Ana Ciurea

Applying the new TNM classification system for primary cutaneous lymphomas other than mycosis fungoides and Sézary syndrome in primary cutaneous marginal zone lymphoma

BACKGROUND Primary cutaneous marginal zone lymphoma is recognized as a unique subset of low-grade cutaneous B-cell lymphoma with indolent course in the current World Health Organization-European Organization on Research and Treatment of Cancer classification system. However, few large series on this entity have been reported, including the new TNM (tumor, (lymph) node, metastasis) classification for non-mycosis fungoides cutaneous lymphomas. OBJECTIVE We aimed to characterize the clinical features including new TNM classification for non-mycosis fungoides cutaneous lymphomas, as well as outcomes and responses to therapy in 30 patients with primary cutaneous marginal zone lymphoma. RESULTS Primary cutaneous marginal zone lymphoma typically presents with deep-seated nodular or papular lesions on the upper extremities or trunk (25/30). Disease course is indolent and none of 30 patients died of disease. Sustainable complete remissions were obtained only in patients with T1a (n = 3) and T2a (n = 1) disease. Most patients have persistent stable disease independent of treatment. Two patients developed systemic disease and 5 developed large cell transformation. LIMITATIONS The average follow-up time was 63 months (range, 3-204 months). Longer follow-up time is needed to determine whether patients with untreated persistent stable disease are at greater risk relative to patients treated aggressively early in the disease course. CONCLUSIONS Primary cutaneous marginal zone lymphoma is a distinct subtype of marginal zone lymphoma with an indolent disease course. Patients with T1a or T2a disease (ie, single lesions or a localized cluster of lesions) may achieve sustained complete remission, whereas patients with multiple nonlocalized lesions are unlikely to maintain complete remission independent of treatment modality. Systemic involvement is typically preceded by large cell transformation and may be an indication for more systemic therapy. Death from disease is rare.

Case of vemurafenib-induced Sweet's syndrome

Vemurafenib is a targeted therapy that has become standard treatment for patients with advanced melanoma with a V600E BRAF mutation. It has been associated with frequent skin toxicity, including photosensitivity, rash and squamous cell carcinomas. We present an 83‐year‐old woman with an advanced V600E BRAF‐mutant melanoma who developed a severe skin rash and fatigue after taking vemurafenib. The dose was reduced from 960 to 720 to 480 mg twice a day; however, she was subsequently admitted to the hospital with fever, chills, fatigue, confusion and a diffuse skin eruption. She then developed hypoxia and acute renal failure that required hemodialysis. A biopsy of her skin lesions revealed a neutrophilic dermatitis with papillary dermal edema, consistent with Sweets syndrome. Her symptoms resolved upon discontinuation of vemurafenib and treatment with prednisone. This constellation of symptoms and clinical course are consistent with drug‐induced Sweets syndrome caused by vemurafenib.

Sorafenib Suppresses JNK-Dependent Apoptosis through Inhibition of ZAK

Sorafenib is U.S. Food and Drug Adminstration–approved for the treatment of renal cell carcinoma and hepatocellular carcinoma and has been combined with numerous other targeted therapies and chemotherapies in the treatment of many cancers. Unfortunately, as with other RAF inhibitors, patients treated with sorafenib have a 5% to 10% rate of developing cutaneous squamous cell carcinoma (cSCC)/keratoacanthomas. Paradoxical activation of extracellular signal–regulated kinase (ERK) in BRAF wild-type cells has been implicated in RAF inhibitor–induced cSCC. Here, we report that sorafenib suppresses UV-induced apoptosis specifically by inhibiting c-jun–NH2–kinase (JNK) activation through the off-target inhibition of leucine zipper and sterile alpha motif–containing kinase (ZAK). Our results implicate suppression of JNK signaling, independent of the ERK pathway, as an additional mechanism of adverse effects of sorafenib. This has broad implications for combination therapies using sorafenib with other modalities that induce apoptosis. Mol Cancer Ther; 13(1); 221–9. ©2013 AACR.

BRAF inhibitor therapy-associated melanocytic lesions lack the BRAF V600E mutation and show increased levels of cyclin D1 expression

