Background: Recent studies have shown that genetic alterations are associated with the effect of patient geographic location on gallbladder cancer development. Peru has a high incidence of gallbladder cancer, but causative factors have not yet been identified. We examined the frequency of mutations in TP53 and K-ras genes in Peruvian patients with gallbladder cancer, and compared this with data from Bolivia, Hungary, Chile, and Japan, which have a high gallbladder cancer incidence. Methods: DNA was extracted from formalin-fixed paraffin-embedded gallbladder tissue sections of 30 gallbladder cancer patients (9 men and 21 women) obtained using microdissection. Mutations in exons 5 to 8 of TP53 and codons 12, 13, and 61 of K-ras were examined using direct sequencing. Results: TP53 mutations were observed in 10 (33.3%) of patients, but K-ras mutations were absent. Nine (90%) TP53 mutations were point mutations (7 missense and 2 silent mutations), and the most frequent substitution was a G:C to A:T transition. G:C to A:T transitions at the CpG site or G:C to T:A transversions were found in one patient each. No significant differences were found in the frequency of TP53 and K-ras mutations among patients in the 5 countries. Conclusions: Our findings suggest that endogenous mechanisms and exogenous carcinogens may affect the carcinogenic process in Peruvian gallbladder cancer patients, similar to that in Bolivian patients. Further studies with a larger sample size are needed to clarify these findings.

BACKGROUND: Incidence and mortality rates of cervical cancer in Bolivia are the highest in Latin America. Vaginal cell self-sampling can improve screening coverage. Information on common reasons for low screening coverage and preferences for future screening are essential to reduce cervical cancer incidence. We aimed to evaluate the knowledge about human papillomavirus (HPV) and cervical cancer of Bolivian women from urban, peri-urban and rural areas of Cochabamba and to determine their degree of acceptability and confidence towards vaginal HPV self-sampling. In addition, we assessed the impact of self-sampling on cervical cancer screening coverage in a selected peri-urban area.
METHODS: We gathered information from women living in urban, peri-urban and rural areas of Cochabamba province in Bolivia using two different structured questionnaires. In Survey1, we collected information from 222 women about their knowledge on HPV and cervical cancer. In Survey 2, the acceptance and confidence towards vaginal HPV self-sampling compared to the physician-sampling was assessed in 221 women. A non-probabilistic stratified sampling by areas was carried out for the two questionnaires. In the third phase of the study, we determined the impact of HPV self-sampling collection on screening coverage in a peri-urban area of Cochabamba.
RESULTS: Bolivian women knew little or nothing about cervical cancer and HPV infection in all areas. They all found self-sampling collection easier to perform (86.9 to 93.2%) and more comfortable (79.4 to 83.3%) compared to physician sampling. Sampling accuracy to detect cervical cancer was probably higher in their point of view when it was taken by physician (35.1 to 63.5%). However in rural areas women preferred self-sampling. Accordingly, the campaign of vaginal HPV self-sampling in this peri-urban area increased screening coverage, reaching in three months the annual rate average.
CONCLUSIONS: The knowledge about cervical cancer and HPV infection is poor in Bolivia. Despite greater acceptance of the vaginal HPV self-sampling in all areas, women kept greater confidence in the screening performed by the gynecologist although HPV self-sampling improved coverage rate.

Adherence to healthy dietary guidelines has been related to a lower risk of several cancers, but its role in primary liver cancer (PLC) has not been fully investigated, especially among Eastern populations. This study enrolled 720 PLC patients and 720 healthy controls who were frequency-matched by age and sex between September 2013 and October 2017 in South China. Dietary quality was assessed by the Chinese Healthy Eating Index (CHEI) and the Healthy Eating Index 2015 (HEI-2015), which manifests as scores of adhering to the 2016 Dietary Guidelines for Chinese and adhering to the 2015⁻2020 Dietary Guidelines for Americans, respectively. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression models, adjusting for potential confounders. Higher scores in both the CHEI and HEI-2015 were associated with a lower risk of PLC (per 5-points increment of the total scores: OR: 0.43, 95% CI: 0.38⁻0.50 for CHEI; OR: 0.47, 95% CI: 0.40⁻0.55 for HEI-2015). The protective associations persisted significantly in the stratified analyses by sex, smoker status, alcohol consumption, HBV infection, and histological types of PLC, without statistical evidence for heterogeneity (

Lower gastrointestinal bleeding is a common pathology with diverse causes depending on the patients´ age. The most common causes in adults are polyps, neoplasias, diverticular disease and angiodysplasia. In neonates, necrotizing enterocolitis and volvulus, and anal fissures and bowel intussusception in infants. Polyps are reported as a cause of bleeding only in children of preschool age.

