Cutaneous squamous cell carcinoma (SCC) is the second most common skin cancer in Caucasians, most frequently occurring on sun-exposed areas of the body. Most SCCs are treated surgically, either by excision or Mohs micrographic surgery. Despite the large amount of English literature with regard to cutaneous SCC in many instances the surgical treatment is not appropriate resulting in recurrences and/ or metastasis. The following brief review highlights the histology, molecular biology and surgical treatment of skin SCC. Clin Ter 2013; 164(2):143-147. doi: 10.7417/CT.2013.1534.

Cutaneous squamous cell carcinoma, the second most common form of non-melanotic skin cancer, may develop in long-standing discoid lesions, especially those that are depigmented and located in sun-exposed areas. The clinical course of this complication may be aggressive, with early metastases and a risk of mortality. We report three cases demonstrating this emerging trend of secondary squamous cell carcinoma in discoid lesions as the incidence of this secondary malignancy in other diseased skin lesions is on the decline.

Squamous cell carcinoma (SCC) and keratoacanthoma (KA) are skin neoplasms of epithelial origin. In contrast to clearly malignant skin neoplasm SCC, KA is an unusual cutaneous neoplasm with a tendency to regression. The distinction between these two neoplasms, on histological grounds only, is still a challenge. In order to investigate further and to assess the possible differences in transforming growth factor-alpha (TGF-alpha) expression between SCC and KA, 40 of skin tumor specimens, 20 cases of each SCC and KA were analyzed immunohystochemicaly. We have found a significant difference in staining patterns between KA and SCC. In KAs we have detected TGF-alpha staining mainly diffusely (90% of cases) and without peripheral staining of cells in 1-2 layers (60% of cases). Contrary, there was a mostly patchy staining (55% of cases) with peripheral staining of cells in 1-2 layers (100% of cases) in SCCs. Generally, differentiation between KA and SCC can be based on clinical and histological ground, but the distinction between these two skin tumors could sometimes be difficult. We have shown that these skin neoplasms could be differentiated based on staining patterns of TGF-alpha expression, thus this method could aid in differentiation between these two closely related entities in clinical practice.

Vascular endothelial growth factor-C (VEGF-C) and VEGF-D were identified as lymphangiogenic growth factors and later shown to promote tumor metastasis, but their effects on carcinogenesis are poorly known. We have here studied the effects of VEGF-C and VEGF-D on tumor development in the murine multi-step chemical carcinogenesis model of squamous cell carcinoma (SCC) by using a soluble VEGF-C/D inhibitor. After topical treatment with a tumor initiator and repeated tumor promoter applications, transgenic mice expressing a soluble VEGF-C/D receptor (sVEGFR-3) in the skin developed significantly fewer squamous cell tumors with a delayed onset when compared to wild-type mice or mice expressing sVEGFR-3 lacking the ligand-binding site. Epidermal proliferation was reduced in the carcinogen treated transgenic skin, whereas epidermal keratinocyte proliferation in vitro was not affected by VEGF-C or VEGF-D, indicating indirect effects of sVEGFR-3 expression. Importantly, transgenic mouse skin was less sensitive to tumor promoter induced inflammation, with reduced angiogenesis and blood vessel leakage. Cutaneous leukocytes, especially macrophages, were reduced in transgenic skin without major changes in macrophage polarization or blood monocyte numbers. Several macrophage-associated cytokines were also reduced in transgenic papillomas, although the dermal macrophages themselves did not express VEGFR-3. These findings indicate that VEGF-C/D are involved in shaping the inflammatory tumor microenvironment that regulates early tumor progression. Our results support the use of VEGF-C/D blocking agents not only to inhibit metastatic progression, but also during the early stages of tumor growth.

: Dermal-based combined squamous and melanocytic neoplasms are emerging clinicopathologic entities that tend to appear on sun-exposed areas of elderly patients. The biologic behavior of such cutaneous neoplasms remains uncertain because of their rarity. Histopathologic differential includes the following diagnostic entities: (1) dermal squamomelanocytic tumor, (2) melanocytic matricoma, and (3) rare histologic variant of pilomatrical carcinoma, the so-called pilomatrical carcinoma with intralesional melanocytes. Herein, we present a novel case of locally invasive dermal squamomelanocytic tumor. A 72-year-old man presented with a pigmented papule on nasal ala that was clinically concerning for basal cell carcinoma. Histopathologic evaluation demonstrated atypical melanocytic cells architecturally and intimately intermixed with single units and clusters of atypical squamous cells. Most notable feature of this case is focal matrical differentiation and locally invasive tumor growth, characterized by multifocal perineural invasion.

