Amanda Phelps

CD10-positive blastoid mantle cell lymphoma with secondary cutaneous involvement

To the Editor, Mantle cell lymphoma (MCL) comprises 3–10% of all non-Hodgkin lymphoma subtypes and usually pursues an aggressive clinical course.1– 4 Skin involvement is found in 2–6% of patients. Classical MCL (constituting the majority of cases) shows a monotonous proliferation of smallto mediumsized centrocyte-like lymphoid cells with slightly irregular nuclear contours, low mitotic index and expression of pan B-cell antigens and CD5 but not CD23 or bcl-6. The hallmark of MCL is the t(11;14)(q13;q32)/CCND1-IGH translocation, resulting in aberrant expression of the CCND1 gene and expression of cyclin D1 protein by tumor cells.1– 4 The vast majority of cases are negative for CD10 protein expression.1– 5 In concert with the typical chromosomal translocation and other immunophenotypic findings, the absence of CD10 reactivity is commonly used to distinguish MCL from other subtypes of B-cell lymphoma. The blastoid variant of MCL develops in 10–30% of patients with classical MCL and likely represents transformation of the original clone.1– 4 Blastoid MCL may be cytologically indistinguishable from other high-grade B-cell lymphomas, in particular lymphoblastic lymphoma.4 There are rare reports of cutaneous involvement by blastoid MCL, with most examples representing secondary involvement of the skin by underlying widespread systemic disease.1– 4 A 71-year-old man presented to his dermatologist with rapidly growing papules of recent onset on his right cheek (Fig. 1). The patient had a history of classical MCL of the left tonsil 5 years before with multiple subsequent recurrences involving the base of the tongue, but no evidence of oral disease at present. A skin punch biopsy Fig. 1. Rapidly growing papules of recent onset are noted on the right cheek.

Molluscum contagiosum virus infection in benign cutaneous epithelial cystic lesions-report of 2 cases with different pathogenesis?

To the Editor: The coexistence of molluscum contagiosum virus (MCV) infection in an epidermal inclusion cyst is rarely described. We report 2 additional cases of MCV infection in benign cutaneous epithelial cystic lesions with different histopathologic features. The possible different pathogenesis of these cystic skin lesions with regard to MCV infection is discussed. Case 1 is a 51-year-old woman presented to her dermatologist with a flesh-colored papule (approximately 0.7 cm in diameter) on her left upper posterior thigh. A small central ostium was noted. The lesion was present for approximately 2 months but was asymptomatic. The patient had no known history or evidence at presentation of MCV lesions on the skin surface. The preliminary clinical diagnosis was of an epidermal inclusion cyst (EIC). A shave excision of the lesion was performed. The specimen was routinely formalin fixed, paraffin embedded and entirely sectioned with 5-mM sections stained with hematoxylin and eosin (H+E) for histopathologic review. H+E-stained sections revealed a small unilocular cyst with scattered foci of eosinophilic inclusion bodies within the cyst wall, consistent with MCV cytopathic changes. The intervening cyst wall showed an intact granular layer with overlying cornified cells in a laminated and basket weave pattern (Fig. 1). Case 2 is a 32-year-old man presented to his dermatologist with

Nodular localized primary cutaneous amyloidosis: a bullous variant

Primary cutaneous amyloidosis describes a group of disorders in which amyloid is deposited in the skin without evidence of systemic involvement. Nodular localized primary cutaneous amyloidosis (NLPCA) is a rare form of these skin‐restricted amyloidoses. We present an unusual case of NLPCA in a 51‐year‐old man, who had clinical and histopathological evidence of subepidermal bullous formation, a unique feature in NLPCA. The possible pathogenesis of this change is discussed.

Molecular diagnostic strategies: a role in the practice of dermatology

Molecular diagnostic strategies are gaining wider acceptance and use in dermatology and dermatopathology as more practitioners in this field develop an understanding of the principles and applications of genomic technologies. Molecular testing is facilitating more accurate diagnosis, staging, and prognostication, in addition to guiding the selection of appropriate treatment, monitoring of therapy, and identification of novel therapeutic targets, for a wide variety of skin diseases.

Pigmented classic poroma: a tumor with a predilection for nonacral sites?