Salmonella typhi and Helicobacter infections have been shown to increase risk of gallbladder cancer (GBC), but findings have been inconsistent. Other bacterial infections may also be associated with GBC. However, information on microbial pathogens in gallbladder bile of GBC patients is scarce. We aimed to investigate the microbial communities in gallbladder bile of patients with GBC and cholelithiasis (CL). Seven GBC patients and 30 CL patients were enrolled in this study. Genomic DNA was extracted from bile and the V3-V4 region of 16S rRNA was amplified. The sequencing results were compared with the 16S database, and the bacteria were identified by homology searches and phylogenetic analysis. DNA was detected in the bile of three GBC (42.9%; Bolivia, 1; Chile, 2) and four CL patients (13.3%; Bolivia, 1; Chile, 3). Of the 37 patients, 30 (81.1%) were negative and unable to analyze. Salmonella typhi and Helicobacter sp. were not detected in bile from any GBC patients. As the predominant species, Fusobacterium nucleatum, Escherichia coli, and Enetrobacter sp. were detected in bile from GBC patients. Those in bile from CL patients were Escherichia coli, Salmonella sp., and Enerococcus gallinarum. Escherichia coli was detected in bile samples from both GBC and CL patients. Whether the bacteria detected in bile from GBC patients would associated with the development of GBC warrant further investigation.

Lung cancer is a public health problem worldwide and Latin America (LATAM) cannot escape this reality. This malignant disease has not only a high prevalence in the region, but is also the main cause of cancer related deaths, and in other emerging countries, the incidence rates are still on the rise. Interestingly in most LATAM countries, lung cancer mortality has been decreasing in men but not in women, reflecting smoking patterns in countries such as Chile, Bolivia, and Brazil. Despite the fact that these issues are well known to government agencies, physicians and patients in the region, current efforts still fall behind those needed in order to face this problem of epidemic proportions. Tobacco control and smoking cessation are the most important interventions against lung cancer, but even with their optimal implementation (which is far from reality at this time) the number of cases in the foreseeable future would still be significant. Beyond tobacco control, advances in our understanding of the molecular component of lung cancer have resulted in new targeted therapies and immune check point inhibitors, which have improved clinical outcomes but at a considerably higher financial cost. LATAM has not widely and speedily adopted these strategies, including new technology and approved novel drugs, due to a number of facts, and therefore only a dismal proportion of LATAḾs patient population have benefited from these new advances. A keen focus on a heterogeneous education system for caregivers in lung cancer treatment would likely help standardize care and improve future potential gains from domestic research. In this review we discuss the challenges of treatment implementation, focusing on new technologies.

BACKGROUND: Cervical cancer incidence and mortality rates in Bolivia are among the highest in Latin America. This investigation aims to evaluate the possibility of using simple devices, e.g. a cotton swab and a glass slide, for self-sampling in order to detect human papillomavirus (HPV) DNA by PCR in cervico-vaginal cells.
METHODS: In the first phase of our study we evaluated the use of a glass slide as a transport medium for cervical cells. A physician took paired-cervical samples from 235 women. One sample was transported in Easyfix® solution and the other sample was smeared over a glass slide. Both were further analyzed and compared for human DNA recovery and HPV detection. A kappa value was determined to evaluate the agreement between the HPV DNA detection rates. In the second phase of the study, 222 women from the urban, peri-urban and rural regions of Cochabamba were requested to perform self-sampling using the following devices: a cotton swab combined with a glass slide, and a vaginal tampon. Women gave their opinion about the self-sampling technique. Finally, the agreement for high risk-HPV detection between self- and physician-collected samples was performed in 201 samples in order to evaluate the self-sampling technique.
RESULTS: Firstly, the comparison between Easyfix® solution and the glass slide to transport clinical samples gave a good agreement for HPV DNA detection (κ = 0.71, 95% CI 0.60-0.81). Secondly, self-sampling, especially with cotton swab combined with glass slide, would generally be preferred over clinician sampling for a screening program based on HPV detection. Finally, we showed a good agreement between self- and physician collected samples for high risk-HPV detection (κ = 0.71, 95% CI 0.55-0.88).
CONCLUSIONS: Simple devices such as a cotton swab and a glass slide can be used to perform self-sampling and HPV DNA detection. Furthermore, most Bolivian women preferred self-sampling over clinician-sampling for cervical cancer screening.

