Imaging mass spectrometry assists in the classification of diagnostically challenging atypical Spitzoid neoplasms.

BACKGROUND: Previously, using imaging mass spectrometry (IMS), we discovered proteomic differences between Spitz nevi and Spitzoid melanomas. OBJECTIVE: We sought to determine whether IMS can assist in the classification of diagnostically challenging atypical Spitzoid neoplasms (ASN), to compare and correlate the IMS and histopathological diagnoses with clinical behavior. METHODS: We conducted a retrospective collaborative study involving centers from 11 countries and 11 US institutions analyzing 102 ASNs by IMS. Patients were divided into clinical groups 1 to 4 representing best to worst clinical behavior. The association among IMS findings, histopathological diagnoses, and clinical groups was assessed. RESULTS: There was a strong association between a diagnosis of Spitzoid melanoma by IMS and lesions categorized as clinical groups 2, 3, and 4 (recurrence of disease, metastases, or death) compared with clinical group 1 (no recurrence or metastasis beyond a sentinel node) (P < .0001). Older age and greater tumor thickness were strongly associated with poorer outcome (P = .01). CONCLUSIONS: IMS diagnosis of ASN better predicted clinical outcome than histopathology. Diagnosis of Spitzoid melanoma by IMS was strongly associated with aggressive clinical behavior. IMS analysis using a proteomic signature may improve the diagnosis and prediction of outcome/risk stratification for patients with ASN.

Rhabdomyosarcoma arising in a giant congenital melanocytic nevus.

A number of lesions have been documented to arise within congenital melanocytic nevi (CMNs). Although the most frequent malignancy arising within a CMN is melanoma, the association between rhabdomyosarcoma and CMN has rarely been documented. We present a case arising in a 4-month-old girl with a giant CMN. She presented for evaluation of a pedunculated lesion at the superior gluteal crease that had been present since birth and exhibited rapid growth. Biopsy of the lesion revealed two distinct components: an expansile proliferation of pleomorphic cells with varying degrees of cellularity and a proliferation of banal-appearing melanocytic nevic cells. The cells of the expansile proliferation displayed a wide range of morphologic features, including nests of round cells, spindle-shaped cells, and more differentiated rhabdomyoblasts within a myxoid, highly vascularized stroma. Cross-striations, a marker of skeletal muscle differentiation, were present. These tumor cells were strongly immunoreactive with desmin, myo-D1, and myogenin. Fluorescence in situ hybridization analysis with PAX3/7-FKHR probes was negative. A diagnosis of embryonal rhabdomyosarcoma in association with CMN was made. Initial excision revealed tumor at the margins, and the patient underwent reexcision with subsequent chemotherapy with vincristine, actinomycin D, and cyclophosphamide. She was disease-free at the 6-year follow-up. It has been postulated that the combination of melanocytic and rhabdomyoblastic cells within the same lesion may imply derivation from a common pluripotent stem cell or neural crest cell. Clinicians following patients with giant CMN should consider rhabdomyosarcoma in the differential diagnosis of lesions arising within the nevus.

'Monster cell' melanoma with pulmonary metastasis and cyclin D1 amplification.

Markedly pleomorphic epithelioid cells with high mitotic activity, giant cell formation, very large atypical nuclei, multiple nucleoli and abundant cytoplasm characterize 'monster' cells and may indicate aggressive tumor behavior. Very rare reports of melanomas comprised of 'monster cells' or cells with comparable histomorphological features, found in tissue samples from skin, lymph nodes, CNS, oral cavity and ileum have been published in the literature. This case is the first such description in the lung, and it is characterized with a battery of immunohistochemical stains; BRAF mutation status was negative, and fluorescence in situ hybridization analysis revealed increased copy number gains in 11q (cyclin D1), which is associated with poor prognosis in melanoma. The presence of monster cells in melanoma was associated with aggressive behavior in the reported patient.

Necrotizing Sweet syndrome: a new variant of neutrophilic dermatosis mimicking necrotizing fasciitis.

