Search

Objective To prepare a dermatologic addendum to the 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides (CHCC2012) to address vasculitides affecting the skin (D-CHCC). The goal was to standardize the names and definitions for cutaneous vasculitis. Methods A nominal group technique with a facilitator was used to reach consensus on the D-CHCC nomenclature, using multiple face-to-face meetings, e-mail discussions, and teleconferences. Results Standardized names, definitions, and descriptions were adopted for cutaneous components of systemic vasculitides (e.g., cutaneous IgA vasculitis as a component of systemic IgA vasculitis), skin-limited variants of systemic vasculitides (e.g., skin-limited IgA vasculitis, drug-induced skin-limited antineutrophil cytoplasmic antibody–associated vasculitis), and cutaneous single-organ vasculitides that have no systemic counterparts (e.g., nodular vasculitis). Cutaneous vasculitides that were not included in the CHCC2012 nomenclature were introduced. Conclusion Standardized names and definitions are a prerequisite for developing validated classification and diagnostic criteria for cutaneous vasculitis. Accurate identification of specifically defined variants of systemic and skin-limited vasculitides requires knowledgeable integration of data from clinical, laboratory, and pathologic studies. This proposed nomenclature of vasculitides affecting the skin, the D-CHCC, provides a standard framework both for clinicians and for investigators.

Herein, we report the case of a 12-year-old female who noted the recent onset of an oval, circumscribed, 10-cm papillomatous plaque affecting the thigh and vulva that showed histologic signs of lymphedema without evidence of secondary lymphedema. The sequencing of genes associated with a delayed onset of lymphedema or epidermal nevi (EN) - GATA2 and GJC2, and HRAS and KRAS, respectively - showed wild-type alleles. Polymerase chain reaction for human papillomavirus (HPV) DNA demonstrated infections with 15 HPV genotypes. Evidence of productive HPV infection, HPV capsid expression, and cytopathic changes was detected. At the 6-month follow-up, no evidence of recurrence was found after complete excision. The analysis of a consecutive series of 91 EN excision specimens revealed that 76% exhibited histologic evidence of lymphostasis. Notably, multiple acrochordon-like EN, which most closely resembled this case, showed similar signs of localized lymphedema. The late onset and evidence of lymphedema favors the diagnosis of congenital unisegmental lymphedema. However, the clinical findings and epidermal changes point to the diagnosis of EN. Moreover, localized verrucosis also accurately describes this patient's cutaneous findings. Based on the above evidence, we postulate that an abnormal development of lymphatics may play a primary role in the pathogenesis of some types of EN and facilitate productive HPV infection. © 2014 S. Karger AG, Basel

Hybrid carcinoma of salivary glands is a very rare subtype of malignant salivary gland neoplasm with a little more than 30 cases documented in the literature [1–20] (See Table 1). Most cases of hybrid carcinoma of salivary glands have been reported in the parotid gland and palate. To date, only a single case of salivary hybrid carcinoma has been observed in the maxillary sinus [14]. Although dedifferentiation/high grade transformation has been described in a variety of malignant salivary gland tumors, this phenomenon has not been reported in salivary hybrid carcinoma [21, 22]. Furthermore, while pagetoid spread of neoplastic cells from a malignant salivary gland tumor to the overlying lining mucosa has been documented in the oral mucosa [21–23], such an incidence has not been reported in the maxillary sinus. Herein, we describe an additional case of hybrid carcinoma of salivary glands in the maxillary sinus that demonstrated simultaneous occurrence of high-grade transformation and intraepithelial pagetoid spread to the overlying sinus mucosa. This rarely reported phenomenon is not only of academic interest but can also pose significant diagnostic difficulties, particularly in distinguishing from a HPV-related carcinoma with adenoid cystic-like features. Table 1 Reports of hybrid salivary gland carcinomas Case Report A 68-year-old male patient was admitted to our hospital with the clinical presentation of a mass in the left maxillary sinus. A previous biopsy performed at an outside institute was diagnosed as squamous cell carcinoma involving a polyp originating in the left maxillary sinus. His clinical history was otherwise significant for hypertension, diabetes mellitus, and coronary artery disease. In May 2013, the patient underwent partial maxillectomy including complete removal all mucosa from the left maxillary sinus as well as the anterior skull