BACKGROUND: Genetic counselling and testing for Lynch syndrome (LS) have recently been introduced in several Latin America countries. We aimed to characterize the clinical, molecular and mismatch repair (MMR) variants spectrum of patients with suspected LS in Latin America.
METHODS: Eleven LS hereditary cancer registries and 34 published LS databases were used to identify unrelated families that fulfilled the Amsterdam II (AMSII) criteria and/or the Bethesda guidelines or suggestive of a dominant colorectal (CRC) inheritance syndrome.
RESULTS: We performed a thorough investigation of 15 countries and identified 6 countries where germline genetic testing for LS is available and 3 countries where tumor testing is used in the LS diagnosis. The spectrum of pathogenic MMR variants included MLH1 up to 54%, MSH2 up to 43%, MSH6 up to 10%, PMS2 up to 3% and EPCAM up to 0.8%. The Latin America MMR spectrum is broad with a total of 220 different variants which 80% were private and 20% were recurrent. Frequent regions included exons 11 of MLH1 (15%), exon 3 and 7 of MSH2 (17 and 15%, respectively), exon 4 of MSH6 (65%), exons 11 and 13 of PMS2 (31% and 23%, respectively). Sixteen international founder variants in MLH1, MSH2 and MSH6 were identified and 41 (19%) variants have not previously been reported, thus representing novel genetic variants in the MMR genes. The AMSII criteria was the most used clinical criteria to identify pathogenic MMR carriers although microsatellite instability, immunohistochemistry and family history are still the primary methods in several countries where no genetic testing for LS is available yet.
CONCLUSION: The Latin America LS pathogenic MMR variants spectrum included new variants, frequently altered genetic regions and potential founder effects, emphasizing the relevance implementing Lynch syndrome genetic testing and counseling in all of Latin America countries.

Primary oral mucosal melanoma is an extremely rare and aggressive tumor arising from melanocytes located in the mucosal epithelium of the oral cavity. Although malignant melanoma of oral mucosa shares some clinical features with its cutaneous counterpart, it has been associated with a worst prognosis; its etiopathogenesis are still only partially unraveled as there is no influence of UV radiation. It is known that the mitogen-activated protein kinase pathway mediates cellular responses to growth signals and its activation is an important phenomenon in melanoma. The aim of this study was to evaluate NRAS and BRAF genes, both components of mitogen-activated protein kinase molecular pathway, and compare with their protein expression. Point mutations of NRAS (codons 12, 13, and 61) and BRAF (codon 600) were screened by pyrosequencing method, and its results were associated to the protein expression of RAS and BRAF performed by immunohistochemistry. The authors observed mutation in BRAF 600 (3/14), NRAS codons 12 and 13 (2/14), and NRAS codon 61 (2/8). One case showed positive RAS protein expression, but no mutation was observed. Twelve in 14 cases showed positive BRAF protein expression: 3 cases showed BRAF mutation; 2 cases showed NRAS codon 61 mutation; 2 cases showed NRAS codons 12 and 13 mutation but not simultaneously. Although NRAS and BRAF mutation frequency and RAS protein expression are low, BRAF protein expression was intense; probably, NRAS and BRAF mutations are independent events and alternative molecular mechanisms in the primary oral mucosal melanoma tumorigenesis.

