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Effective treatment of cutaneous and subcutaneous malignant tumours by electrochemotherapy.

Electrochemotherapy (ECT) enhances the effectiveness of chemotherapeutic agents by administering the drug in combination with short intense electric pulses. ECT is effective because electric pulses permeabilize tumour cell membranes and allow non-permeant drugs, such as bleomycin, to enter the cells. The aim of this study was to demonstrate the anti-tumour effectiveness of ECT with bleomycin on cutaneous and subcutaneous tumours. This article summarizes results obtained in independent clinical trials performed by five cancer centres. A total of 291 cutaneous or subcutaneous tumours of basal cell carcinoma (32), malignant melanoma (142), adenocarcinoma (30) and head and neck squamous cell carcinoma (87) were treated in 50 patients. Short and intense electric pulses were applied to tumours percutaneously after intravenous or intratumour administration of bleomycin. The tumours were measured and the response to the treatment evaluated 30 days after the treatment. Objective responses were obtained in 233 (85.3%) of the 273 evaluable tumours that were treated with ECT. Clinical complete responses were achieved in 154 (56.4%) tumours, and partial responses were observed in 79 (28.9%) tumours. The application of electric pulses to the patients was safe and well tolerated. An instantaneous contraction of the underlying muscles was noticed. Minimal adverse side-effects were observed. ECT was shown to be an effective local treatment. ECT was effective regardless of the histological type of the tumour. Therefore, ECT offers an approach to the treatment of cutaneous and subcutaneous tumours in patients with minimal adverse side-effects and with a high response rate.

Differential expression of thyroid transcription factor 1 in small cell lung carcinoma and merkel cell tumor

The distinction between metastatic small cell lung carcinoma (SCLC) and Merkel cell tumor is difficult by routine histology, prompting the search for specific markers that could separate these neoplasms. Thyroid transcription factor 1 (TFF-1) is a homeodomain containing transcription factor expressed in the normal airway epithelium. The expression of TTF-1 has also been shown in adenocarcinomas and small cell carcinomas of the lung. However, the utility of TTF-1 to differentiate between SCLC and Merkel cell tumor has not yet been investigated. In this study, paraffin sections of 36 SCLCs and 21 Merkel cell tumors were analyzed for the presence of immunoreactive TTF-1 and cytokeratin 20 (CK20), a marker previously demonstrated in Merkel cell tumors. Monoclonal TTF-1 and CK20 antibodies were used with a biotin-streptavidin detection system. Immunostaining for TTF-1 was observed in 97% of SCLCs and in no Merkel cell tumors. Immunoreactivity for CK20 was demonstrated in 76% of Merkel cell tumors and 3% of SCLCs. These data indicate that TTF-1 is a sensitive (97%) and specific (100%) marker for SCLCs and can be used to differentiate SCLCs from Merkel cell tumors.

Pathologic examination of the sentinel lymph node in malignant melanoma.

Sentinel lymphadenectomy is gaining increasing popularity in the staging and treatment of patients with melanoma at risk for metastases. As a result, pathologists are encountering these specimens more frequently in their daily practice. The pathologic status of the sentinel lymph node is pivotal to the patients care because it provides staging information that dictates the need for further therapy, and therefore detailed pathologic assessment is warranted. A standard pathology protocol to handle these nodes has been developed at our institution and involves complete submission of all tissue with routine use of immunohistochemical staining for S-100 protein. By using this protocol, 838 sentinel lymph nodes from 357 patients have been examined, and metastases were found in 16% of patients. Although the metastasis was clearly seen on sections stained with hematoxylin and eosin in 55% of the positive patients, the immunostain showed metastatic disease not appreciable on initial hematoxylin and eosin screening in an additional 28 lymph nodes (45% of node-positive patients). Intraoperative touch preparation cytology may be used as an adjunct technique in sentinel lymph nodes grossly suspicious for metastatic disease. This technique has been performed on 23 sentinel lymph nodes, with no false positives and an overall sensitivity of 62%. The thorough pathologic evaluation of sentinel lymph nodes in patients with malignant melanoma requires complete submission of all tissue, routine use of immunohistochemistry, and touch preparation cytology in selected cases.

Intralesional bleomycin-mediated electrochemotherapy in 20 patients with basal cell carcinoma☆☆☆★

BACKGROUND A new anticancer therapy, electrochemotherapy (ECT), has been introduced that entails exposing cancerous tissues to short pulses of electricity during chemotherapy. This enhances cell membrane permeability and has been shown to have potent antitumor effects in vitro in animal models and in several clinical trials, including nevoid basal cell carcinoma (BCC). OBJECTIVE We report the effects of ECT on 20 patients with primary BCC. METHODS Electrical pulses were delivered to 54 tumors after administration of intralesional bleomycin sulfate. RESULTS Complete responses were observed in 53 (98%), and in the majority of these (94%) after a single treatment. No recurrences have been recorded with a mean of 18 months of observation. CONCLUSION Although these are preliminary results, ECT appears to be an effective alternative to surgical excision for the treatment of primary BCC.