base. Secondary to positive surgical margins, a complete maxillectomy and partial resection of the hard palate with left osteocutaneous radial forearm flap was performed in July 2013, followed by radiation therapy. In May 2014, the patient developed lymphadenopathy of the left neck consistent with nodal metastasis. A left neck dissection were performed in June 2014 revealing two positive level II lymph nodes. The partial maxillectomy was composed of a 4.5 × 4 × 1.1 cm aggregate of multiple fragmented pieces of erythematous, pink-grey soft tissue resembling mucosa, partially covering cartilage and bone. The microscopic sections exhibited a peculiar interplay of morphologies: the majority of the tumor displayed typical morphologic features of an adenoid cystic carcinoma characterized by a dual population of relatively low-grade, monotonous basaloid myoepithelial and eosinophilic cuboidal ductal cells arranged in cribiform, solid, and tubular architectures. Basophilic mucoid and collagenous eosinophilic material was observed in the pseudocytsic spaces of the cribiform tumor nests (See Fig. 1a). The adenoid cystic carcinoma comprised approximately 50 % of the total mass. In addition, 20 % of the tumor exhibited distinct areas of solid nests and tubules of polygonal myoepithelial cells with clear cytoplasm in the periphery and central cuboidal eosinophilic ductal cells consistent with an epithelial–myoepithelial carcinoma (See Fig. 1b). The third component of the tumor was composed of high-grade polygonal eosinophilic neoplastic cells that displayed pleomorphic, vesicular nuclei and scattered prominent nucleoli. The high-grade neoplastic cells were arranged either as distinct solid nests (See Fig. 1c) or intimately intermingled with the basaloid cells within the nests of the adenoid cystic carcinoma. Notably, this high-grade component focally filled and expanded superficial ducts that opened directly to the overlying lining mucosa (See Fig. 1d). The surface epithelium was also infiltrated by the high-grade neoplastic cells in a pagetoid spread pattern (See Fig. 1e). The high-grade neoplastic cells were predominantly identified in the upper levels of the surface epithelium, sparing the basal layer of the lining mucosa. Fig. 1 a–f Salivary hybrid carcinoma composed of adenoid-cystic carcinoma (a) and epithelial-myoepithelial carcinoma (b) with foci of high-grade transformation (c). High-grade transformed neoplastic cells expand a secretory duct opening to the surface ... Immunohistochemical studies with a panel of antibodies demonstrated a diverse immunohistochemical-staining pattern between the different neoplastic components as illustrated in Table 2, which supported the spectrum of histologic differentiation in this tumor. Notably, most of the solid nests of high-grade neoplastic cells were surrounded by an intact layer of p63 positive myoepithelial layer (See Fig. 2a),indicative of their predominantly intraductal/in situ growth. In addition, there were significant differences in the expression of Ki-67, p53, and Her2-neu in the high-grade neoplastic cells compared to the low grade components of adenoid cystic carcinoma and epithelial-myoepithelial carcinoma (See Fig. 2b–f). Overall, the histologic and immunohistochemical findings were consistent with those of a salivary hybrid carcinoma composed of adenoid cystic and epithelial-myoepithelial carcinoma, associated with high-grade transformation and pagetoid spread in the lining epithelium. Table 2 Tumor immunophenotypes Fig. 2 a–f Immunohistochemical studies display a layer of p53 positive myoepithelial cells at the periphery of the nests of transformed neoplastic cells (a). There is a significantly higher expression of Ki-67 (b) and p53 in the high grade component ... The re-excision showed predominantly residual adenoid cystic carcinoma and scattered foci of invasive high-grade adenocarcinoma. Interestingly, whereas the adenoid cystic component was mostly confined within the stroma of the respiratory mucosa, the high-grade adenocarcinoma primarily invaded the underlying bone (See Fig. 1f), indicative of the aggressive nature of this component. The lining mucosa still demonstrated focal involvement by high-grade carcinoma in a pagetoid spread pattern. A residual component of epithelial-myoepithelial carcinoma was not identified. The left neck dissection performed 1 year later demonstrated two positive lymph nodes harboring high grade adenoid cystic carcinoma. To evaluate the possibility of high-risk HPV infection, in situ hybridization was performed utilizing primers that can detect high risk HPV genotypes (i.e. 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 66) (methods previously described by Carlson et al. [24]). By in situ hybridization, no high-risk HPV DNAs were detected in any components of the tumor.