Syringomas are benign adnexal tumors that are characterized histologically by the presence of small solid and cystic epithelial structures in the upper half of the reticular dermis. Reflectance confocal microscopy is a noninvasive diagnostic method that enables in vivo visualization of tissues with a resolution that approximates that of conventional histopathology. The use of this method in skin imaging over the past several years has improved dermatological diagnoses, creating the potential for its wide application in such diagnoses, especially for benign and malignant skin tumors. We describe its use in the diagnosis of syringoma in 2 patients and correlate the resulting clinical, histopathological, and digital reflectance confocal microscopy images.

Dietary intake of vitamin A (VA) and carotenes has shown beneficial effects for decreasing the risk of some types of cancer, but findings on the risk of primary liver cancer (PLC) are inconsistent. This case-control study explored the associations between the dietary intake of VA and carotenes and the risk of PLC. We recruited 644 incident PLC patients (diagnosed within one month of each other) and 644 age- and gender-matched controls in Guangzhou, China. A food frequency questionnaire was used to assess habitual dietary intake. Logistic regression analyses found that higher intakes of VA and carotenes were independently associated with decreased PLC risk (all

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.

The Plurinational State of Bolivia (Bolivia) has a high incidence rate of gallbladder cancer (GBC). However, the genetic and environmental risk factors for GBC development are not well understood. We aimed to assess whether or not cytochrome P450 (CYP1A1), glutathione S-transferase mu 1 (GSTM1), theta 1 (GSTT1) and tumor suppressor protein p53 (TP53) genetic polymorphisms modulate GBC susceptibility in Bolivians. This case-control study covered 32 patients with GBC and 86 healthy subjects. GBC was diagnosed on the basis of histological analysis of tissues at the Instituto de Gastroenterologia Boliviano-Japones (IGBJ); the healthy subjects were members of the staff at the IGBJ. Distributions of the CYP1A1 rs1048943 and TP53 rs1042522 polymorphisms were assayed using PCR-restriction fragment length polymorphism assay. GSTM1 and GSTT1 deletion polymorphisms were detected by a multiplex PCR assay. The frequency of the GSTM1 null genotype was significantly higher in GBC patients than in the healthy subjects (odds ratio [OR], 2.35; 95% confidence interval [CI], 1.03-5.37; age-adjusted OR, 3.53; 95% CI, 1.29-9.66; age- and sex-adjusted OR, 3.40; 95% CI, 1.24-9.34). No significant differences were observed in the frequencies of CYP1A1, GSTT1, or TP53 polymorphisms between the two groups. The GSTM1 null genotype was associated with increased GBC risk in Bolivians. Additional studies with larger control and case populations are warranted to confirm the association between the GSTM1 deletion polymorphism and GBC risk suggested in the present study.

BACKGROUND: We conducted a large international study to estimate fractions of head and neck cancers (HNCs) attributable to human papillomavirus (HPV-AFs) using six HPV-related biomarkers of viral detection, transcription, and cellular transformation.
METHODS: Formalin-fixed, paraffin-embedded cancer tissues of the oral cavity (OC), pharynx, and larynx were collected from pathology archives in 29 countries. All samples were subject to histopathological evaluation, DNA quality control, and HPV-DNA detection. Samples containing HPV-DNA were further subject to HPV E6*I mRNA detection and to p16(INK4a), pRb, p53, and Cyclin D1 immunohistochemistry. Final estimates of HPV-AFs were based on HPV-DNA, HPV E6*I mRNA, and/or p16(INK4a) results.
RESULTS: A total of 3680 samples yielded valid results: 1374 pharyngeal, 1264 OC, and 1042 laryngeal cancers. HPV-AF estimates based on positivity for HPV-DNA, and for either HPV E6*I mRNA or p16(INK4a), were 22.4%, 4.4%, and 3.5% for cancers of the oropharynx, OC, and larynx, respectively, and 18.5%, 3.0%, and 1.5% when requiring simultaneous positivity for all three markers. HPV16 was largely the most common type. Estimates of HPV-AF in the oropharynx were highest in South America, Central and Eastern Europe, and Northern Europe, and lowest in Southern Europe. Women showed higher HPV-AFs than men for cancers of the oropharynx in Europe and for the larynx in Central-South America.
CONCLUSIONS: HPV contribution to HNCs is substantial but highly heterogeneous by cancer site, region, and sex. This study, the largest exploring HPV attribution in HNCs, confirms the important role of HPVs in oropharyngeal cancer and drastically downplays the previously reported involvement of HPVs in the other HNCs.