BACKGROUND: We report a series of patients initially given the diagnosis of necrotizing fasciitis whose course progressed despite surgical debridement, antibiotic therapy, or both, but who responded rapidly to systemic corticosteroids. OBJECTIVE: We sought to evaluate the clinical data, histopathologic and microbiology information, and treatment course of this unusual entity. METHODS: This was a descriptive study/case series. RESULTS: Three immunocompromised patients who presented with signs and symptoms of necrotizing fasciitis were included. They appeared septic, failed multiple courses of antibiotics, demonstrated pathergy, and two of them underwent extensive surgical debridement. None of the cases yielded a microbial source. Dermatologic consultation and histopathology confirmed deep Sweet syndrome in all cases, with marked necrosis of the soft tissue--including myonecrosis--in the two patients with debridement. All patients responded rapidly to high-dose systemic corticosteroids. LIMITATIONS: To our knowledge, this is the first report of this unusual presentation; there are a limited number of cases. CONCLUSION: We propose that these cases represent a new variant of neutrophilic dermatosis: "necrotizing Sweet syndrome," an acute necrotizing neutrophilic dermatosis. This subtype is also characterized by the rapid onset of progressive erythematous, warm, edematous cutaneous lesions with deep-tissue neutrophilic infiltration and soft-tissue necrosis, in the absence of infectious cause. Awareness of this entity and early dermatologic consultation is critical as debridement results in expansion of the process, resulting in additional and aggressive resection--a vicious cycle with significant possible morbidity.

Two distinct viral infections complicating pemphigus foliaceus.

We describe a patient with pemphigus foliaceus who developed two distinct disseminated cutaneous viral infections. Our patient is an 83-year-old female with a recent diagnosis of pemphigus foliaceus, who presented with painful ulcerations while on corticosteroids. Histopathology examination revealed disseminated herpes simplex virus (HSV). Despite adequate treatment with anti-herpetic treatment, some ulcerations failed to heal. A second biopsy revealed the presence of cytomegalovirus (CMV). This was treated successfully with appropriate antiviral therapy. In patients with autoimmune bullous disease, the development of new skin pain or new constitutional symptoms, change in primary morphology, rapid disease progression, or failure to respond to appropriate therapies should prompt the clinician to consider a concurrent cutaneous viral infection. There should be a low threshold to perform ancillary tests, to re-biopsy, and in severe cases, to consider empiric treatment with antiviral treatment therapy and modification of immunosuppressive regimens.

Spitz nevi and other Spitzoid lesions part I. Background and diagnoses.

Spitz nevi are melanocytic proliferations that are characterized by spindled and/or epithelioid nevomelanocytes. First interpreted as juvenile melanoma, these lesions were later characterized as benign and were observed to affect all age groups. Today, contrasting opinions persist regarding the fundamental benignancy versus malignancy within the spectrum of Spitz tumors. Beyond clinical outcome, this controversy has also been fueled by complex and sometimes convoluted classification schemes based on pathologic characteristics. More recently, immunophenotypic and molecular analyses have begun to clarify the etiologic nature of these tumors. Recent evidence suggests that histopathologic features that suggest more aggressiveness in Spitz tumors relate to mitoses and inflammation.

Spitz nevi and other Spitzoid lesions part II. Natural history and management.

For dermatologists, evidence-based management guidelines for Spitz tumors have not been established. Despite the lack of a standardized approach, most dermatologists recommend the excision of Spitz tumors occurring in adults and adopt more conservative measures towards pediatric cases. The histopathologic attributes and the clinical scenario are factored into management in each case. While the metastatic behavior of certain Spitz tumors is well known, the malignant potential of these lesions remains unclear because they only rarely result in negative outcomes. The risks and benefits of adjunctive measures, such as sentinel lymph node biopsy and interferon use, remain untested and are subjects of ongoing controversy. (In part II of this continuing medical education article, we will continue to use the terminology defined in part I for purposes of continuity. "Spitz tumor" is used as the umbrella term for the entire category of lesions, "common Spitz nevi" refers to only the most typical lesions seen in pediatric cases, and "atypical Spitz tumors" encompass the "all other" category, which continues to cause debate.).

Granulomatous pigmented purpura: report of a case and review of the literature.

The pigmented purpuric dermatoses (PPD) are a group of diseases characterized by petechiae and bronze discoloration of the skin on the lower extremities. Histopathologically, extravasation of erythrocytes with hemosiderin deposition, a perivascular lymphocytic infiltrate centered on the superficial capillaries and endothelial cell swelling are seen. The granulomatous variant of PPD (GPPD) was described in 1996 and only 10 cases have been reported since in the literature, almost exclusively in patients of East Asian descent only involving the extremities. We present a case of GPPD in a Caucasian, North American Ashkenazi Jewish woman involving the thighs, back, forearms and wrists with concomitant non-granulomatous PPD of the shins. She presented with an asymptomatic, spreading, cayenne pepper-like rash. This rash intermittently involved the lower extremities and back for 15 years, but now involves the thighs with accompanying pink papules on the back, wrists and forearms. Histopathology of the thigh and back lesions revealed superficial lichenoid granulomatous dermatitis with palisading lymphocytes and focal interface changes. Extravasated erythrocytes were seen, but vasculitis was absent. No lymphocytic atypicality was noted and T-cell gene rearrangement studies were non-clonal. This is the second reported case of GPPD in a non-Asian patient and the first case involving sites other than the extremities.

