Alireza Sepehr

Socio-economic status and oesophageal cancer: results from a population-based case–control study in a high-risk area

BACKGROUND Cancer registries in the 1970s showed that parts of Golestan Province in Iran had the highest rate of oesophageal squamous cell carcinoma (OSCC) in the world. More recent studies have shown that while rates are still high, they are approximately half of what they were before, which might be attributable to improved socio-economic status (SES) and living conditions in this area. We examined a wide range of SES indicators to investigate the association between different SES components and risk of OSCC in the region. METHODS Data were obtained from a population-based case-control study conducted between 2003 and 2007 with 300 histologically proven OSCC cases and 571 matched neighbourhood controls. We used conditional logistic regression to compare cases and controls for individual SES indicators, for a composite wealth score constructed using multiple correspondence analysis, and for factors obtained from factors analysis. RESULTS We found that various dimensions of SES, such as education, wealth and being married were all inversely related to OSCC. The strongest inverse association was found with education. Compared with no education, the adjusted odds ratios (95% confidence intervals) for primary education and high school or beyond were 0.52 (0.27-0.98) and 0.20 (0.06-0.65), respectively. CONCLUSIONS The strong association of SES with OSCC after adjustment for known risk factors implies the presence of yet unidentified risk factors that are correlated with our SES measures; identification of these factors could be the target of future studies. Our results also emphasize the importance of using multiple SES measures in epidemiological studies.

Distinct pattern of TP53 mutations in squamous cell carcinoma of the esophagus in Iran.

Extremely high rates of squamous cell carcinoma of the esophagus (SCCE) are observed in Iran, reflecting unknown, genetic and/or epidemiological risk factors. Among genetic alterations in SCCE, TP53 mutations are the most frequent, vary among populations, and may provide clues on etiological mechanisms. We have analysed mutations in TP53 (exons 5–8) in 98 SCCE from Iran by temporal temperature gel electrophoresis and direct sequencing. We found 58 mutations in 49 patients (50%), with a high prevalence of C to T transitions at CpG dinucleotides (29.3%). The TP53 mutation pattern in Iran was significantly different from that observed in SCCEs from high incidence areas of China and Western Europe (P=0.007). Moreover, the prevalence of mutations at A : T base pairs (transitions and transversions) was higher in men than in women (38.7% vs 11.1%, P=0.033). COX-2 overexpression was detected in 69% of the cases evaluated (24/35), without significant association with TP53 mutation. Accumulation of nitrotyrosine, a marker of protein damage by excess levels of nitric oxide, was observed in tumor cells in six of 16 cases analysed. These results are consistent with the hypothesis that several factors are involved in TP53 mutagenesis in Iran. These factors include a baseline of chronic inflammatory stress, which may have a multiplicative impact on the sensitivity of esophageal cells to exogenous factors of risk.

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.

Case 5-2009: A 47-Year-Old Woman with a Rash and Numbness and Pain in the Legs

Dr. John H. Stone: A 47-year-old woman was seen in the Rheumatology Clinic of this hospital because of numbness and pain in the legs and a rash. The patient had been well until approximately 2 years earlier, when numbness developed, first on the lateral aspect of the left leg, ankle, and foot, and then in an identical distribution on the right. Approximately 3 months later, pain developed on the medial aspect of the left foot, followed by pain in the same distribution on the right foot. During the next 9 months, the pain spread to involve both lower legs diffusely. One year before presentation, acute swelling of the distal left leg developed after an airplane trip. Ultrasonography of the legs, performed at another hospital, showed no evidence of deep venous thrombosis. The swelling subsided spontaneously during a 2-week period. Six to 8 months before this evaluation, mottled discoloration of the skin developed on the feet, ankles, and lower legs, with isolated, tender nodules up to 1.5 cm in diameter that blanched partially with pressure. Intermittent swelling of the legs and ankles occurred. Results of laboratory tests are shown in Table 1. Approximately 8 weeks before presentation, the patient saw a physician at another facility. Levels of serum electrolytes, albumin, globulin, thyrotropin, ferritin, folate, and vitamin B12 and results of renaland liver-function tests were normal. Results of other laboratory tests are shown in Table 1. The next day, a dermatologist performed a biopsy of the skin of the left temple. Pathological examination of the specimen reportedly showed perivascular and perifollicular inflammation with telangiectasias, which was thought to be consistent with rosacea-like dermatitis. One week later, pathological examination of a biopsy specimen of a cutaneous nodule on the left ankle reportedly revealed a focal lymphohistiocytic infiltrate around a small muscular artery in the subcutis, with no evidence of vasculitis or erythema nodosum. Three weeks before presentation, the patient saw a rheumatologist at another facility. The patient reported a history of dry eyes (for which she used cyclosporine eye drops) and numbness, tingling, and color changes in her fingers in conditions Case 5-2009: A 47-Year-Old Woman with a Rash and Numbness and Pain in the Legs

