Beth S. Ruben

The Genetic Evolution of Melanoma from Precursor Lesions

BACKGROUND The pathogenic mutations in melanoma have been largely catalogued; however, the order of their occurrence is not known. METHODS We sequenced 293 cancer-relevant genes in 150 areas of 37 primary melanomas and their adjacent precursor lesions. The histopathological spectrum of these areas included unequivocally benign lesions, intermediate lesions, and intraepidermal or invasive melanomas. RESULTS Precursor lesions were initiated by mutations of genes that are known to activate the mitogen-activated protein kinase pathway. Unequivocally benign lesions harbored BRAF V600E mutations exclusively, whereas those categorized as intermediate were enriched for NRAS mutations and additional driver mutations. A total of 77% of areas of intermediate lesions and melanomas in situ harbored TERT promoter mutations, a finding that indicates that these mutations are selected at an unexpectedly early stage of the neoplastic progression. Biallelic inactivation of CDKN2A emerged exclusively in invasive melanomas. PTEN and TP53 mutations were found only in advanced primary melanomas. The point-mutation burden increased from benign through intermediate lesions to melanoma, with a strong signature of the effects of ultraviolet radiation detectable at all evolutionary stages. Copy-number alterations became prevalent only in invasive melanomas. Tumor heterogeneity became apparent in the form of genetically distinct subpopulations as melanomas progressed. CONCLUSIONS Our study defined the succession of genetic alterations during melanoma progression, showing distinct evolutionary trajectories for different melanoma subtypes. It identified an intermediate category of melanocytic neoplasia, characterized by the presence of more than one pathogenic genetic alteration and distinctive histopathological features. Finally, our study implicated ultraviolet radiation as a major factor in both the initiation and progression of melanoma. (Funded by the National Institutes of Health and others.).

Consensus on melanonychia nail plate dermoscopy

This statement, focused on melanonychia and nail plate dermoscopy, is intended to guide medical professionals working with melanonychia and to assist choosing appropriate management for melanonychia patients. The International Study Group on Melanonychia was founded in 2007 and currently has 30 members, including nail experts and dermatopathologists with special expertise in nails. The need for common definitions of nail plate dermoscopy was addressed during the Second Meeting of this Group held in February 2008. Prior to this meeting and to date (2010) there have been no evidence-based guidelines on the use of dermoscopy in the management of nail pigmentation.

Keratitis, ichthyosis, and deafness (KID) syndrome: A review of infectious and neoplastic complications

Keratitis, ichthyosis, and deafness (KID) syndrome is a rare genodermatosis associated with mutations in the connexin 26 gene. Although characterized by this clinical triad, KID syndrome predisposes to a heterogeneous spectrum of cutaneous manifestations and complications, both infectious and neoplastic in nature. Chronic mucocutaneous candidiasis and/or superinfection of skin lesions commonly occur and warrant aggressive therapeutic intervention. Benign neoplasms, namely trichilemmal tumors, have also been reported and can herald malignant growth and invasive disease. Squamous cell carcinoma of both mucosa and skin, especially acral sites, occurs in approximately 15% of patients. The pathogenesis of KID syndrome can be at least partially explained by the role of connexin 26 in intercellular communication and carcinogenesis, but the precise mechanism of disease remains unclear. Treatment strategies, which have ranged from antifungals and antibiotics to systemic retinoids, pose an ongoing challenge given the spectrum of disease. A review of the literature, with a particular focus on infection and malignancy associated with KID syndrome, and updates on the pathogenesis of disease, is discussed.

Calcium may preferentially deposit in areas of elastic tissue damage

BACKGROUND Cutaneous calcification is an acquired disorder whereby insoluble, amorphous calcium salts deposit in the skin. Classically, cutaneous calcification is categorized as metastatic, dystrophic, idiopathic, or iatrogenic. OBJECTIVE The purpose of this study was to further elucidate the underlying pathogenic mechanism for cutaneous calcification. METHODS Three cases of cutaneous calcification, including clinical characteristics and associated histopathology, were reviewed. Previous reports of cutaneous calcification were searched for in the published literature and included. RESULTS Calcium is distributed within areas of underlying tissue damage (ie, locus minoris resistentiae), and in our cases, occurred specifically at sites of chronic actinic damage and intravenous extravasation tissue injury. LIMITATIONS A small number of clinical cases and previously published reports were reviewed. CONCLUSION We hypothesize that cutaneous calcification may preferentially occur at anatomic sites where tissue integrity has been compromised (ie, locus minoris resistentiae). We suggest one potential mechanism: that cutaneous calcification occurs within dermis that contains damaged elastic fibers. Pseudoxanthoma elasticum may serve as a possible genetic disease model for this process.

Gnathostomiasis in a patient who frequently consumes sushi.