Unilateral nevoid telangiectasia syndrome: a case report and review of the literature.

We report on a 43-year-old Caucasian female who presented with bright red macules in a unilateral distribution in the left C5-8 and L3-5 dermatomes. Histopathologic examination showed superficial papillary dermal telangiectasia with minimal chronic inflammation. Immunohistochemical stains for estrogen and progesterone receptors (ER/PR) were negative. A diagnosis of unilateral nevoid telangiectasia syndrome (UNTS) was given. UNTS is an uncommon disorder first described by Alfred Blaschko in 1899. It is comprised of telangiectasias occurring in a predominantly unilateral dermatomal distribution and often affecting the trigeminal, cervical, and upper thoracic dermatomes. It can be either congenital or acquired and has a 2:1 female:male ratio. UNTS has been reported in relation to hyperestrogenic states, with half of the reported cases related to pregnancy, puberty, or liver disease. However, the vast majority of cases show no increase in estrogen and progesterone receptors in lesional skin. UNTS may be more common than previously believed, and shows some response to vascular laser therapy. Differential diagnoses include hemangioma, angioma serpiginosum, and rarely, nevus flammeus.

Terbinafine-induced acute generalized exanthematous pustulosis (AGEP) responsive to high dose intravenous corticosteroid.

Acute generalized exanthematous pustulosis (AGEP) is a febrile pustular drug eruption. Terbinafine, an allylamine fungicidial agent, is the most common anti-mycotic associated with AGEP. Here, we report a case of terbinafine-induced AGEP that was recalcitrant to oral corticosteroid but responsive to high-dose intravenous corticosteroid.

Endoscopic mucosal resection: an improved diagnostic procedure for early gastroesophageal epithelial neoplasms.

Endoscopic mucosal resection (EMR), which is advocated for the treatment of early (superficial) gastroesophageal neoplasms, has also been alluded to represent a superior diagnostic and staging modality. We compared the diagnostic concordance of preceding biopsies with EMR specimens in 31 gastric and 10 esophageal EMRs consisting of 6 low-grade and 12 high-grade dysplasias, 21 intramucosal adenocarcinomas, and 2 submucosal invasive adenocarcinomas. Discrepancies were considered as either major or minor if the histologic grades differed by 2 or more, or by only 1, respectively. Discrepant and concordant cases were compared with regard to the size of lesion (maximum dimension and surface area), number of biopsy fragments, and extent of biopsy sampling (ratio between lesion size and number of biopsy fragments). These same variables were used to evaluate the differences seen between gastric and esophageal cases. Of the 41 cases, 16 (39%) had discrepant diagnoses, including 14 gastric and 2 esophageal neoplasms. A major discrepancy was seen in 2% of the cases (n = 1, gastric) and a minor discrepancy, in 15 cases. All but 2 of the discrepant cases were found to have a higher grade on EMR. The average number of biopsy fragments was 4.4 in both concordant and discrepant groups. The maximal dimension, surface area, and biopsy sampling ratios of the lesion were significantly greater in the discrepant cases than in the concordant cases. The esophageal cases trended toward having smaller size and a significantly extensive biopsy sampling. We conclude that EMR is superior to biopsy for diagnosing superficial gastroesophageal tumors. Discrepancies between the specimens occur in larger lesions (>10 mm) with less extensive biopsy sampling. EMR can substantially modify the diagnostic grade of a lesion and therefore facilitate optimal therapeutic decisions by avoiding undertreatment and overtreatment based on inaccurate grading and staging.

Poor oral health as a risk factor for esophageal squamous dysplasia in northeastern Iran.

