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Cyclin-dependent kinase subunit 1 (Cks1) regulates the degradation of p27, an important G1-S inhibitor, which is up regulated by MAPK pathway activation. In this study, we sought to determine whether Cks1 expression is increased in melanocytic tumors and correlates with outcome and/or other clinicopathologic prognostic markers. Cks1 expression was assessed by immunohistochemistry in 298 melanocytic lesions. The frequency and intensity of cytoplasmic and nuclear expression was scored as a labeling index and correlated with clinico-pathological data. Nuclear Cks1 protein was found in 63% of melanocytic nevi, 89% primary and 90% metastatic melanomas with mean labeling index of 7 ± 16, 19 ± 20, and 30 ± 29, respectively. While cytoplasmic Cks1 was found in 41% of melanocytic nevi, 84% primary and 95% metastatic melanomas with mean labeling index of 18 ± 34, 35 ± 34, and 52 ± 34, accordingly. Histologic stepwise model of tumor progression, defined as progression from benign nevi to primary melanomas, to melanoma metastases, revealed a significant increase in nuclear and cytoplasmic Cks1 expression with tumor progression. Nuclear and cytoplasmic Cks1 expression correlated with the presence of ulceration, increased mitotic rate, Breslow depth, Clark level, tumor infiltrating lymphocytes and gender. However, other well-known prognostic factors (age, anatomic site, and regression) did not correlate with any type of Cks1 expression. Similarly, increasing nuclear expression of Cks1 significantly correlated with worse overall survival. Thus, Cks1 expression appears to play a role in the progression of melanoma, where high levels of expression are associated with poor outcome. Cytoplasmic expression of Cks1 might represent high turnover of protein via the ubiquination/proteosome pathway.

Zusammenfassung Hintergrund: Altere Klassifikationen fur Vaskulitiden weisen verschiedene Mangel auf. Erstens kann die Klassifikation unterschiedlichen Prinzipien folgen, wie klinisch-pathologischen Befunden, Atiologie, Pathogenese, Prognose oder therapeutischen Optionen. Zweitens unterscheiden die Autoren nicht zwischen Vaskulitis und Koagulopathie. Drittens sind Vaskulitiden systemische Erkrankungen. Aufgrund organspezifischer Variationen sind morphologische Befunde schwierig zu vergleichen. Viertens sind geringfugige Veranderungen zwar an der Haut erkennbar, verursachen jedoch an anderen Organen moglicherweise keine Symptome. Unser Ziel war es, die Haut und die Subkutis als Modell und die klinisch-pathologische Korrelation als Grundlage fur die Klassifikation zu verwenden. Methoden und Ergebnisse: Wir verwenden einen algorithmischen Ansatz mit Musteranalyse, der konsistente Angaben zu mikroskopischen Befunden ermoglicht. Zunachst differenzieren wir zwischen Vaskulitiden kleiner und mittelgroser Gefase. Im zweiten Schritt unterscheiden wir die Subtypen kleiner (Kapillaren versus postkapillare Venolen) und mittelgroser (Arteriolen/Arterien versus Venen) Gefase. Im letzten Schritt unterscheiden wir, je nach vorherrschendem Zelltyp, zwischen leukozytoklastischer und/oder granulomatoser Vaskulitis. Schlussfolgerungen: Ausgehend von der leukozytoklastischen Vaskulitis als zentralem Reaktionsmuster bei kutanen Vaskulitiden kleiner und mittelgroser Gefase konnen Zusammenhange oder Variationen darum herum angeordnet werden wie die Speichen eines Rades um die Nabe. Dies kann dazu beitragen, eine gewisse grundlegende Ordnung im vergleichsweise komplexen Bereich der kutanen Vaskulitiden einzufuhren, um zu einem besseren Verstandnis eines komplizierten Gebiets beizutragen. Summary Background: Previous classifications of vasculitides suffer from several defects. First, classifications may follow different principles including clinicopathologic findings, etiology, pathogenesis, prognosis, or therapeutic options. Second, authors fail to distinguish between vasculitis and coagulopathy. Third, vasculitides are systemic diseases. Organ-specific variations make morphologic findings difficult to compare. Fourth, subtle changes are recognized in the skin, but may be asymptomatic in other organs. Our aim was to use the skin and subcutis as a model and the clinicopathologic correlation as the basic process for classification. Methods and Results: We use an algorithmic approach with pattern analysis, which allows for consistent reporting of microscopic findings. We first differentiate between small and medium vessel vasculitis. In the second step, we differentiate the subtypes of small (capillaries versus postcapillary venules) and medium-sized (arterioles/arteries versus veins) vessels. In the final step, we differentiate, according to the predominant cell type, into leukocytoclastic and/or granulomatous vasculitis. Conclusions: Starting from leukocytoclastic vasculitis as a central reaction pattern of cutaneous small/medium vessel vasculitides, its relations or variations may be arranged around it like spokes of a wheel around the hub. This may help establish some basic order in this rather complex realm of cutaneous vasculitides, leading to a better understanding in a complicated field.