With a lifetime incidence of approximately 10% in the general population, cutaneous squamous cell carcinoma (CSCC) is the second most common type of nonmelanoma skin cancer. Most CSCCs are benign and can be completely eradicated by surgery or other dermatological procedures. There is, however, a subgroup associated with an increased likelihood of lymph node metastases and, therefore, with high morbidity and mortality. This article analyzes the various factors that define aggressive CSCC. We propose a method for defining high-risk SCC on the basis of a series of major and minor criteria. This method will allow better prognostic evaluation and enable personalized management of patients with high-risk SCC, possibly leading to improved overall survival.

Erythema annulare centrifugum (EAC) is a permanent or migrating eruption characterized by annular, arcuate, or polycyclic erythematous lesions that expand to the periphery when the medial parts fade. Darier was the first to described it in 1916 (1,2). Defining the incidence and prevalence of EAC is difficult because the literature mostly consists of case reports and brief reviews. Although its etiology is not known for certain, it is assumed to be hypersensitivity reaction to malignancies, infections, and drugs. However, there have not been any underlying factors detected in the majority of cases. The prognosis for EAC is excellent, except when associated with an underlying malignancy and other systemic disease (1-3). A diagnosis of EAC should be followed by diagnostic work-up because it may result in discovery of an underlying disease. We describe a 52-year-old man affected by EAC, who upon further examination was diagnosed with squamous cell carcinoma of the lung (SCCL). A 52-year-old male patient was admitted to our department with itchy, erythematous, annular, polycyclic plaques, with a trailing scale present on the inner aspect of the advancing edges (Figs. 1 and 2). The plaques had been present on his trunk, extremities, and face for more than 3 months. The patient reported that the itchy lesions had first appeared on his forearms, then spread to his trunk, lower extremities, and face in a few weeks. Skin punch biopsy revealed orthokeratotic, parakeratotic hyperkeratosis observed occasionally on the epidermis, and mild vascular proliferation and perivascular mononuclear cell infiltration on the papillary dermis. The deep dermis, subcutis, and epidermal appendages were normal. The patient was diagnosed as EAC based on histopathologic and clinical findings. There was no history of antecedent infections or recent initiation of a new drug. Routine blood count and other chemistry tests produced normal results. Chest x-ray showed changes in the paracardiac areas of the middle and lower zones of the left lung, nodular opacities with peripheral reticulolinear extensions, and tubular radiolucent areas compatible with bronchiectasis in this region (Fig. 3). Thoracic computed tomography scan revealed a thick-walled, cavitary lesion, 4.5 cm in diameter, centrally located in the suprahilar region of the upper lobe of the left lung, observed to have a subsidiary of the upper lobe bronchus, micronodules and branching linear opacities on the parenchyma, intra-interlobular irregular septal thickening, and tractional bronchiectasis with pleuroparenchymal density increments in peripheral areas (Fig. 4). In consultation with pulmonologist, the patient was diagnosed with lung cancer; laboratory findings: CA 15-3, 32.7 U/mL (reference range: 0-31.3); CEA 7.75 ng/mL (reference range: 0-3); and erythrocyte sedimentation rate 21 mm/h (reference range: 0-15). The patient was hospitalized for treatment at department of pulmonary disease. Tumorous cells were observed on histopathologic examination of the lung biopsy obtained during bronchoscopy, which stained positive for P63 and negative for CYT7-20, CEA, TTF1, and MUC31. Clinical and histopathologic findings, and in consultation with a pulmonologist, indicated SCCL presented with superficial EAC. The patient was referred to thoracic surgery department for surgical treatment. Erythema annulare centrifugum is among diseases of unknown etiology (4). Erythema giratum repens and EAC are figure erythemas associated with malignancy (5). A review of medical literature reveals that malignancies related to EAC are squamous cell carcinoma, nasopharyngeal carcinoma, acute myelocytic leukemia, peritoneal carcinomatosis, primary bronchial carcinoid, Hodgkin's lymphoma, chronic lymphocytic leukemia, multiple myeloma, prostate carcinoma, malignant histiocytosis, mucinous ovarian carcinoma, and breast cancer (3,4,6-9). Monsieur et al. report on EAC, pulmonary osteoarthropathy, palmoplantar hyperkeratosis, inappropriate secretion of antidiuretic hormone, ectopic secretion of adrenocorticotropic hormone and calcitonin in poorly differentiated lung adenocarcinoma (10). Some other publications also report on a random relationship of EAC and malignancy (4). One study of 66 cases identified cutaneous fungal infection as the most important etiologic factor (72%), while other causes included benign internal neoplasm (13%), skin diseases (18%) and internal diseases (21%) (11). A study involving 73 EAC patients revealed neoplasia in 7% of deep type EAC cases (12). Squamous cell carcinoma of the lung accounts for 25%-30% of all lung cancers. Most lung carcinomas are diagnosed at an advanced stage, conferring a poor prognosis. The need to diagnose lung cancer at an early and potentially curable stage is thus obvious. Approximately 7%-10% of patients with lung cancer are asymptomatic, and their cancers are diagnosed incidentally after a chest radiograph performed for other reasons. Paraneoplastic syndromes may be the first or most prominent manifestation. Most paraneoplastic syndromes are caused by small cell lung cancer (SCLC). However, many paraneoplastic syndromes also occur in non-small cell lung cancer (NSCLC) patients. The symptoms may be endocrine, neuromuscular, musculoskeletal, cardiovascular, cutaneous, hematologic, gastrointestinal, renal, or miscellaneous in nature. Cutaneous itching is the most frequent cutaneous manifestation in patients with cancer. Herpes zoster, ichthyosis, flushes, alopecia, acanthosis nigricans, dermic melanosis, or hypertrichosis may also be observed. When a patient is diagnosed as a "typical" paraneoplastic syndrome, a diagnosis of cancer should be considered and investigated (13). Although our patient did not have any symptoms of lung carcinoma, etiologic study of EAC revealed early stages of SCCL. To our knowledge, this is the first case of EAC presented with SCCL. Etiology oriented research performed in EAC patients will help in early diagnosis and treatment of malignancies. This report is presented to emphasize the importance of etiologic research of EAC and EAC association with SCCL.