The Use of Intraoperative Radiolymphoscintigraphy for Sentinel Node Biopsy in Patients with Malignant Melanoma

background Selective lymphadenectomy or “sentinel node” biopsy Ms been introduced recently by Morton and colleagues (Arch Surg 1992;127:392–9) to stage patients with intermediate and thick malignant melanomas. It has proven to be an effective way to identify nodal basins at risk for metastasis without the morbidity of a complete lymph node dissection. The majority of biopsies can be performed under local anesthesia with small incisions, but technical difficulties occasionally result in unsuccessful explorations. Identification of the sentinel node can be enhanced by a intraoperative radiolymphoscintigraphy, a technique introduced Alex and Krag (Surg Oncol 1993;137–43) tint uses radiolabeled sulfur colloid and a hand‐held gamma probe. objective We used intraoperative radiolymphoscintigraphy in conjunction with 1% lymphazurin blue dye to define the sentinel node(s) in 148 patients with greater than 0.76 mm in thickness or Clark level TV melanomas. Sentinel lymph nodes were isolated, harvested, and examined using conventional histopathology, and immunohistochemistry for S‐100 and HMB‐45 antibodies. results The overall success rate of sentinel lymph node localization was 97% using a combination of the two techniques. Twenty‐one (34%) patients had micrometastasis, and 17 of these subsequently underwent complete lymph node dissection. A total of 220 of 275 (80%) sentinel nodes harvested were radioactive or “hot” compared with 165 of 275 (60%) with the blue dye alone. Four of the patients with micrometastasis had sentinel nodes positive by gamma probe, but negative by blue dye mapping techniques. conclusion Our results suggest that intraoperative radiolymphosintigraphy using a hand‐held gamma detecting probe improves the identification of sentinel lymph nodes during selective lymphadenectomy. This may reduce the number of “unsuccessful explorations” using the vital blue dye technique for lymphatic mapping, and appeal to a greater variety of surgeons, including dermatologic surgeons.

Histologic variants of squamous cell carcinoma of the skin.

Squamous cell carcinoma (SCC) is the second most common type of skin cancer, with basal cell carcinoma being the most common. However, some argue that an actinic keratosis should be considered as an SCC that is superficial.1 If so, then SCC could be considered the most common type of skin cancer. The tumor typically appears as a papule or nodule, with varying degrees of hyperkeratosis and ulceration that arises on the sun-exposed skin of elderly patients (Fig 1). The disease has been linked to immunosuppression, arsenic exposure, radiation, chronic ulceration, and human papillomavirus (HPV) infection.2 The histology reveals a proliferation of atypical keratinocytes that invade the dermis, with areas of detachment from the overlying epidermis. These anastomosing growths of cords and nests are composed of cells that have a glassy eosinophilic cytoplasm and enlarged nuclei. Mitotic figures, keratin pearls, and dyskeratotic keratinocytes are variably present. On higher power, intercellular bridges may be seen.

Accurate Nodal Staging of Malignant Melanoma.

The incidence of malignant melanoma is increasing at a faster pace than that of any other cancer in the United States. It is estimated that people born in the year 2000 will have a 1:75 risk of developing melanoma sometime during his or her lifetime. Stimulated by novel lymphatic mapping techniques, the surgical care of the melanoma patient is evolving toward more conservative resections that can provide the same staging information but without the added morbidity of more radical surgeries. This approach promises to yield positive results in the age of health care reform, outcome measurements, and cost:benefit considerations.

Measures of cutaneous human papillomavirus infection in normal tissues as biomarkers of HPV in corresponding nonmelanoma skin cancers

Cutaneous human papillomavirus (HPV) may be associated with the development of nonmelanoma skin cancer (NMSC), as suggested by reports of HPV DNA in NMSC tumors. HPV has also been investigated as an NMSC risk factor in epidemiologic studies, although findings vary across studies that used different biomarkers of HPV infection in normal tissues. To identify appropriate biomarkers for use in future epidemiologic studies, we conducted a sampling validation study. NMSC tumor tissue was obtained from 20 patients with pathology‐confirmed basal or squamous cell carcinoma of the skin, in addition to several normal tissues, including eyebrow hairs, normal skin swabs obtained using multiple techniques, normal skin punch and shave biopsies, and serum for antibody measurement. Presence of cutaneous HPV DNA in tissues was measured with multiplex PCR using HPV type‐specific primers and array primer extension (APEX) for HPV typing. Antibody detection was based on glutathione‐S‐transferase capture ELISA in combination with fluorescent bead technology. Using HPV DNA in tumor tissues as a gold standard, sensitivity and specificity were calculated for each measure of HPV infection in normal tissues. β‐Papillomavirus DNA was observed in tumor tissues in 60% of patients. The normal skin punch biopsy demonstrated optimal sensitivity (75%) and specificity (75%). Biomarkers obtained using less‐invasive techniques demonstrated poor specificity when considered individually, although specificity improved when biomarkers were combined. Based on the current case series, the combinations of antibodies+eyebrow hairs or antibodies+eyebrow hairs+Dacron swabs are the optimal, minimally invasive markers of cutaneous HPV infection for use in epidemiologic studies.