Is Opium a Real Risk Factor for Esophageal Cancer or Just a Methodological Artifact? Hospital and Neighborhood Controls in Case-Control Studies

Background Control selection is a major challenge in epidemiologic case-control studies. The aim of our study was to evaluate using hospital versus neighborhood control groups in studying risk factors of esophageal squamous cell carcinoma (ESCC). Methodology/Principal Findings We compared the results of two different case-control studies of ESCC conducted in the same region by a single research group. Case definition and enrollment were the same in the two studies, but control selection differed. In the first study, we selected two age- and sex-matched controls from inpatient subjects in hospitals, while for the second we selected two age- and sex-matched controls from each subjects neighborhood of residence. We used the test of heterogeneity to compare the results of the two studies. We found no significant differences in exposure data for tobacco-related variables such as cigarette smoking, chewing Nass (a tobacco product) and hookah (water pipe) usage, but the frequency of opium usage was significantly different between hospital and neighborhood controls. Consequently, the inference drawn for the association between ESCC and tobacco use did not differ between the studies, but it did for opium use. In the study using neighborhood controls, opium use was associated with a significantly increased risk of ESCC (adjusted OR 1.77, 95% CI 1.17–2.68), while in the study using hospital controls, this was not the case (OR 1.09, 95% CI 0.63–1.87). Comparing the prevalence of opium consumption in the two control groups and a cohort enrolled from the same geographic area suggested that the neighborhood controls were more representative of the study base population for this exposure. Conclusions/Significance Hospital and neighborhood controls did not lead us to the same conclusion for a major hypothesized risk factor for ESCC in this population. Our results show that control group selection is critical in drawing appropriate conclusions in observational studies.

Histopathologic manifestations of systemic diseases: the example of cutaneous lupus erythematosus

Dr Martin C. Mihm, Jr is one of the most prolific and influential voices in dermatopathology today with greater than 400 peer-reviewed publications to his credit. He has devoted his life to the pathology and pathophysiology of cutaneous disease and has made enormous contributions to our understanding of a variety of cutaneous disease processes. Most notably, Dr Mihm is a leading authority in the field of malignant melanoma. Although melanoma has been a primary focus throughout much of his career, he has also published numerous influential studies and reviews on inflammatory and autoimmune dermatological disorders, including lupus erythematosus, cutaneous vasculitides, interface dermatitis, panniculitis and others,1– 7 which we will highlight in this review. In 1973, in Human Pathology, Dr Mihm published, along with co-authors Drs Wallace Clark and Richard Reed, a seminal paper on the key histopathological features useful in distinguishing between acute systemic lupus erythematosus (SLE) and chronic cutaneous or discoid lupus erythematosus (DLE).1 He co-authored seminal papers with Dr Terence Harrist on the direct immunofluorescence patterns of numerous cutaneous inflammatory disorders, with a special focus on the utility of the lupus band test.8,9 In addition, he has published many fascinating case reports and series on extraordinary presentations of various autoimmune disorders and vasculitides.10– 14 He has broadened our understanding of the pathophysiology of cutaneous disease and provided us with precise and elaborate histopathological descriptions of both common and obscure processes. In honor of Dr Mihm’s contributions, in this review we will describe the histologic manifestations of cutaneous lupus erythematosus (CLE), updating the histomorphologic descriptions of various subcategories according to the latest literature. Regarding the histologic presentations of CLE, we will discuss DLE, acute SLE, subacute cutaneous lupus erythematosus (SCLE), hypertrophic (or verrucous) lupus erythematosus, lupus erythematosus tumidus (LET) (or tumid lupus), chilblain lupus erythematosus (CHLE), lupus erythematosus panniculitis (or lupus profundus), bullous lupus erythematosus (BLE), druginduced lupus erythematosus (DILE), lymphomatoid lupus erythematosus (LLE) and neonatal lupus erythematosus (NLE). Also, we will discuss livedoid vasculopathy (LV) as an example of the vasculitic cutaneous manifestations often encountered in the different settings of CLE. This review is focused only on the histopathology of these entities, as other reviews have provided excellent information on the clinical aspects of these disorders.15– 31

Clinical Utility of a Blood-Based BRAFV600E 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 BRAFV600E 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 BRAFV600E 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 BRAFV600 mutation in patients with melanoma. Mol Cancer Ther; 13(12); 3210–8. ©2014 AACR.