Newly appearing or changing melanocytic lesions (MLs) are a recently reported toxicity of BRAF inhibitor (BRAFi) therapy. Morphologically, MLs associated with BRAFi therapy (BRAFi-MLs) may demonstrate alarming features of melanoma with an epithelioid cell phenotype with notable cytologic atypia. We sought to characterize the clinicopathological and molecular features of BRAFi-MLs. A retrospective review over a 4-year period revealed 20 patients in which 44 MLs (including 11 control nevi) were characterized by histopathology, review of clinical medical records, and immunohistochemical (IHC) studies (with anti-BRAF V600E, anti-BAP1, anti-cyclin D1, and anti-p16); the percentage of IHC+ cells was scored. Of the 20 patients, 3 (15%) whose BRAFi-MLs were biopsied had a second primary cutaneous melanoma. Of the 44 BRAFi-MLs tested, 37 (100%) of 37 MLs available for BRAF V600E testing lacked expression in contrast to 1 (9%) of 11 control nevi (lesions not associated with targeted therapy). A significantly higher level of cyclin D1 expression (>50% IHC+ cells) was more commonly seen in BRAFi-MLs (44%) than in control nevi (9%). No difference in p16 expression in melanocytes was seen between the 2 groups. BRAF mutation status distinctly differs between BRAFi-MLs from melanomas and nevi biopsied in patients who do not receive BRAFi therapy. Morphologically, BRAFi-MLs demonstrate a greater degree of atypia than do control nevi. Furthermore, BRAFi-MLs with coexisting cutaneous keratinocyte toxicity developed during fewer days of targeted therapy. Paradoxical activation of the MAPK pathway in BRAF(WT) melanocytes may account for ~15% to 21% of patients developing a second new primary melanoma within a year of starting BRAFi therapy; thus, close clinical surveillance is warranted.

Eruptive squamous cell carcinomas after vemurafenib therapy.

Background: Vemurafenib is an oral BRAF inhibitor recently approved for the treatment of metastatic melanoma. Patients treated with this medication have been reported to have the occurrence of squamous cell carcinoma (SCC) and/or actinic keratosis (AK). Objective: We report the case of a patient treated with vemurafenib for papillary thyroid carcinoma who subsequently developed multiple SCCs and AK of the skin. The lesions were deemed related to the medication and treated with excision. In addition, subsequent development of SCCs and AK was successfully prevented with a combination of isotretinoin and 5-fluorouracil in this patient. We discuss postulated mechanisms for these findings, as well as potential preventive therapy with the aforementioned combination regimen in patients undergoing treatment with vemurafenib.

The diagnostic yield of skin biopsy in patients with leukemia and suspected infection

OBJECTIVE To determine the diagnostic yield of skin biopsy in patients with leukemia, new skin lesions, and suspected infection. METHODS We reviewed the medical records of all patients with leukemia who underwent skin biopsy for new lesions and clinical suspicion of infection over 4 years. Biopsy was considered to have changed the diagnosis, if the results differed from the prior leading clinical impression. RESULTS Seventy-six (39%) of 195 patients had infections identified via skin biopsy. Among the remaining patients, the most common diagnoses were leukemia cutis, drug reactions and Sweets syndrome. Ulcerated or necrotic lesions and bacteremia or fungemia were the only independent predictors of infection. 55% of patients with severe neutropenia had biopsy-proven infectious causes of their skin lesions. One third of all afebrile patients had skin manifestations owing to infection. Skin biopsy results differed from the initial clinical impression in 34% of all patients. In 45% of infected patients, pathogens were identified by skin biopsy alone. CONCLUSIONS Noninfectious causes accounted for a large proportion of new skin lesions in leukemia patients with suspected infections. Absence of neutropenia or fever did not rule out infection. Ulcerated or necrotic lesions and bacteremia or fungemia were independent predictors of infection. In the evaluation of patients with leukemia and new skin lesions, skin biopsy remains an important procedure to rule out infection, and is particularly useful for pathogen identification.

In Situ Photoimmunotherapy: A Surgery- and Limb-Sparing Approach to the Treatment of Cutaneous Metastases in Advanced Melanoma

Stephanie A. St Pierre, MD; Jennee Rommel, MD; Ana Ciurea, MD; Douglas Fife, MD; Simon S. Yoo, MD; Mary Martini, MD; Timothy M. Kuzel, MD; Jeffrey Wayne, MD; Alfred Rademaker, PhD; Dennis P. West, PhD; Murad Alam, MD; Department of Dermatology (Drs St Pierre, Yoo, Martini, and West) and Robert H. Lurie Comprehensive Cancer Center (Drs Yoo, Martini, Kuzel, Wayne, Rademaker, West, and Alam), Northwestern University Feinberg School of Medicine, Chicago, Illinois; Department of Dermatology and Department of Medicine, Washington Hospital Center, Washington, DC (Dr Rommel); Department of Dermatology, MD Anderson Cancer Center, Houston, Texas (Dr Ciurea); Surgical Dermatology and Laser Center, Las Vegas, Nevada (Dr Fife); and Division of Hematology-Oncology (Dr Kuzel), Division of Surgical Oncology (Dr Wayne), and Department of Preventive Medicine (Dr Rademaker) and Dermatology (Dr Alam), Northwestern University, Chicago

Dermatologic Toxicities to Melanoma Targeted Therapies

The development of targeted therapeutic agents has revolutionized the medical treatment of melanoma. Compared to chemotherapy, patients treated with targeted therapy benefit from reduction in tumor burden and improved overall survival.

