‐PD‐1) antibodies such as pembrolizumab and cemiplimab have shown promising results in Phase 2 studies for patients with locally advanced and/or metastatic cSCC. We are presenting a review of the latest results in the treatment of cSCC with ICI. Patients with locally advanced or metastatic cSCC have been treated with cemiplimab 3 mg/kg every 2 weeks. For locally advanced cSCC, an objective response was observed in 44% of patients, 13% patients with a complete response, and 31% with a partial response. For metastatic patients, the overall response rate was 49.2%. The approved dose for cemiplimab in the United States and Europe is 350 mg every 3 weeks. These ICI seem to achieve higher response rates compared with epidermal growth factor receptor (EGFR) inhibitors, with a durable response superior to both chemotherapy and EGFR inhibitors. The side effect profile of anti‐PD‐1 antibodies appears to be favorable compared to chemotherapy. In this way, PD‐1 inhibitors are expected to become the new gold‐standard treatment for patients with locally advanced and metastatic cSCC.     

Increased mast cell expression of PAR‐2 in skin inflammatory diseases and release of IL‐8 upon PAR‐2 activation

Please cite this paper as: Increased mast cell expression of PAR‐2 in skin inflammatory diseases and release of IL‐8 upon PAR‐2 activation. Experimental Dermatology 2010; 19: 117–122. Abstract: Mast cells are increasingly present in the lesional skin of chronic skin inflammatory diseases including psoriasis and basal cell carcinoma (BCC). It has previously been shown that proteinase‐activated receptor (PAR)‐2 is expressed by mast cells, and tryptase is a potent activator of this receptor. In this study, skin biopsies from both healthy‐looking and lesional skin of patients with psoriasis and superficial spreading BCC were collected and the expression of PAR‐2 immunoreactivity in tryptase‐positive mast cells was analysed. PAR‐2 expression was confirmed in vitro in different mast cell populations. Cord‐blood derived mast cells (CBMC) were stimulated with a PAR‐2 activating peptide, 2‐furoyl‐LIGRLO‐NH₂. Consequently, IL‐8 and histamine production was analysed in the supernatants. We observed a significant increase in the percentage of mast cells expressing PAR‐2 in the lesional skin of psoriasis and BCC patients compared with the healthy‐looking skin. HMC‐1.2, LAD‐2 and CBMC mast cells all expressed PAR‐2 both intracellularly and on the cell surface. CBMC activation with the PAR‐2 activating peptide resulted in an increased secretion of IL‐8, but no histamine release was observed. Furthermore, both PAR‐2 and IL‐8 were co‐localized to the same tryptase‐positive mast cells in the lesional BCC skin. These results show that mast cells express increased levels of PAR‐2 in chronic skin inflammation. Also, mast cells can be activated by a PAR‐2 agonist to secrete IL‐8, a chemokine which can contribute to the progress of inflammation.     

First‐in‐human trial of nanoelectroablation therapy for basal cell carcinoma: proof of method

This nanoelectroablation therapy effectively treats subdermal murine allograft tumors, autochthonous basal cell carcinoma (BCC) tumors in Ptch1+/‐K14‐Cre‐ER p53 fl/fl mice, and UV‐induced melanomas in C57/BL6 HGF/SF mice. Here, we described the first human trial of this modality. We treated 10 BCCs on three subjects with 100–1000 electric pulses 100 ns in duration, 30 kV/cm in amplitude, applied at 2 pulses per second. Seven of the 10 treated lesions were completely free of basaloid cells when biopsied and two partially regressed. Two of the 7 exhibited seborrheic keratosis in the absence of basaloid cells. One of the 10 treated lesions recurred by week 10 and histologically had the appearance of a squamous cell carcinoma. No scars were visible at the healed sites of any of the successfully ablated lesions. One hundred pulses were sufficient for complete ablation of BCCs with a single, 1‐min nanoelectroablation treatment.     

Recurrent endocrine mucin‐producing sweat gland carcinoma in the eyelid

Endocrine mucin‐producing sweat gland carcinoma (EMPSGC) has recently been recognised as a low‐grade carcinoma that almost always occurs on the eyelid. This carcinoma is very rare, with only 20 cases (including the present one) having been reported in the literature. EMPSGC is frequently found in association with invasive mucinous carcinoma. While EMPSGC treatments consist of a complete surgical removal, there has been no consensus regarding the surgical margin. Therefore, reports on surgical management of EMPSGC may potentially provide important therapeutic information. Here, we present a case of a 74‐year‐old man with EMPSGC of the eyelid that repeatedly recurred despite surgical treatments at another institution. After referral to our department, the patient underwent tumour excision. However, the specimen revealed a positive surgical margin and thus, he subsequently underwent a wider excision. There has been no sign of tumour recurrence or metastasis 6 months after his last operation. This article reviews the current literature and discusses the surgical management of EMPSGC.