SummaryBackground Previous classifications of vasculitides suffer from several defects. First, classifications may follow different principles including clinicopathologic findings, etiology, pathogenesis, prognosis, or therapeutic options. Second, authors fail to distinguish between vasculitis and coagulopathy. Third, vasculitides are systemic diseases. Organ-specific variations make morphologic findings difficult to compare. Fourth, subtle changes are recognized in the skin, but may be asymptomatic in other organs. Our aim was to use the skin and subcutis as a model and the clinicopathologic correlation as the basic process for classification. Methods and Results We use an algorithmic approach with pattern analysis, which allows for consistent reporting of microscopic findings. We first differentiate between small and medium vessel vasculitis. In the second step, we differentiate the subtypes of small (capillaries versus postcapillary venules) and medium-sized (arterioles/arteries versus veins) vessels. In the final step, we differentiate, according to the predominant cell type, into leukocytoclastic and/or granulomatous vasculitis. Conclusions Starting from leukocytoclastic vasculitis as a central reaction pattern of cutaneous small/medium vessel vasculitides, its relations or variations may be arranged around it like spokes of a wheel around the hub. This may help establish some basic order in this rather complex realm of cutaneous vasculitides, leading to a better understanding in a complicated field.

BACKGROUND The authors hypothesized that comprehensive genomic profiling of advanced-stage cutaneous squamous cell carcinoma (cSCC) could identify genomic-derived drug targets of therapy for patients with conventional therapy-resistant disease. METHODS Comprehensive genomic profiling of 315 cancer genes was applied to 50 ng of DNA from 122 cSCC cases for the evaluation of all classes of genomic alterations (GAs). Clinically relevant genomic alterations (CRGAs) were defined as those identifying anticancer drugs on the market or in registered clinical trials. RESULTS There were 21 women (17%) and 101 men (83%) with a median age of 64.9 years (range, 21-87 years). Eleven cSCC cases (9%) were histologic AJCC grade 1, 69 (57%) were grade 2, and 42 (34%) were grade 3. The primary cSCC was used for sequencing in 77 cases (63%). Metastatic lesions were sequenced in 37% of cases. There were 1120 total GAs identified (average of 9.2 GAs per tumor), with 100% of cases harboring at least 1 alteration. Of the 122 cSCCs, 107 (88%) harbored at least 1 CRGA (2.5 CRGAs per cSCC) includingNOTCH1 (43%); patched 1 (PTCH1) (11%); BRCA2 (10%); HRAS (8%); ataxia telangiectasia mutated (ATM) (7%); erb-B2 receptor tyrosine kinase 4 (ERBB4) (7%); neurofibromatosis type 1 (NF1) (7%); erb-B2 receptor tyrosine kinase 2 (ERBB2) (6%); phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) (6%); cyclin D1 (CCND1) (6%); epidermal growth factor receptor (EGFR) (5%); and F-box and WD repeat domain containing 7, E3 ubiquitin protein ligase (FBXW7) (5%). CONCLUSIONS In the current study, approximately 88% of patients with cSCC were found to harbor clinically relevant GAs that have the potential to guide the treatment of patients with advanced-stage tumors with targeted therapeutic agents. Cancer 2016;122:249–257. © 2015 American Cancer Society.

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

Because melanogenesis can affect immune responses to and chemotherapy and radiotherapy for melanoma, we analyzed overall survival and disease-free survival times in melanoma patients in relation to the degree of tumor pigmentation. Clinicopathologic data were obtained from the Oncology Centre, Prof Franciszek Łukaszczyk Memorial Hospital, Bydgoszcz, Poland. The overall survival and disease-free survival analyses were performed using the log-rank test, whereas differences between mean/median overall survival and disease-free survival (days) were analyzed using the Student t test. In patients with metastatic disease, those with melanotic melanomas exhibited significantly shorter disease-free survival and overall survival than those with amelanotic lesions. Similarly, melanin-producing lymph node metastases were linked to shorter overall survival and disease-free survival, which was confirmed by a significantly longer mean/median disease-free survival for amelanotic versus melanotic metastases. Melanogenesis shortens overall survival and disease-free survival in patients with metastatic melanoma. Inhibition of melanogenesis appears a rational adjuvant approach to the therapy of metastatic melanoma.