To the Editor, Classic poromas (CPs) are relatively common benign adnexal neoplasms that are typically located on the palms and soles, although other cutaneous sites can be affected. CPs are usually nonpigmented, but lesional pigmentation can occasionally be seen. A 66-year-old man presented with a crusted pigmented nodule on his left forearm. The clinical impression was concerning for nodular melanoma and an excisional biopsy was performed. Histopathological review revealed broad anastomosing cords and lobules of small monomorphous-appearing polygonal epithelial cells extending from the epidermis into the subjacent dermis (Fig. 1A and B). Duct formation with focal cystic degeneration was present centrally. Prominent melanin deposition, confirmed by Fontana-Masson staining, was

Blastoid mantle cell lymphoma with cutaneous involvement and aberrant immunophenotype.

1. Rongioletti F, Gallo R, Cozzani E, et al. Leprosy: a diagnostic trap for dermatopathologists in nonendemic area. Am J Dermatopathol. 2009;31:607–610. 2. World Health Organization. Global leprosy situation, 2009. Wkly Epidemiol Rec. 2009;84: 333–340. 3. Jolliffe DS. Leprosy reactional states and their treatment. Br J Dermatol. 1977;97:345–352. 4. Gomes JG, Penna GO, Castro LCM, et al. Erythema nodosum leprosum: clinical and therapeutic update. An Bras Dermatol. 2002;4:389– 407. 5. Lopez C, Oliver M, Olavarria R, et al. KikuchiFujimoto necrotizing lymphadenitis associated with cutaneous lupus erythematosus: a case report. Am J Dermatopathol. 2000;22:328–333. 6. Toll A, Gilaberte M, Matias-Guiu X, et al. Kikuchi’s disease (necrotizing lymphadenitis) with cutaneous involvement associated with subacute cutaneous lupus erythematosus. Clin Exp Dermatol. 2004;29:240–243. 7. Yen A, Fearneyhough P, Raimer SS, et al. EBV-associated Kikuchi’s histiocytic necrotizing lymphadenitis with cutaneous manifestations. J Am Acad Dermatol. 1997;36:342–346.

Surgical Management of Melanoma: Concept of Field Cancerization and Molecular Evaluation of Tissue Margins

The concept of field cancerization, first proposed by Slaughter in 1953, describes a process whereby cells in a particular tissue or organ are sequentially transformed by multiple cumulative genetic and epigenetic alterations, such that a clonal expansion of pre-neoplastic genetically-altered, but morphologically normal-appearing cells is present, prior to the development of overt malignancy. Additional genomic aberrations are required for cancer development, but these precursor cells may persist with the malignant cells of a tumor.

Hypoxia‐induced response of cell cycle and apoptosis regulators in melanoma

regulators in melanoma Hypoxia is a characteristic feature of solid tumors and results from inadequate vascularization and/or an imbalance between oxygen supply and demand within the tumor microenvironment. It is associated with poor prognosis in non-melanoma human cancers and promotes tumor resistance to ionizing radiation, chemotherapy, and immunotherapy. Recent evidence suggests that pharmacological modulation of proteins associated with the hypoxic response may have potential in the treatment of human tumors. The identification of hypoxiainducible factor (HIF), a major transcription factor family activated by hypoxia, has significantly enhanced our knowledge of the molecular aspects of the hypoxic response. In addition to HIF, other signaling pathways (i.e. mTOR and UPR) and transcription factors are activated by exposure to reduced oxygen. These hypoxiaresponsive factors integrate with other cellular pathways, such as chromatin remodeling, microRNA induction, translation regulation, and protein expression and modification, and thereby contribute to the coordinated cellular response observed following hypoxic stress. Hypoxia is known to regulate angiogenesis-associated proteins, metastasis-promoting proteins, metabolic enzymes, transcription factors, and apoptosis and cell cycle-regulating proteins. The genetic changes associated with hypoxia may select for tumor cells that can both modify their proliferative capacity (i.e. cell cycle) and withstand hypoxiainduced apoptosis and thus promote the development of more clinically aggressive tumors. Many aspects of gene regulation by hypoxia are celltype specific. Although common cellular functions are modulated by hypoxia, there are significant differences in hypoxia-induced gene expression profiles within and between different tumors. The highly dynamic intratumoral microenvironment can demonstrate many forms of hypoxia, which vary in severity and/or duration. As a consequence, the cellular response to hypoxia can show significant heterogeneity, and subpopulations of hypoxic tumor cells may activate different hypoxic response pathways at different times. While it has been extensively studied in many other cancer types, the mechanisms of hypoxia-mediated tumor survival and progression in melanoma are largely unexplored. The A2058 (BRAF) melanoma cell line was cultured under normoxic (21% O2) and hypoxic (1% O2) conditions for up to 48 hours. Cells were grown at £70% confluence and cell viability was maintained. At both 24and 48-hour culture, total RNA was extracted from both normoxic and hypoxic cells, transcribed into cDNA, differentially labeled, and co-hybridized with a customized cDNA microarray (GEArray Human Apoptosis and Cell Cycle Gene cDNA Microarray; SABiosciences, Frederick, MO, USA; Fig. 1). This cDNA expression array contains 267 human cDNA fragments from genes associated with apoptosis and the cell cycle. Gene expression was measured by chemiluminescent detection and normalized against housekeeping genes on the microarray. Data were filtered for genes whose expression level increased or decreased by at least two-fold (i.e. ‡2.0 or £0.5). To validate the accuracy of the microarray results, a number of differentially expressed genes were further analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR). All samples were run in triplicate. At 24-hour culture, a total of 41 genes were found to be upregulated and five genes were downregulated, as a function of hypoxia (Table 1). At 48-hour culture, only 12 genes were upregulated, while 92 genes showed downregulation by hypoxia (Table 1). Interestingly, 11 genes maintained upregulation at both 24-hour and 48-hour hypoxic culture (Table 1); these included Cyclin G2, Nip3, TIMP3, Rank, DR3/Apo3, TNFRSF17, 4-1BB, TRAIL, and CD40L (CD154/TRAP), in addition to IL-8