Desmoplastic melanoma (DM) is histologically characterized by a proliferation of spindle melanocytes dispersed in a collagenous stroma that can be mistaken for a variety of neoplasms. The purpose of this study was to analyze 40 cases of DM with a comprehensive panel of immunohistochemical markers (KBA.62, p16, Ezrin, WT-1, MITF-1, SOX-10, CD117, SOX-2, nestin, PNL2, p75, MART-1, gp100 and S100p) to obtain a more complete understanding of the potential use of these antibodies in the diagnosis of DM. We found that all cases of DM expressed p16, WT-1, SOX-10, nestin and S100p and 95% of cases expressed p75. There was variable expression with Ezrin, SOX-2, KBA.62, MART-1 and HMB-45. Most DMs did not express MITF-1, PNL2 and CD117. Conditions that may enter in the histologic differential diagnosis of DM, including dermal scars, fibromatosis and dermatofibromas were also studied. Nearly all control cases also stained positive for p16 but were negative for WT1, SOX10, nestin, p75 and S-100p, as well as for most of the other markers tested. We conclude that a panel of S-100p, WT1, SOX10, p75 and nestin may constitute the optimal panel with the most sensitive and specific combination of immunostain available for the diagnosis of DM.

The etiology and pathogenesis of lentiginous acral melanomas are poorly understood. Recent studies have postulated that DNA repair mechanisms and cell growth pathways are involved in the development of melanoma, particularly changes in the MAPK pathways (RAS, BRAF, MEK 1/2, and ERK 1/2). The aim of this study is to assess the status of the MAP kinase pathways in the pathogenesis of acral melanomas. The authors examined the components of the RAS-RAF-MEK-ERK cascades by immunohistochemistry in a series of 16 primary acral melanomas by tissue microarray. The expression of MAP kinase cascade proteins changed in most cases. The authors observed that 57.14% of cases were BRAF positive and that 61.53%, 71.42%, and 71.42% of cases were positive for MEK2, ERK1, and ERK2, respectively; RAS was not expressed in 92.31%, and all cases were negative for MEK1. The absence of RAS and positivity for MEK2, ERK1, and ERK2 were most seen in invasive cases with high thickness. These aspects of the MAPK pathway require further examination in acral melanomas between different populations. Nevertheless, the results highlight significant alterations in the MAP kinase cascades that are related to histological indicators of prognosis in primary acral melanomas.

Sebaceous carcinoma (SC) is a relatively uncommon malignant epithelial neoplasm with a predilection for the periocular region. The diagnosis of SC can be difficult to make at initial presentation, as it can clinically and histopathologically resemble other common benign and malignant epithelial lesions. A diagnosis of SC is made by confirmation of sebaceous differentiation of neoplastic cells, which can often be accomplished by conventional microscopic findings; however, its recognition may be sometimes difficult and requires ancillary studies such as immunohistochemistry (IHC). Many studies have evaluated the role of IHC as a potential technique to differentiate SC from its mimics; however, most of these studies have used a limited panel of antibodies with variable results. The aim of this study was to determine the efficacy of IHC in the diagnosis of SC and to provide some guidelines for interpretation in the diagnosis of these neoplasms. We studied 27 cases of SC with a broad panel of IHC markers using a tissue microarray technique. We also studied 21 control cases of basal cell carcinoma (BCC) and 22 control cases of squamous cell carcinoma (SCC). Representative tissue cores were taken and processed from each case, and the tissue microarrays were stained by standard methods using antibodies to EMA, CK7, Ber-EP4, Factor XIIIA, androgen receptor, p53, adipophilin, progesterone receptor membrane component 1 (PGRMC1), squalene synthase (SQS), and alpha/beta hydrolase domain-containing protein 5 (ABHD5). Our studies show that EMA was expressed in all cases of SC, CK7 was expressed in 24 of 27 cases, Ber-EP4 was expressed in 7 of 27 cases, Factor XIIIA was negative in all cases, androgen receptor was expressed in 9 of 27 cases, P53 was expressed in 12 of 27 cases, adipophilin was expressed in all cases, PGRMC1 was expressed in 22 of 27 cases, SQS was expressed in 11 of 27 cases, and ABHD5 was expressed in 9 of 27 cases. EMA was negative in all cases of BCC, CK7 was expressed in 6 of 21 cases, Ber-EP4 was expressed in 21 of 21 cases, Factor XIIIA was negative in all cases, androgen receptor was expressed in 3 of 21 cases, P53 was expressed in 4 of 21 cases, adipophilin, PGRMC1, SQS, and ABHD5 were negative in all cases of BCC. Similarly, EMA was expressed in 16 of 22 cases of SCC, CK7 was expressed in 2 of 22 cases, Ber-EP4, Factor XIIIA, and androgen receptor were negative in all cases, P53 was expressed in 3 of 22 cases, adipophilin, PGRMC1, SQS, and ABHD5 were negative in all cases of SCC. Our study indicates that adipophilin represents a sensitive and reliable marker for the diagnosis of SC and can be of help in separating this tumor from some of its mimics. Additionally, inclusion of various epithelial markers in the panel will be of help if adequately used. Other antibodies against the PAT family of lipid droplet-associated proteins including PGRMC1, SQS, and ABHD5 were not as sensitive as adipophilin for identifying sebaceous differentiation and may therefore not be as useful for differential diagnosis as adipophilin.