The authors present a case of a gradually enlarging pigmented mass of the upper eyelid and anterior orbit that was discovered to be the graphite tip of a pencil surrounded by macrophages bearing graphite and fibrous tissue. A 25-year-old woman with no medical history presented with a gradually enlarging pigmented lesion of her left upper eyelid. She denied any history of previous skin cancer, trauma, or previous surgery. A biopsy was performed. This revealed an encapsulated grayish, pigmented mass within the medial portion of the left upper eyelid and anterior orbit. Within the pigmented cocoon, the graphite core of a pencil (“pencil lead”) was identified. Histopathology demonstrated granulomatous inflammation with fibrosis and macrophages.

Giant basal cell carcinomas (GBCCs), (BCC ≥ 5 cm), are often painless, destructive tumors resulting from poorly understood patient neglect.To elucidate etiopathogenic factors distinguishing GBCC from basal cell carcinoma (BCC) and identify predictors for disease-specific death (DSD).Case-control study examining clinicopathologic and neuroactive factors (β-endorphin, met-enkephalin, serotonin, adrenocorticotropic hormone, and neurofilament expression) in GBCC and BCC. Systematic literature review to determine DSD predictors.Thirteen GBCCs (11 patients) were compared with 26 BCCs (25 patients). GBCC significantly differed in size, disease duration, and outcomes; patients were significantly more likely to live alone, lack concern, and have alcoholism. GBCC significantly exhibited infiltrative/morpheic phenotypes, perineural invasion, ulceration, and faster growth. All neuromediators were similarly expressed. Adenoid phenotype was significantly more common in GBCC. Adenoid tumors expressed significantly more β-endorphin (60% vs. 18%, P = 0.01) and serotonin (30% vs. 4%, P = 0.02). In meta-analysis (n ≤ 311: median age 68 years, disease duration 90 months, tumor diameter 8 cm, 18.4% disease-specific mortality), independent DSD predictors included tumor diameter (cm) (hazard ratio (HR): 1.12, P = 0.003), bone invasion (HR: 4.19, P = 0.015), brain invasion (HR: 8.23, P = 0.001), and distant metastases (HR: 14.48, P = 0.000).GBCC etiopathogenesis is multifactorial (ie, tumor biology, psychosocial factors). BCC production of paracrine neuromediators deserves further study.

Vasculitis is defined as inflammation directed at vessels, which compromises or destroys the vessel wall leading to haemorrhagic and/or ischaemic events. Skin biopsy is the gold standard for the diagnosis of cutaneous vasculitis, whose manifestations include urticaria, infiltrative erythema, petechiae, purpura, purpuric papules, haemorrhagic vesicles and bullae, nodules, livedo racemosa, deep (punched out) ulcers and digital gangrene. These varied morphologies are a direct reflection of size of the vessels and extent of the vascular bed affected, ranging from a vasculitis affecting few superficial, small vessels in petechial eruptions to extensive pan-dermal small vessel vasculitis in haemorrhagic bullae to muscular vessel vasculitis in lower extremity nodules with livedo racemosa. Skin biopsy, extending to subcutis and taken from the earliest, most symptomatic, reddish or purpuric lesion is crucial for obtaining a high-yielding diagnostic sample. Based on histology, vasculitis can be classified on the size of vessels affected and the dominant immune cell mediating the inflammation (e.g. neutrophilic, granulomatous, lymphocytic, or eosinophilic). Disruption of small vessels by inflammatory cells, deposition of fibrin within the lumen and/or vessel wall coupled with nuclear debris allows for the confident recognition of small vessel, mostly neutrophilic vasculitis (also known as leukocytoclastic vasculitis). In contrast, muscular vessel vasculitis can be identified solely by infiltration of its wall by inflammatory cells. Extravasation of red blood cells (purpura) and necrosis are supportive, but not diagnostic of vasculitis as they are also seen in haemorrhagic and/or vaso-occlusive disorders (pseudovasculitis). Vasculitic foci associated with extravascular granulomas (palisaded neutrophilic and granulomatous dermatitis), tissue eosinophilia, or tissue neutrophilia signal the risk for, or co-existence of systemic disease. This essential histological information coupled with direct immunofluorescence and anti-neutrophil cytoplasmic data and clinical findings enables more precise and accurate diagnosis of localized and systemic vasculitis syndromes.