Epidemiology and Clinical Characteristics of Melanoma

Melanoma represents a significant and growing health problem throughout the world. Global incidence is approximately 160,000 new cases per year, with 48,000 deaths. According to the Centers for Disease Control and Prevention, the rates of melanoma have doubled in the United States in the past 30 years. Melanoma is now the fifth most common cancer among men and the sixth most common cancer in women in the United States. Among people under age 50, women are about 30 % more likely than men to develop the disease. By contrast, among people aged 50 and older, men are nearly twice as likely as women to develop melanoma, and by age 60, men are nearly three times more likely to develop melanoma. The annual incidence of melanoma among whites has increased by more than 70 % over the past two decades. Increases have been most rapid among whites aged 60 and older.

A slowly growing plaque on the lower back: Answer

MICROSCOPIC FINDINGS The overlying epidermis showed mild elongation and irregular widening of the rete ridges. An interstitial proliferation of spindle cells, extensively involving the dermis and superficial subcutaneous tissue was observed. Some of these cells were seen surrounding the inferior segments of hair follicles and adjacent eccrine sweat glands. The intervening stroma was collagenous and fibrillary. At high power, the spindle cells showed a scanty pale cytoplasm and elongated wavy nuclei. There were no evident nuclear pleomorphism, mitotic figures, or necrosis. Some of the cells contained finely distributed intracytoplasmic melanin granules. Immunohistochemical studies showed that most of the spindle cells strongly expressed S-100 protein and MART1 but only some of them reacted with HMB-45. Scattered cells within the proliferation expressed CD34. There was no significant expression of Smooth muscle actin, FXIIIa, or CD163 (dermal dendrocytes). The expression of melanocytic markers [S-100 protein, MART1, and gp100 (with HMB-45)] supported the diagnosis of a melanocytic lesion. The pattern of growth as fascicles within the dermis was consistent with a congenital origin or a neurocristic hamartoma. The later diagnosis was favored based on the lack of a junctional component, lack of evident pigmentation, and almost complete absence of epithelioid melanocytes. Focal expression of CD34 along with the lack of FXIIIa, CD163, or SMA expression ruled out the diagnoses of dermatofibrosarcoma protuberans (CD34), dermatofibroma (usually positive for FXIIIa and CD163), and a smooth muscle tumor (SMA-positive). DISCUSSION Neurocristic cutaneous hamartoma (NCH) is an extremely rare lesion that involves the skin and subcutaneous tissue resulting from the aberrant development of pluripotential neural crest cells as they migrate through the dermis during embryogenesis. Because neural crest cells migrate and differentiate either into melanocytes or into supportive cells of the peripheral nervous system, cutaneous NCH may display a combination of melanocytes, spindle cells, pigmented dendritic cells, and Schwann-like cells. Clinically, NCH usually presents as a brown, blue, or black keratotic macule, papule, or nodule of 3–10 cm in diameter, most often located on the scalp and back. Involvement of the scalp may result in an alopecic plaque. The majority of NCHs reported are congenital lesions, although in some instances the lesions may be acquired and probably arise from local stem cells. Histologically, NCH is a deep dermal and subcutaneous lesion composed of a variable admixture of melanocytic, neurosustentacular, and neuromesenchymal cells with different degrees of differentiation. The lesion may often show a decreased number of hair follicles. The melanocytic component originates subepidermally without a junctional component and is usually characterized by collections of melanin-rich, epithelioid, and fusiform melanocytes, which resemble a conventional intradermal nevus or cellular blue nevus. Sometimes, the cells show propensity to involve the inferior segments of the hair follicle and adjacent sweat glands besides blood vessels and nerves. Areas of schwannian differentiation may be prominent, sometimes resembling Meissner tactoid bodies and floret-like giant cells. These also express S-100 protein and Leu 7 antigen but are negative with HMB-45. The fibrogenic component is represented by a variable proliferation of CD34 mesenchymal cells. In some cases, the melanocytes may not be numerous or may be absent and schwannian and fibrogenic cells may be the principal component. The differential diagnosis should include other dermal melanocytic lesions, such as congenital nevus, the so-called plaque-like blue nevus, and melanoma. In contrast with these disorders, NCHs are characteristically heterogeneous, with multiple areas showing different patterns. Congenital nevi may have areas of schwannian differentiation and, less commonly, mesenchymal differentiation; however, congenital nevi usually have a junctional component and well-formed Schwann cell tumors are usually absent. The plaque-like blue nevi have dermal melanocytes without a junctional component, and the majority of cells show positive labeling with both HMB-45 and anti-S-100 protein; however, they do not express CD34, From the *Department of Dermatology, Hospital del Mar, Universitat Autònoma de Barcelona, Barcelona, Spain; and Departments of †Pathology; and ‡Dermatology, University of Texas, MD Anderson Cancer Center, Houston, TX. The authors declare no conflicts of interest. Reprints: Eduardo Rozas-Muñoz, MD, Department of Dermatology, Hospital del Mar, IMAS, Passeig Marı́tim 25-29, 08003 Barcelona, Spain (e-mail: docrozas@yahoo.com). Copyright 2012 by Lippincott Williams & Wilkins