Our previous study detected aflatoxins in red chili peppers from Chile, Bolivia, and Peru, each of which have a high incidence of gallbladder cancer (GBC). Since the aflatoxin B1 concentration was not so high in these peppers, it is important to clarify the presence of other mycotoxins. Here we attempted to determine any associations between the concentrations of aflatoxins and ochratoxin A (OTA) in red chili peppers, and the corresponding GBC incidences. We collected red chili peppers from three areas in Peru: Trujillo (a high GBC incidence area), Cusco (an intermediate GBC incidence area), and Lima (a low GBC incidence rate), and from Chile and Bolivia. Aflatoxins and OTA were extracted with organic solvents. The concentrations of aflatoxins B1, B2, G1, and G2, and OTA were measured by high-performance liquid chromatography. The values obtained were compared with the incidence of GBC in each area or country. All of the red chili peppers from the three areas showed contamination with aflatoxins below the Commission of the European Communities (EC) recommended limits (5 μg/kg), but the OTA contamination of two samples was above the EC recommended limit (15 μg/kg). The mean concentrations of OTA in the peppers from Chile (mean 355 μg/kg, range <5-1,059 μg/kg) and Bolivia (mean 207 μg/kg, range 0.8-628 μg/kg), which has a high incidence of GBC, were higher than that in Peru (14 μg/kg, range <5-47 μg/kg), which has an intermediate GBC incidence. The OTA contamination in the red chili peppers from Chile, Bolivia, and Peru was stronger than that of aflatoxins. Our data suggest that OTA in red chili peppers may be associated with the development of GBC.

Atypical fibroxanthoma (AFX) is a low-grade, dermal, mesenchymal neoplasm, which lacks a specific lineage of differentiation. The classical histologic appearance of AFX is that of a pleomorphic and spindle cell neoplasm with marked nuclear pleomorphism, mitotic figures, and often prominent storiform pattern that superficially resembles a pleomorphic high-grade sarcoma ("malignant fibrous histiocytoma"). Many histologic variants have been described. We have reviewed 15 cases of AFX characterized by a pure spindle cell morphology that could be easily mistaken for other spindle cell dermal neoplasms. All of our cases were stained with CD68, CD163, CD10, S-100p, p63, wide-spectrum keratin, CD31, CD34, smooth muscle actin (SMA), desmin, calponin, and h-caldesmon. All 15 cases showed an immunoprofile consistent with AFX. In 9 cases, SMA was also strongly expressed; this finding, coupled with the malignant spindle cell histomorphology, can lead to an erroneous diagnosis of cutaneous leiomyosarcoma with potential clinical consequences. Awareness of this pattern of immunoreactivity in this unusual variant of AFX is of importance for avoiding diagnostic misinterpretation. This study intends to characterize the nature and frequency of SMA immunoreactivity in AFX and to discuss the potential diagnostic pitfalls of immunohistochemical markers in distinguishing this entity from other malignant spindle cell neoplasms.