The main cause of death in melanoma patients is widespread metastases. Staging of melanoma is based on the primary tumor thickness, ulceration, lymph node and distant metastases. Metastases develop in regional lymph nodes, as satellite or in-transit lesions, or in distant organs. Lymph flow and chemotaxis is responsible for the homing of melanoma cells to different sites. Standard pathologic evaluation of sentinel lymph nodes fails to find occult melanoma in a significant proportion of cases. Detection of small numbers of malignant melanoma cells in these and other sites, such as adjacent to the primary site, bone marrow or the systemic circulation, may be enhanced by immunohistochemistry, reverse transcription PCR, evaluation of lymphatic vessel invasion and proteomics. In the organs to which melanoma cells metastasize, extravasation of melanoma cells is regulated by adhesion molecules, matrix metalloproteases, chemokines and growth factors. Melanoma cells may travel along external vessel lattices. After settling in the metastatic sites, melanoma cells develop mechanisms that protect them against the attack of the immune system. It is thought that one of the reasons why melanoma cells are especially resistant to killing is the fact that melanocytes (cells from which melanoma cells derive) are resistant to such noxious factors as ultraviolet light and reactive oxygen species. Targeted melanoma therapies are, so far, largely unsuccessful, and new ones, such as adjuvant inhibition of melanogenesis, are under development.

Single base substitution mutations in codons 248 and 273 of TP53 and codon 12 Kirsten-ras (KRAS) are commonly found in human carcinomas. To determine whether these mutations also occur in normal and inflamed tissues from which carcinomas arise, we utilized the ultra-sensitive polymerase chain reaction/restriction endonuclease/ligase chain reaction mutation assay. Ninety samples of genital skin, including lichen sclerosus (LS) affected skin, adjacent normal and non-adjacent normal, were assayed. Mutations were detected in 103 of 349 assays and consisted of KRAS G34A, G34T, G35A, and TP53 C742T, G818C, C817T, and G818A mutations. Mutant prevalence varied from 1 to 20 per 10(6) wild-type cells. Mutations occurred significantly more frequently in LS (78/224 (35%)) than adjacent normal (20/88 (23%)) and non-adjacent normal genital skin (5/38 (13%)). KRAS G34A mutation was relatively common to all classes of specimen, whereas TP53 gene C742T and G818C mutations were significantly more frequent in LS than normal genital skin. In matched samples, immunohistochemistry evaluation of p53 protein expression revealed the presence of epidermal p53 clones in LS whose presence and number significantly correlated with the presence of TP53 C742T and G818C mutations. Based on these results, it appears oncogenic point mutations occur in normal genital skin, and are selected for in LS.

The prognosis associated with Stage III melanoma is variable (17-65% 5-year survival) and primarily influenced by the number of lymph nodes involved, the presence of ulceration in a primary lesion, and the tumor burden present in each lymph node. In patients with metastatic (Stage IV) melanoma, the prognosis remains dismal (6-18% 5-year survival) and is influenced primarily by the sites (and extent) of metastatic involvement. Serum lactate dehydrogenase is the only prognostic biomarker useful in metastatic melanoma and it has been incorporated into the 2002 American Joint Committee on Cancer tumor, node, metastasis staging system. In this review, the known prognostic factors in Stage III and IV melanoma are reviewed. Selected investigational therapies and associated biomarkers are also discussed.

Currently, melanoma remains a surgical disease since early detection and excision of thin melanomas offers the best chance of a cure. Despite intensive clinical investigation, no effective systemic therapies exist for metastatic melanoma. Sentinel lymph node biopsy has greatly aided the staging and prognostic evaluation of primary cutaneous melanoma, however, approximately a third of patients diagnosed with metastatic melanomas present without prior regional lymph node involvement. Additional prognostic biomarkers exist which help determine the risk of advanced melanoma but the accuracy for each current marker is less than 100%. A greater understanding of the biology of melanomas and the development of new methods to identify patients with early (subclinical) metastatic disease may allow for selective and more effective therapy for patients at-risk for advanced disease. In this paper, current and novel potentially more accurate biomarkers for the staging and prognostic evaluation of melanoma patients, and for the detection of subclinical metastases are reviewed.