A 45-year-old woman presented for evaluation of a solitary pruritic nodule on the abdomen that suddenly appeared 3 weeks before. She was healthy without a significant medical history, travel history, exposures, medications, or pets. She reported that she consumed sushi at least weekly in the city of San Francisco. A punch biopsy revealed a superficial and deep perivascular and interstitial infiltrates consisting of lymphocytes, plasma cells, and many eosinophils. Most notably, there was a parasite centered in the reticular dermis with prominent lateral chords, a well-developed muscular esophagus, and an intestine that contained a brush border and multinucleate cells. Evaluation of these histological sections by the Centers for Disease Control and Prevention determined the parasite to be a nematode of the genus Gnathostoma. The patient underwent a systemic work-up for gnathostomiasis, including imaging, and no other abnormalities were found. She completed a 3-week course of albendazole and has remained asymptomatic since the biopsy of her abdominal lesion. Although gnathostomiasis is often a systemic illness, this patient did well with apparently only localized cutaneous disease. Gnathostomiasis should be considered in patients who present with nonspecific papules and nodules, especially when there is a history of frequent consumption of raw fish.

Isolated plantar collagenoma not associated with Proteus syndrome

Isolated plantar cerebriform collagenomas are a relatively rare type of connective tissue nevus. They have been suggested to be pathognomonic of Proteus syndrome. However, their presence is now considered to be a major criterion of Proteus syndrome, but the diagnosis of Proteus syndrome also requires the presence of other minor criteria. We present an unusual case of an acquired plantar cerebriform collagenoma, which is not associated with Proteus syndrome. Collagenomas, or connective tissue nevi of the collagen type, represent a hamartomatous overgrowth of normal collagen. Isolated plantar collagenoma is rare, and most commonly presents in childhood. We report an interesting case of an isolated plantar cerebriform collagenoma in an adult.

PUSTULAR PSORIASIS LIMITED TO THE PENIS

A 23-year-old white man, who was without medical problems and on no medications, presented with a pustular eruption on the penis that had been present intermittently for 2 years. He had been seen by several physicians in the past for this problem and had been diagnosed variously as having lichen nitidus or lichen planus. He reported improvement with topical application of hydrocortisone, triamcinolone, desonide, mometasone furoate, and a baking soda preparation. Past use of naftifine hydroehloride had no effect. He reported no other skin lesions. There was no personal or family history of skin disease. On physical examination, the patient was a healthy white man. He was uncircumcised. His glans penis and distal penile shaft demonstrated numerous scattered minute, white papules and pustules on an erythematous base (Fig. 1). There were no other skin or mucosal lesions present. Nails were normal, without pitting or onycholysis. A KOH examination and a fungal culture were negative. A chemistry panel, CBC, RPR, ESR, and urinalysis were normal. A 3 mm punch biopsy of a representative lesion was performed. The specimen showed psoriasiform hyperplasia with marked pallor, hypogranulosis, compact orthokeratosis, and subcorneal spongiform pustules. Telangiectasia and scattered lymphocytes were also seen. This was consistent with pustular psoriasis (Fig. 2). No fungal organisms were identified by staining with Gomoris methenamine silver or periodic acidSchiff reagents. Treatment with hydrocortisone, 1%, and coal tar 2%, resulted in little improvement. The patient then received oral itraconazole, 200 mg twice daily for 6 weeks, which resulted in some improvement. This latter treatment was directed towards possible candidal colonization, a potential triggering factor. In follow-up evaluation, physical examination revealed minute pustules on a base of erythema, but at other times there were erythematous, scaly papules.

Subungual blue nevus with combined phenotypic features

Blue nail dyschromia may represent melanocytic, vascular, or other etiologies. A case of a subungual blue nodule is presented, with a pseudo-clubbed nail. On histopathologic examination, there was a combined subungual blue nevus, with features of a common blue nevus and a pigmented epithelioid melanocytoma. This unusual presentation is reviewed, with a discussion of blue nail dyschromia and subungual blue nevi.

SOX-10 expression in cutaneous myoepitheliomas and mixed tumors.

SOX‐10 expression can be demonstrated by immunohistochemistry in salivary gland myoepitheliomas, but its expression in cutaneous myoepitheliomas and in cutaneous mixed tumors with prominent myoepithelial cells has not been studied.

IgM-λ paraproteinemia with associated cutaneous lymphoplasmacytic infiltrate in a patient who meets diagnostic criteria for POEMS syndrome

POEMS is a rare multisystem paraneoplastic syndrome featuring polyneuropathy, organomegaly, endocrinopathy, a monoclonal protein, and skin changes. In the relatively few reported biopsies of POEMS-associated cutaneous hyperpigmentation, the most common skin finding seen in patients with the disorder, only a non-specific inflammatory infiltrate has been demonstrated histologically. We present the case of a 79-year-old man with polyneuropathy, autoimmune thyroiditis, pancytopenia, and a history of lymphadenopathy who presented to the inpatient dermatology service with cutaneous hyperpigmentation. A skin biopsy of a hyperpigmented area showed a cutaneous lymphoplasmacytic infiltrate, prompting further investigation. A monoclonal IgM-lambda paraprotein was subsequently identified, leading to administration of combination chemotherapy for a diagnosis of POEMS syndrome. The novel finding of a lymphoplasmacytic infiltrate in POEMS-associated hyperpigmentation suggests a diagnostic role for skin biopsy in these patients.