OBJECTIVES: Differential pricing, based on countries' purchasing power, is recommended by the World Health Organization to secure affordable medicines. However, in developing countries innovative drugs often have similar or even higher prices than in high-income countries. We evaluated the potential implications of trastuzumab global pricing policies in terms of cost-effectiveness (CE), coverage, and accessibility for patients with breast cancer in Latin America (LA).
METHODS: A Markov model was designed to estimate life-years (LYs), quality-adjusted life-years (QALYs), and costs from a healthcare perspective. To better fit local cancer prognosis, a base case scenario using transition probabilities from clinical trials was complemented with two alternative scenarios with transition probabilities adjusted to reflect breast cancer epidemiology in each country.
RESULTS: Incremental discounted benefits ranged from 0.87 to 1.00 LY and 0.51 to 0.60 QALY and incremental CE ratios from USD 42,104 to USD 110,283 per QALY (2012 U.S. dollars), equivalent to 3.6 gross domestic product per capita (GDPPC) per QALY in Uruguay and to 35.5 GDPPC in Bolivia. Probabilistic sensitivity analysis showed 0 percent probability that trastuzumab is CE if the willingness-to-pay threshold is one GDPPC per QALY, and remained so at three GDPPC threshold except for Chile and Uruguay (4.3 percent and 26.6 percent, respectively). Trastuzumab price would need to decrease between 69.6 percent to 94.9 percent to became CE in LA.
CONCLUSIONS: Although CE in other settings, trastuzumab was not CE in LA. The use of health technology assessment to prioritize resource allocation and support price negotiations is critical to making innovative drugs available and affordable in developing countries.

The analysis of published epidemiological data on colon and breast cancer reveals a remarkable concordance for most regions of the world. A low incidence for both cancers has been recorded in Mongolia and Bolivia. Discrepant data, however, have been reported for India, Japan and Korea. In India, the incidence of breast cancer is significantly higher than for colon cancer, in Japan and Korea colon cancer exceeds by far the rate of breast cancer. Here, studies are summarized pointing to a species-specific risk for colon cancer after consumption of beef originating from dairy cattle. Uptake of dairy products of Bos taurus-derived milk cattle, particularly consumed at early age, is suggested to represent one of the main risk factors for the development of breast cancer. A recent demonstration of reduced breast cancer rates in individuals with lactose intolerance (Ji et al., Br J Cancer 2014; 112:149-52) seems to be in line with this interpretation. Species-specific risk factors for these cancers are compatible with the transmission of different infectious factors transferred via meat or dairy products. Countries with discordant rates of colon and breast cancer reveal a similar discordance between meat and milk product consumption of dairy cattle. The recent isolation of a larger number of novel presumably viral DNAs from serum, meat and dairy products of healthy dairy cows, at least part of them infectious for human cells, deserves further investigation. Systemic infections early in life, resulting in latency and prevention of subsequent infections with the same agent by neutralizing antibodies, would require reconsideration of ongoing prospective studies conducted in the adult population.

Hydroa vacciniforme-like lymphoma (HVL) is a rare cutaneous T-cell lymphoma that is usually seen in children of Hispanic or Asian origin. Association between chronic latent Epstein-Barr virus infection in both hydroa vacciniforme (HV) and HVL has been demonstrated and has recently been categorized by the World Health Organization as one of the Epstein Barr virus-positive lymphoproliferative disorders of childhood. Patients with HVL present with a cutaneous rash characterized by edema, blisters, ulcers, and scars mainly seen on the face and extremities that mimic HV; however, unlike in HV, the lesions tend to be extensive and deeper and are associated with severe scarring, necrosis, and systemic manifestations. We are reporting 7 cases of an unusual clinical variant of HVL with primarily periorbital edema. All of our patients in this series presented with progressive periorbital edema that was accompanied with systemic symptoms including fever, malaise, and lymphadenopathy. Most cases were initially misinterpreted as inflammatory processes including cellulitis, arthropod bite reactions, and periorbital lupus erythematosus. The biopsy of these lesions revealed an atypical lymphocytic infiltrate predominantly distributed in the deep dermis and in subcutaneous fat. Immunohistochemistry studies revealed a cytotoxic T-cell (CD8) profile. All cases were associated with Epstein-Barr virus infection. Our study presents a rare clinical variant of HVL with predominant periorbital edema. This variant could potentially be overlooked and misdiagnosed as an inflammatory condition; thus, it needs to be included in the differential diagnosis of periorbital edema in young patients.