Melanoma's incidence and mortality for certain groups has appeared to level off after a steady increase over the last half century. This trend is suspected to be due to better detection and removal of thin, biological early melanomas. However, to date, no prospective evidence exists to clearly demonstrate the efficacy of prevention and early detection in decreasing melanoma mortlity. Nonetheless, many studies suggest that both self-assessment of risk factors or clinician examination can identify a proportion of patients at highest risk for melanoma who may benefit from behavior modification (primary prevention) and routine screening (secondary prevention). Compromising these goals is the fact that neither the clinical or histologic diagnosis of melanoma is 100% accurate. Clinical diagnosis of melanoma, based on evaluation of a skin lesion's color and shape, correlates best with the experience of the clinician. Ancillary technologies have been developed to improve clinical accuracy of suspicious skin lesions but a subset of melanomas exist that do not fall in the spectrum of the 'ABCDE' guidelines commonly used for melanoma identification. Similarly, at the histologic level (the 'gold standard' of diagnosis), overlap exists between benign and malignant melanocytic proliferations leading to both over and underdiagnosis of melanoma. A better understanding of melanoma's pathogenesis has identified disease-related biomarkers that may more reliably differentiate a melanocytic nevus from melanoma. In this paper, we review current and novel, potentially more accurate, biomarkers and supplementary technologies that can be used for the prevention, screening and diagnosis of melanoma.

Pigmented epithelioid melanocytoma (PEM) is a tumor encompassing epithelioid blue nevus of Carney complex (EBN of CNC) and was previously termed animal-type melanoma. Histologically PEMs are heavily pigmented spindled and epithelioid dermal melanocytic tumors with infiltrative borders, however, their origin remains unclear. Stem cells for the epidermis and hair follicle are located in the bulge area of the hair follicle with the potential to differentiate into multiple lineages. Multiple cutaneous carcinomas, including follicular cutaneous squamous cell carcinoma (FSCC), are thought to arise from stem cells in the follicular bulge. We present two cases of PEM/ATM in a 63 year-old male on the scalp with follicular origin and a 72 year-old female on the upper back arising in an intradermal nevus. Biopsy of both cases revealed a proliferation of heavily pigmented dermal nests of melanocytes with atypia. The Case 1 tumor was in continuation with the outer root sheath of the hair follicle in the bulge region. Case 2 arose in an intradermal melanocytic nevus. Rare mitotic figures, including atypical mitotic figures, were identified in both cases. We present two cases of PEM, with histologic evidence suggesting two origins: one from the follicular bulb and one from an intradermal nevus.

Purpose Rosacea-related cutaneous inflammation is a common cause of ocular surface disease. Currently, there are no specific pharmacologic therapies to treat ocular rosacea. Here, we aimed at determining the differences in intracellular signaling activity in eyelid skin from patients with and without ocular rosacea. Methods This was an observational, comparative case series including 21 patients undergoing lower lid ectropion surgery at one practice during 2013 and 2014 (18 patients with rosacea, 13 control patients), and 24 paraffin-embedded archival samples from Albany Medical Center, selected randomly (12 patients with rosacea, 12 control patients). Cutaneous biopsies resulting from elective lower lid ectropion surgery were analyzed by Proteome Profiler Human Phospho-Kinase Array, Western blot, and/or immunohistochemistry. Results Samples derived from ocular rosacea patients showed increased levels of phosphorylated (active) p38 and Erk kinases. Phosphoproteins were mainly localized to the epidermis of affected eyelids. Conclusions This finding provides a novel potential therapeutic target for treatment of ocular rosacea and possibly other forms of rosacea. Further testing is required to determine if p38 and Erk activation have a causal role in ocular rosacea. The selective activation of keratinocytes in the affected skin suggests that topical pathway inhibition may be an effective treatment that will ultimately prevent ocular surface damage due to ocular rosacea.

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.