Cutaneous tuberculosis (TB) is less common than other forms of TB but accounts for 1.5% of all cases of extrapulmonary TB. The source of mycobacterial infection and the immune status of the host determine the presentation of any of a wide spectrum of clinical manifestations. Lupus vulgaris (LV) is a post-primary, paucibacillary form of TB caused by hematogeneous, lymphatic, or contiguous spread from elsewhere in the body.We report two recent cases of LV in women presenting with the exclusive involvement of the ear lobe. In Patient 1, clinical presentation appeared as an apparently benign chronic eczematous process. In Patient 2, it appeared as a fulminant ulceronecrotic process. Both women were immunocompetent, and neither had a personal or family history of TB.Both patients were diagnosed with LV and treated with standard antitubercular therapy (ATT). In both patients, mycobacterial culture showed growth of Mycobacterium tuberculosis sensitive to streptomycin, rifampicin, and ethambutol.Lupus vulgaris is the most common form of cutaneous TB. It is important to diagnose LV because it can result in chronic disfigurement and because 10-20% of LV patients have active pulmonary TB or TB of the bones and joints. In addition, longstanding LV is known to lead to the development of squamous cell carcinoma, which can be avoided by early diagnosis and treatment with ATT.

Over the past two decades, advances in the fields of cancer genetics and molecular biology have elucidated molecular pathways that cause numerous cutaneous malignancies. This in turn has spurred the rational design of molecularly targeted therapies. In this review, we discuss the molecular pathways critical to the development of nonmelanoma skin cancers and the novel pharmacologic agents that target them. Included is a review of vismodegib for basal cell carcinoma, cetuximab for squamous cell carcinomas, imatinib for dermatofibrosarcoma protuberans, and sirolimus for Kaposi's sarcoma.