Rapid frozen section immunostaining of melanocytes by microphthalmia-associated transcription factor.

Mohs micrographic surgery (MMS) has increasingly become an accepted therapy for melanoma in situ on chronically sun damaged skin (CSDS). However, melanocytes are difficult to locate in frozen material on hematoxylin and eosin. In addition, determining the cut-off between the melanoma and the “atypical melanocytic hyperplasia” in CSDS can be challenging in frozen or formalin-fixed paraffin-embedded sections, with or without immunohistochemistry (IHC). In this article, we report the use of a rapid, 35-minute protocol using microphthalmia-associated transcription factor (MITF) IHC for identifying melanocytes in frozen tissue for its potential use in MMS. In contrast to melanoma antigen recognized by T cells (MART-1), MITF is a nuclear stain, which simplifies identification of melanocytes and quantification of melanocytic parameters. In this study, MITF IHC in frozen sections yielded equivalent melanocyte nuclear diameter and density measurements compared with formalin-fixed paraffin-embedded sections. Nuclear diameter measurements obtained with MITF were similar to that previously reported with MART-1, but the melanocyte density figures were lower. Reliable labeling of melanocytes in frozen sections required the use of diaminobenzidine (DAB) chromogen with Giemsa counterstaining and a buffer devoid of surfactant. Our experience with MITF IHC indicates that it is a dependable immunostain in frozen sections, and may prove to be useful in MMS as an adjunct to hematoxylin and eosin and MART-1 IHC for interpretation of margins for melanoma in situ on CSDS.

Multiple keratoacanthomas arising in the setting of sorafenib therapy: novel chemoprophylaxis with bexarotene.

Address correspondence to Basil S. Cherpelis, MD, Department of Dermatology, University of South Florida, 12901 Bruce B. Downs Boulevard, MDC 79, Tampa, FL 33612. E-mail: bcherpel@hsc.usf.edu as two cycles of paclitaxel and carboplatin chemotherapy and four cycles of docetaxel and carboplatin. Subsequently, her serum CA-125 level returned to normal, indicating remission of the cancer. However, 5 months after completing chemotherapy, her serum CA-125 level again elevated to 95 from a nadir of 5, indicating that cancer had returned. A PET/CT scan confirmed multiple hypermetabolic peritoneal masses as well as right inguinal nodal activity. An excisional biopsy was performed on the right inguinal node, and histology disclosed metastatic adenocarcinoma. The patient was referred to our institute for consideration of a clinical trial. In late 2007, she began a clinical trial using a combination of carboplatin, paclitaxel, and sorafenib. The patient continued her monthly follow-up meetings in the Gynecologic Oncology Program. Three months after beginning treatment with carboplatin, tamoxifen, and sorafenib, she reported a rapidly enlarging, non-healing erythematous papule on her left nares and presented to dermatology for evaluation. By this time, she had developed a similar lesion on the left leg (Fig 1). Histologic examination of these lesions revealed well-demarcated crateriform squamous proliferations with a central keratin plug consistent with kerIntroduction Sorafenib is a novel antineoplastic drug that targets multiple intracellular and cell-surface kinases, inhibiting tumor cell proliferation and angiogenesis. While it is currently approved to treat metastatic or unresectable renal cell or hepatocellular carcinoma, studies are underway to evaluate its utility in other solid organ tumors. We present a case of a 61-year-old woman with metastatic ovarian cancer and no history of skin cancer who developed multiple keratoacanthomas while on a clinical trial using sorafenib. Surgical excision was performed palliatively for large and symptomatic lesions. Because of the patient’s terminal condition and unwillingness to undergo multiple surgical procedures, we instituted chemoprophylaxis with oral bexarotene. After two months of therapy, the patient has reported partial regression of some of the tumors and has not developed any new lesions. This is the second known report of multiple keratoacanthomas arising in the setting of sorafenib therapy.1 In addition, this is the first known report of using bexarotene for chemoprophylaxis or treatment of keratoacanthomas.