Case records of the Massachusetts General Hospital. Case 5-2009. A 47-year-old woman with a rash and numbness and pain in the legs.

Dr. John H. Stone: A 47-year-old woman was seen in the Rheumatology Clinic of this hospital because of numbness and pain in the legs and a rash. The patient had been well until approximately 2 years earlier, when numbness developed, first on the lateral aspect of the left leg, ankle, and foot, and then in an identical distribution on the right. Approximately 3 months later, pain developed on the medial aspect of the left foot, followed by pain in the same distribution on the right foot. During the next 9 months, the pain spread to involve both lower legs diffusely. One year before presentation, acute swelling of the distal left leg developed after an airplane trip. Ultrasonography of the legs, performed at another hospital, showed no evidence of deep venous thrombosis. The swelling subsided spontaneously during a 2-week period. Six to 8 months before this evaluation, mottled discoloration of the skin developed on the feet, ankles, and lower legs, with isolated, tender nodules up to 1.5 cm in diameter that blanched partially with pressure. Intermittent swelling of the legs and ankles occurred. Results of laboratory tests are shown in Table 1. Approximately 8 weeks before presentation, the patient saw a physician at another facility. Levels of serum electrolytes, albumin, globulin, thyrotropin, ferritin, folate, and vitamin B12 and results of renaland liver-function tests were normal. Results of other laboratory tests are shown in Table 1. The next day, a dermatologist performed a biopsy of the skin of the left temple. Pathological examination of the specimen reportedly showed perivascular and perifollicular inflammation with telangiectasias, which was thought to be consistent with rosacea-like dermatitis. One week later, pathological examination of a biopsy specimen of a cutaneous nodule on the left ankle reportedly revealed a focal lymphohistiocytic infiltrate around a small muscular artery in the subcutis, with no evidence of vasculitis or erythema nodosum. Three weeks before presentation, the patient saw a rheumatologist at another facility. The patient reported a history of dry eyes (for which she used cyclosporine eye drops) and numbness, tingling, and color changes in her fingers in conditions Case 5-2009: A 47-Year-Old Woman with a Rash and Numbness and Pain in the Legs

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.

Case 5-2009

Dr. John H. Stone: A 47-year-old woman was seen in the Rheumatology Clinic of this hospital because of numbness and pain in the legs and a rash. The patient had been well until approximately 2 years earlier, when numbness developed, first on the lateral aspect of the left leg, ankle, and foot, and then in an identical distribution on the right. Approximately 3 months later, pain developed on the medial aspect of the left foot, followed by pain in the same distribution on the right foot. During the next 9 months, the pain spread to involve both lower legs diffusely. One year before presentation, acute swelling of the distal left leg developed after an airplane trip. Ultrasonography of the legs, performed at another hospital, showed no evidence of deep venous thrombosis. The swelling subsided spontaneously during a 2-week period. Six to 8 months before this evaluation, mottled discoloration of the skin developed on the feet, ankles, and lower legs, with isolated, tender nodules up to 1.5 cm in diameter that blanched partially with pressure. Intermittent swelling of the legs and ankles occurred. Results of laboratory tests are shown in Table 1. Approximately 8 weeks before presentation, the patient saw a physician at another facility. Levels of serum electrolytes, albumin, globulin, thyrotropin, ferritin, folate, and vitamin B12 and results of renaland liver-function tests were normal. Results of other laboratory tests are shown in Table 1. The next day, a dermatologist performed a biopsy of the skin of the left temple. Pathological examination of the specimen reportedly showed perivascular and perifollicular inflammation with telangiectasias, which was thought to be consistent with rosacea-like dermatitis. One week later, pathological examination of a biopsy specimen of a cutaneous nodule on the left ankle reportedly revealed a focal lymphohistiocytic infiltrate around a small muscular artery in the subcutis, with no evidence of vasculitis or erythema nodosum. Three weeks before presentation, the patient saw a rheumatologist at another facility. The patient reported a history of dry eyes (for which she used cyclosporine eye drops) and numbness, tingling, and color changes in her fingers in conditions Case 5-2009: A 47-Year-Old Woman with a Rash and Numbness and Pain in the Legs