Vulvar squamous cell carcinoma (SCC) affects a spectrum of women with granulomatous vulvar diseases, human papillomavirus (HPV) infections, and chronic inflammatory vulvar dermatoses. To determine whether there is evidence of chromosomal instability occurring in synchronous skin surrounding vulvar SCCs, we investigated abnormalities in chromosome 17 copy number. Samples of SCC, vulvar intraepithelial neoplasia (VIN), and surrounding vulvar skin were obtained from all vulvar excisions performed for squamous neoplasia at Albany Medical College from 1996 to 1997. Histological categorization, fluorescent in situ hybridization (FISH) for the alpha satellite region of chromosome 17, DNA content by image analysis, and Ki-67 labeling were evaluated. Controls of normal vulvar skin not associated with cancer were used for comparison. One hundred ten specimens were obtained from 33 patients with either SCC or VIN 3 and consisted of 49 neoplastic, 52 nonneoplastic, and 9 histologically normal vulvar skin samples. The majority of SCCs (88%) and a minority (18%) of VIN 3 excisions were associated with lichen sclerosus. Normal vulvar skin controls did not exhibit chromosome 17 polysomy (cells with more than four FISH signals), whereas 56% of normal vulvar skin associated with cancer did. Moreover, the frequency of polysomy significantly increased as the histological classification progressed from normal to inflammatory to neoplastic lesions. The largest mean value and variance for chromosome 17 copy number was identified in SCCs (2.4 +/- 1.0) with intermediate values identified, in decreasing order, for SCC in situ (2.1 +/- 1.0), VIN 2 (2.1 +/- 0.8), lichen sclerosus (2.0 +/- 0.5), lichen simplex chronicus (1.9 +/- 0.4), and normal skin associated with SCC (1.8 +/- 0.4) compared with control vulvar skin (1.5 +/- 0. 05). Concordance of chromosome 17 aneusomy between cancers and synchronous skin lesions was found in 48% of patients. Loss of chromosome 17 was identified 5% of all samples and was significantly associated with women with SCC in situ (HPV-related). Both DNA content and Ki-67 labeling positively and significantly correlated with mean chromosome 17 copy number (r = 0.1, P: = 0.007). A high degree of genetic instability (aneuploidy) occurs in the skin surrounding vulvar carcinomas. As these events could be detected in histologically normal skin and inflammatory lesions (lichen sclerosus), chromosomal abnormalities may be a driving force in the early stages of carcinogenesis. Differences in chromosomal patterns (loss or gain) support the concept of at least two pathways in vulvar carcinogenesis.

Background. Desmoplastic neurotropic melanoma (DNM) is a rare variant of malignant melanoma, the natural history and histogenesis of which still are being defined. Methods. The clinical and histologic features of 28 cases of DNM were studied. All published cases of DNM to date were reviewed. Paraffin sections from 26 cases were investigated with a panel of 10 tissue markers. The ultra-structural features of seven cases were evaluated. Results. A comparison of this study's findings with that of other published cases revealed many similarities regarding clinical and pathologic findings and outcome. The patients were white (15 men:13 women; mean and median age, 59 years; range, 22-83 years). Most tumors were located on the head and neck (75%) and were non-pigmented (57%). An associated intraepidermal melanocytic proliferation was identified in 85% of the patients (lentigo maligna in 56%). Histologically, the dermal tumors were composed of tapered, nonpigmented spindle cells in peripheral nerve sheath patterns resembling neuromas, schwannomas, neurofibromas, and perineurial proliferations accompanied by variable neurotropism and desmoplasia; desmoplasia was the most notable feature in most tumors. The mean depth of tumor invasion was 4.1 mm (range, 0.32-9.0 mm). Tumors with continuity between the epidermal and dermal components had a significantly thinner depth of invasion and a more extensive intraepidermal melanocytic proliferation than those tumors with a grenz zone between the two components (2.3 mm vs. 4.6 mm, P = 0.015). Mitotic activity ranged from 0/HPF in 10 cases, 1-6/high power field (HPF) in 12 cases, and to greater than 6/HPF in 4 cases. An ulcer was present in 5/27 tumors, regression in 4/27, a microsatellite in 1, and brisk and had nonbrisk tumor infiltrating lymphocytic responses in 2 and 14, respectively. Vimentin was uniformly positive and keratins AE1.3 and Cam 5.2 and Leu-7 were uniformly negative. S100 protein, also uniformly positive, had patchy reactivity in most tumors that expressed EMA (43%). Smooth muscle actin (52%), neuron-specific enolase (42%), and FXIIIa (30%) had patchy positivity. HMB-45 was reactive only in the epidermal and superficial papillary dermal component in 21% of cases. Ultrastructurally, the common features were long, often intertwining cellular processes, intercellular junctions, and discontinuous basal lamina. Melanosomes were not identified. Follow-up data available on 26/28 patients (mean, 36 months; median, 24 months; range, 5-132 months) showed 20 (70%) alive without disease, 2 alive with disease and 3 dead from disease. Seven patients had recurrent local tumor (multiple in four); four had lymph node metastases, and three had visceral metastases. Patients with recurrent disease of any type had significantly thicker tumors (5.4 mm vs. 3.4 mm, P = 0.046) and were more likely to have an ulcerated tumor (P = 0.03). Actuarial 5-year survival for tumors with greater than a 4-mm thickness was 72%, which was greater than that for other types of melanoma with greater than a 4-mm thickness. Conclusions. Desmoplastic neurotropic melanomas are neuroectodermal tumors that usually arise from an intraepidermal melanocytic proliferation but rarely develop de novo in the dermis. Schwannian and perineurial differentiation may account for the desmoplasia and neurotropism encountered in these neoplasms. Desmoplastic neurotropic melanomas present at a more advanced stage locally and may be associated with a better survival than associated with conventional melanomas of similar depth of invasion. Cancer 1995;75:478-94.