Inflammatory Disorders of the Skin

Inflammatory disorders of the skin, including eczematous, psoriasiform, lichenoid-interface, xadautoimmune, and neutrophilic dermatoses, probably represent the group of cutaneous diseases in which molecular pathology currently has the least impact in daily clinical practice. Many of these diseases are readily diagnosed through the correlation of clinical features with histopathological findings on hematoxylin and eosin (H + E)-stained tissue sections. In general, microscopic pattern analysis offers a very useful and reliable method to diagnose inflammatory skin diseases. The application of additional histochemical stains, immunohistochemistry, and/or immunofluorescence analysis is occasionally required. However, in some instances, diagnostic difficulties do arise. For example, the clinical and/or microscopic distinction of allergic contact dermatitis (ACD) from irritant contact dermatitis (ICD), pompholyx (dyshidrotic eczema) from pustular psoriasis, and even classic chronic psoriasis from chronic atopic dermatitis (AD) may be challenging. Although chronic psoriasis and AD show distinct differences with respect to cytokine milieu (i.e., Th1 in AD vs. Th2 in psoriasis), bacterial superinfection, surface pH, transepidermal water loss and itch, it is well known that these disorders share many morphological and molecular features [1, 2]. For example, from a dermatopathologist’s perspective, the lesional skin of both conditions can xaddemonstrate the presence of T-cell and CD1a+/CD11c+ dendritic cell infiltrates associated with hyperplasia/altered differentiation of keratinocytes [1, 2]. In addition, cutaneous T-cell dyscrasias (i.e., lymphomas) can occasionally masquerade, both clinically and histopathologically, as inflammatory dermatoses (i.e., cutaneous lupus erythematosus) [3–5].

Letter to the Editor regarding proteomic strategies and biomarker identification in melanoma.

We read with great interest the recent article by Bougnoux and Solassol [1] on the contribution of proteomics to the identification of biomarkers for cutaneous malignant melanoma. The authors provided an updated overview of the biomarkers identified in melanoma through serum, cell lines, and tissue proteomic analysis [1]. However, their description of biomarker research in tissue samples is incompletely referenced and inadequately discussed, being limited to only two of a number of important studies from the scientific literature [1]. Melanoma tissue samples are a potentially valuable resource for both retrospective and prospective protein biomarker discovery studies, as they are widely available in pathology laboratories and linked to a wealth of clinical data, including patient outcomes and/or response to treatment. Proteomic studies of melanoma, and in particular of solid tumor/tissue samples, are indeed both relatively recent and limited [2]. However, the development of novel methods to efficiently extract cross-linked peptides has overcome themajor challenge for mass spectrometry (MS)-based strategies in formalin-fixed paraffin-embedded (FFPE) tissue [2]. In addition to the two studies cited by Bougnoux and Solassol [1], five other MS-based investigations to identify potential protein biomarkers have been accomplished on solid tumor samples from patients withmelanoma [2–6]. Some researchers, including ourselves, have used an integrated MS and immunohistochemistry-based method: (1) to confirm the validity of this approach, by documenting the presence of previously knownmelanoma-related proteins; (2) to identify novel proteins expressed in melanoma; and (3) to correlate the MS-discovery of proteins with their tissue distribution (i.e., tumor cells vs. stroma) and intracellular localization in tumor samples [2,4,6].