In addition to introducing fundamental concepts pertinent to the relationship of morphology to clinical behavior of malignant melanoma, Dr Mihm also pioneered the field of translationally relevant biomarkers. One recently described biomarker, melastatin, (TRPM1) was first identified through differential cDNA display of F1 and F10 murine melanoma cell lines that differed in metastatic capacity. This gene was selected for investigation because it was absent from highly metastatic melanoma cell lines, implying a tumor-suppressor gene function.1 TRPM1, a.k.a. transient receptor potential cation channel, subfamily M, member 1 (TRPM-1), is a melanocyte-specific gene localized to human chromosome 15.2,3 TRPM1 is the founding member of one of 7 families of TRP ion channels, which comprise more than 50 cation-permeable channels that are grouped according to structural homology: TRPM (melastatin), TRPC (canonical), TRPV (vanilloid), TRPP (polycystin), TRPML (mucolipin), TRPA (ankyrin) and TRPN (NO mechanopotential).4 TRPM channels exhibit highly variable permeability to Ca2+ and Mg2+, ranging from impermeable to Ca2+ to highly permeable to both Ca2+ and Mg2+; various gating mechanisms such as hydrogen peroxide and heat; and assorted activating mechanisms such as cooling, cooling agents and cell swelling.4 To date, the functional characteristics of TRPM1 have not been reported; however, it is suspected that TRPM1 plays a role in controlling intracellular Ca2+ concentration,5 by which loss of TRPM1 expression alters bipolar cell signaling and melanocyte function.6 Furthermore, TRPM1 is one of several TRP related to cancer (others include TRPV5, TRPV6 and TRPM8), in which altered expression of Ca2+-entry channels is suspected to play a role in tumor cell proliferation and differentiation.4 Indeed, utilizing radioactive in situ hybridization (RISH) methods, TRPM1 mRNA was expressed in normal melanocytes and nevomelanocytes, whereas some primary melanomas and all melanoma metastases showed some loss of TRPM1 mRNA.1,7,8 Fang et al.9 confirmed TRPM1’s role in differentiation by demonstrating that the differentiation inducer hexamethylene bisacetamide (HMBA) upregulates TRPM1 gene expression in pigmented melanoma cell lines. The expression of TRPM1 itself is tightly controlled by the essential melanocyte transcription factor MITF (microphthalmia-associated transcription factor).10,11 King, Mihm and colleagues12,13 demonstrated that the antibody to MITF protein is a sensitive and relatively specific marker of melanocytes and melanoma. MITF is a member of the basic helix-loop-helix leucine-zipper transcription family and has been shown to be a critical regulator of melanocyte development and survival.14 Indeed, MITF has been termed a master regulator of melanocyte development and a melanoma oncogene,15 as it governs melanoblast survival and melanocyte lineage commitment;15 modulates melanocyte differentiation gene and cell-cycle gene expression;11 is amplified in a fraction of melanomas;16 and is expressed by most melanomas.12,13 In vitro experiments have demonstrated that MITF plays both pro-and anti-tumor roles in melanoma depending on the expression level and cellular context. For example, its expression is essential for melanoma cell proliferation and survival.15 However, it can also inhibit proliferation and cellular viability as well as stimulate differentiation,17 as MITF is expressed at lower levels in melanoma than in melanocytes, where increased levels of MITF reduce melanoma proliferation even in the presence of oncogenic BRAF,18 and high levels of MITF reduce melanoma tumorigenicity. Thus, high levels of MITF predispose to cell-cycle arrest and differentiation; critically low levels lead to cell-cycle arrest and apoptosis; and only at intermediate levels is melanoma proliferation favored.17 The finding that increasing loss of TRPM1 correlates with melanoma progression and aggressive disease supports this molecular pathway of melanoma7,8,20 and points to a tightly coupled relationship between MITF and TRPM1. In addition to TRPM1, MITF regulates the transcription of multiple gene products involved in melanogenesis, including tyrosinase, tyrosinase-related protein-1 (TRP1) (Mel5; gene – TRP1), TRP2 (dopachrome tautomerase; DCT), HMB45 (gp100, PMEL17; SILV), Mart1 (melanoma antigen recognized by T cells) (Melan A; MLANA) and melanocortin 1 receptor (MC1R), whose ligand is α-melanocyte stimulating hormone (αMSH).11,21 The specific pattern of expression of some of these markers of melanogenesis or melanocyte proteins (melanogenesis-related proteins) correlates with the specific stage of melanocyte development.22 For example, adult melanocyte stem cells express TRP2 and MITF, whereas acquisition of tyrosinase and TRP1 expression is a sign of a terminally differentiated melanocyte. In addition, a gradient of decreasing or loss of expression of specific melanin-related proteins has been described for MITF12 and Mart123 as well as for TRPM1 by RISH7 in melanocytic nevi showing zonal maturation. Here, utilizing CISH methods,20 we sought to evaluate the extent of TRPM1 mRNA expression in melanocytes found in normal epidermis and regenerating epidermis-overlying scars. To determine whether TRPM1 mRNA correlates with a specific stage of melanocyte differentiation, its expression was compared to the immunohistochemical detection of melanogenesis-related proteins in matched skin samples. In addition, the expression of TRPM1 was examined in hair follicles and ordinary compound melanocytic nevi and compared to MITF expression.

The emergence of highly aggressive subtypes of human cutaneous squamous cell carcinoma (SCC) often reflects increased autocrine/paracrine TGF-βsynthesis and epidermal growth factor receptor (EGFR) amplification. Cooperative TGF-β/EGFR signaling promotes cell migration and induces expression of both proteases and protease inhibitors that regulate stromal remodeling resulting in the acquisition of an invasive phenotype. In one physiologically relevant model of human cutaneous SCC progression, TGF-β1+EGF stimulation increases the production of several matrix metalloproteinases (MMPs), among the most prominent of which is MMP-10—an MMP known to be elevated in SCC in situ. Activation of stromal plasminogen appears to be critical in triggering downstream MMP activity. Paradoxically, PAI-1, the major physiological inhibitor of plasmin generation, is also upregulated under these conditions and is an early event in progression of incipient epidermal SCC. One testable hypothesis proposes that TGF-β1+EGF-dependent MMP-10 elevation directs focalized matrix remodeling events that promote epithelial cell plasticity and tissue invasion. Increased PAI-1 expression serves to temporally and spatially modulate plasmin-initiated pericellular proteolysis, further facilitating epithelial invasive potential. Defining the complex signaling and transcriptional mechanisms that maintain this delicate balance is critical to developing targeted therapeutics for the treatment of human cutaneous malignancies.

The emergence of highly aggressive subtypes of human cutaneous squamous cell carcinoma (SCC) often reflects increased autocrine/paracrine TGF-βsynthesis and epidermal growth factor receptor (EGFR) amplification. Cooperative TGF-β/EGFR signaling promotes cell migration and induces expression of both proteases and protease inhibitors that regulate stromal remodeling resulting in acquisition of an invasive phenotype. TGF-β1+EGF stimulation increases the production of several matrix metalloproteinases (MMPs) in human SCC. Among the most prominent is MMP-10 which is known to be elevated in SCC in situ. Activation of stromal plasminogen appears to be critical in triggering downstream MMP activity. Paradoxically, PAI-1, the major physiological inhibitor of plasmin generation, is also up-regulated under these conditions and is an early event in progression of incipient epidermal SCC. A model is proposed in which TGF-β1+EGF-dependent MMP-10 elevation directs focalized matrix remodeling events that promote epithelial cell plasticity and tissue invasion. Increased PAI-1 expression serves to temporally and spatially modulate plasmin-initiated pericellular proteolysis, further facilitating epithelial invasive potential. Defining the complex signaling mechanisms that maintain this elegant balance is critical to developing potential therapeutics for the treatment of human cutaneous malignancies.