Syphilis has plagued mankind for centuries and is currently resurgent in the Western hemisphere. Although there has been a significant reduction of tertiary disease and recognition of facilitative interactions with human immunodeficiency virus infection, the natural history of syphilis has remained largely unchanged; thus, new strategies are required to more effectively combat this pathogen. The immunopathologic features of experimental syphilis in the rabbit; the course, stages, and pathology of human syphilis; and a comparison of human syphilis with leprosy suggest that the clinical course of syphilis and its tissue manifestations are determined by the balance between delayed-type hypersensitivity (DTH) and humoral immunity to the causative agent, Treponema pallidum. A strong DTH response is associated with clearance of the infecting organisms in a well-developed chancre, whereas a cytotoxic T-cell response or strong humoral antibody response is associated with prolonged infection and progression to tertiary disease. Many of the protean symptoms/appearances of secondary and tertiary human syphilis are manifestations of immune reactions that fail to clear the organism, due to a lack of recruitment and, more importantly, activation of macrophages by sensitized CD4 T cells. The Bacillus Calmette-Guerin vaccination can enhance DTH and has been shown to produce a low, but measurable, beneficial effect in the prevention of leprosy, a disease that shows a disease spectrum with characteristics in common with syphilis. In the prevention of syphilis, a potential vaccine protective against syphilis should be designed to augment the DTH response.

Routine light microscopy remains a powerful tool to diagnose, stage and prognose melanoma. Although it is very economical and efficient, it requires a significant level of expertise and, in difficult cases the final diagnosis is affected by subjective interpretation. Fortunately, new insights into the genomic aberrations characteristic of melanoma, coupled with ancillary studies, are further refining evaluation and management allowing for more confident diagnosis, more accurate staging and the selection of targeted therapy. In this article, we review the standard of care and new updates including four probe FISH, the 2009 American Joint Commission on Cancer staging of melanoma and mutant testing of melanoma, which will be crucial for targeted therapy of metastatic melanoma.

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.

Regulation of the transcription factor TCF8 (ZEB1) by the microRNA miR-200c and was first identified using a bioinformatic and relative quantitative PCR based approach.(1) Using stable ectopic expression of miR-200c we then demonstrated loss of TCF8 (ZEB1) mRNA and restoration of its primary regulatory target, E-cadherin.(2) Recently, other members of the miR-200 'family' and an additional unrelated microRNA, miR-205, have been reported to be essential for the regulation of TCF8 (ZEB1) and restoration of E-cadherin.(3-5) To investigate, we repeated our initial method(s) and generated individual stable cell-lines, expressing the miR-200 'family' members; miR-200c, miR-200b, miR-141 and the related miR-205. Of these lines, miR-200b produced no mature transcript and miR-205 and miR-141 cells were either morphologically similar to controls or showed some slight changes respectively. However no reduction in TCF8/ZEB1 mRNA or restoration of E-cadherin could be detected in either line. In contrast, cells expressing miR-200c had a significantly altered morphology from mesenchymal to epithelial and restored expression of E-cadherin. These contrasting findings demonstrate that, as transient transfection is in essence an RNAi experiment, results should be treated with caution when investigating microRNAs and that an examination of microRNAs with similar seed regions requires stable ectopic expression to accurately reflect the endogenous mechanism(s).