BACKGROUND: Northeastern Iran has one of the highest rates of esophageal squamous cell carcinoma (ESCC) in the world. The reasons for observing such high rates of ESCC in this area are not fully clear. The current study evaluates the association between some potential risk factors and squamous dysplasia, a precursor lesion of ESCC, in northeastern Iran. MATERIALS AND METHODS: Using logistic regression, we compared potential risk factors of ESCC in 124 individuals with dysplasia and 50 normal individuals from northeastern Iran. Case/control status was histologically proven in all 174 study participants. RESULTS: Poor oral health showed a dose-response association with ESCC risk (p for trend < 0.01). Edentulous individuals had 5-fold higher risk of dysplasia compared to participants with good oral health (p-value < 0.01). CONCLUSION: Our results are consistent with two other published studies that have shown oral health as a risk factor for ESCC. The high incidence of ESCC in northeastern Iran may be partly attributable to poor oral health.

Genetic polymorphisms in three Iranian populations with different risks of esophageal cancer, an ecologic comparison.

The age-standardized incidence of esophageal cancer (EC) varies from 3 to >100/100,000 per year in different provinces of Iran. This striking variation of incidence is associated with differences in ethnic backgrounds, raising the possibility that genetic factors are involved in the pathogenesis of EC. We compared the frequencies of polymorphisms in ten genes that have been hypothesized to have a role in risk of EC (CYP1A1, CYP2A6, CYP2E1, GSTM1, GSTP1, GSTT1, ADH2, ADH3, ALDH2, and O6-MGMT) among three Iranian ethnic groups with highly varying rates of EC. These three groups included high-risk Turkomans, medium-risk Turks, and low-risk Zoroastrian Persians. Compared to Zoroastrians, Turkomans had higher frequency of four alleles that are speculated to favor carcinogenesis (CYP1A1 m1, CYP1A1 m2, CYP2A6*9, and ADH2*1); these results are consistent with an influence of these allele variants on the population risk of EC. However, none of these four alleles had a high enough prevalence in Turkomans to explain the high rates of EC in this group. Three of these four alleles (CYP1A1 m1, CYP1A1 m2, CYP2A6*9) were less frequent among Turkomans than in some Asian populations with lower risks of EC. We conclude that it is unlikely that variations in these polymorphic genes are major contributors to the high incidence of EC among Turkomans in Iran.

Clinical utility of a blood-based BRAF(V600E) mutation assay in melanoma.

BRAF inhibitors (BRAFi) have led to clinical benefit in patients with melanoma. The development of a blood-based assay to detect and quantify BRAF levels in these patients has diagnostic, prognostic, and predictive capabilities that could guide treatment decisions. Blood BRAF(V600E) detection and quantification were performed on samples from 128 patients with stage II (19), III (67), and IV (42) melanoma. Tissue BRAF analysis was performed in all patients with stage IV disease and in selected patients with stage II and III disease. Clinical outcomes were correlated to initial BRAF levels as well as BRAF level dynamics. Serial analysis was performed on 17 stage IV melanoma patients treated with BRAFi and compared with tumor measurements by RECIST. The assay was highly sensitive (96%) and specific (95%) in the stage IV setting, using a blood level of 4.8 pg as "positive." BRAF levels typically decreased following BRAFi. A subset of these patients (5) had an increase in BRAF(V600E) values 42 to 112 days before clinical or radiographic disease progression (PD). From 86 patients with resected, stage II or III melanoma, 39 had evidence of disease relapse (45.3%). Furthermore, BRAF mutation in the blood after surgical resection in these patients was not associated with a difference in relapse risk, although tissue BRAF status was only available for a subset of patients. In summary, we have developed a highly sensitive and specific, blood-based assay to detect BRAF(V600) mutation in patients with melanoma.

The gastro-esophageal malignancies in Northern Iran research project: impact on the health research and health care systems in Iran.

BACKGROUND: The Gastro-Esophageal Malignancies in Northern Iran (GEMINI) research project is an example of recent progress in health research in Iran. The original aim of this project was to identify etiologic factors and prevention measures for upper gastrointestinal cancers in Northern provinces of Iran, but its achievements have gone much beyond this initial goal. METHODS: GEMINI consists of several projects including cancer registries, pilot studies, case-control studies, and the Golestan Cohort Study. GEMINI has been conducted through extensive collaborations between the Digestive Disease Research Center of Tehran University of Medical Sciences with other domestic and international health organizations. The achievements of GEMINI include producing new knowledge, introducing new research methods, developing and expanding health research and health care infrastructures, investing in human resources, and increasing the awareness and knowledge of policy makers and officials at all levels about the importance of chronic diseases in Iran's health priorities. CONCLUSION: The success of GEMINI reveals the feasibility of large-scale health research studies in developing countries and serves as a successful model not only for health research in Iran, but also for similar research studies in other developing nations.