MicroRNAs are ∼22-nucleotide sequences thought to interact with multiple mRNAs resulting in either translational repression or degradation. We previously reported that several microRNAs had variable expression in mammalian cell lines, and we examined one, miR-200c, in more detail. A combination of bioinformatics and quantitative reverse transcription-PCR was used to identify potential targets and revealed that the zinc finger transcription factor transcription factor 8 (TCF8; also termed ZEB1, δEF1, Nil-2-α) had inversely proportional expression levels to miR-200c. Knockout experiments using anti-microRNA oligonucleotides increased TCF8 levels but with nonspecific effects. Therefore, to investigate target predictions, we overexpressed miR-200c in select cells lines. Ordinarily, the expression level of miR-200c in non–small-cell lung cancer A549 cells is low in contrast to normal human bronchial epithelial cells. Stable overexpression of miR-200c in A549 cells results in a loss of TCF8, an increase in expression of its regulatory target, E-cadherin, and altered cell morphology. In MCF7 (estrogen receptor–positive breast cancer) cells, there is endogenous expression of miR-200c and E-cadherin but TCF8 is absent. Conversely, MDA-MB-231 (estrogen receptor–negative) cells lack detectable miR-200c and E-cadherin (the latter reportedly due to promoter region methylation) but express TCF8. The ectopic expression of miR-200c in this cell line also reduced levels of TCF8, restored E-cadherin expression, and altered cell morphology. Because the down-regulation of E-cadherin is a crucial event in epithelial-to-mesenchymal transition, loss of miR-200c expression could play a significant role in the initiation of an invasive phenotype, and, equally, miR-200c overexpression holds potential for its reversal. [Cancer Res 2007;67(17):7972–6]

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.

Objectives To describe the clinicopathologic features of melanocytic proliferations associated with lichen sclerosus (LS) and to compare these findings with those in controls. Design Cohort study. Setting Academic and private practice dermatology and dermatopathology services. Patients Cases of melanocytic proliferations associated with LS and consecutive controls with persistent (recurrent) melanocytic nevi, persistent malignant melanomas, and compound melanocytic nevi. Main Outcome Measures Diagnostic criteria and disease recurrence. Results Eleven patients, all female, with a mean age of 40 years (range, 8-83 years), presented with pigmented lesions clinically suspected to be malignant melanoma or atypical melanocytic nevi affecting the vulva (7 patients), perineum (3 patients), or chest (1 patient). Lichen sclerosus was first identified in the biopsy specimen and subsequently confirmed clinically. In 10 cases, a melanocytic nevus was superimposed on LS (overlying or entrapped by sclerosis), whereas LS was found at the periphery of vulvar malignant melanoma. After complete excision, no recurrences have been reported for the melanocytic nevi in LS (mean follow-up, 29 months; range, 4-60 months). Compared with control lesions, the LS melanocytic nevi most closely resembled persistent melanocytic nevi and could be distinguished from persistent malignant melanoma histologically. Melanocytes, nevoid or malignant, proliferating contiguously with fibrotic or sclerotic collagen, contained abundant melanin, diffusely expressed HMB-45, and had a higher Ki-67 labeling index than ordinary melanocytic nevi. However, persistent malignant melanoma exhibited mitotic figures, significantly higher Ki-67 labeling index, and deep dermal HMB-45 expression compared with LS melanocytic nevi and persistent melanocytic nevi. Conclusions Melanocytic nevi occurring in LS have features in common with persistent melanocytic nevi and can mimic malignant melanoma. An "activated" melanocytic phenotype is seen in LS melanocytic nevi, implicating a stromal-induced change.

Oncostatin M (OSM) is a 28-kDa glycoprotein, produced by stimulated macrophages and T lymphocytes, that inhibits the proliferation and induces differentiation of a number of different cell lines derived from solid tumors. To determine whether keratoacanthoma (KA) is unique or a variant of squamous cell carcinoma (SCC), we compared the immunohistochemical expression of OSM in the tumor cells and peri- and intratumoral macrophages of 21 mature KAs, 7 regressing KAs, and 27 SCCs. An inverse correlation was identified between OSM tumor labeling and the density of OSM-labeled tumor-associated macrophages for KAs (r = -.4; P = .09). OSM tumor expression was significantly more frequent and more intense in KAs than in SCCs (95% versus 63%; P < .01). In contrast, the density of OSM-labeled macrophages was significantly higher in SCCs compared with mature KAs (7/3 high power fields versus 4/3 high power fields; P = .02). These OSM-positive macrophages were predominantly located at the advancing, infiltrative margins of both neoplasms. Regressing KAs demonstrated a decreased level of OSM tumor expression compared with mature KAs (53% versus 95%; P = .001), but there was no difference in density of OSM-labeled macrophages. Both the above differences and the overlapping patterns of OSM expression suggest that KAs are a variant of SCC where OSM, possibly as an autocrine factor, may mediate KA's overwhelming but not absolute tendency to involute.