Malignant melanoma in children, adolescents, and young adults is unusual, especially before puberty. In children (age, 0-14 years), most primary lesions are thick and atypical (amelanotic, simulating pyogenic granuloma). In the population of adolescents and young adults (age, 15-39 years), melanoma is the third most common cancer, only behind lymphoma and breast cancer. Our study investigated the records of 89 patients diagnosed with cutaneous melanoma at age 0-39 years at Hospital das Clínicas, Medical School, University of São Paulo between 1992 and 2002. They were divided into group A (0-14 years of age) and group B (15-39 years of age). The histopathology of all cases was reexamined. Statistical analysis of the data presented was performed, and the obtained data were compared with the literature. The frequency of melanoma in the group aged 15-39 years was higher in women, and the most affected site was the trunk. Additionally, melanomas were more frequent at an earlier age in patients with family history of melanoma (P = 0.014). Most cases were diagnosed, at histopathology, as superficial spreading melanoma. Thick nodular melanomas with Breslow values higher than 2 mm were associated with lymph node metastasis (P < 0.05). Our study revealed that melanoma in children, adolescents, and young adults may present peculiar behavior and outcome, which might reflect the genetic and yet not fully unraveled pathogenesis of this complex disease.

Although genetic characteristics are considered to be a factor influencing the geographic variation in the prevalence of gallbladder cancer (GBC), they have not been well studied in Bolivia, which has a high prevalence rate of GBC. The purpose of this study was to examine the frequency of TP53 and K-ras mutations in Bolivian patients with GBC and to compare them with our previous data obtained in other high-GBC-prevalence countries, namely Japan, Chile, and Hungary. DNA was extracted from cancer sites in paraffin-embedded tissue from 36 patients using a microdissection technique. TP53 mutations at exons 5 to 8 and K-ras mutations at codons 12, 13 and 61 were examined using direct sequencing techniques. The data obtained were compared with those in the other high-GBC-prevalence countries. Of the 36 patients, 18 (50.0%) had a TP53 mutation (one mutation in each of 17 patients and three mutations in one patient), and only one (2.8%) had a K-ras mutation. Of the 20 TP53 mutations, 12 were of the transition type (60.0%). This rate was significantly lower than that in Chile (12/12, P<0.05). In addition, three mutations were of the CpG transition type (15.0%), which is a feature of endogenous mutation. All three were found in the hot spot region of the TP53 gene. In contrast, G:C to T:A transversion was found in Bolivia, suggesting the presence of exogenous carcinogens. Our findings suggest that the development of GBC in Bolivia is associated with both exogenous carcinogens and endogenous mechanisms. The identification of an environmental risk factor for GBC is needed to confirm these findings.

BACKGROUND: Strategies to prevent gastric cancer by decreasing Helicobacter pylori infections in high-prevalence, low-income countries could include a population-based "screen and treat" eradication program.
METHODS: We tested residents of two rural villages for H. pylori infection using urea breath test (UBT), treated infected persons using directly observed therapy (DOT), retested for cure, and retested after 1 year later for H. pylori infection.
FINDINGS: We tested 1,065 (92%) of 1153 residents from two villages in rural Bolivia. Baseline H. pylori prevalence was 80% (95% confidence interval [CI]: 78-84). Age-specific cure rates were similar (≥92%) after DOT. Among those cured, 12% (95% CI: 8-15) had recurrent infection. Age-specific annual H. pylori recurrence rates for combined villages were 20% (95% CI: 10-29) in persons <5 years, 20% (95% CI: 10-29) in 5-9 years, 8% (95% CI: 1-15) in 10-14 years, and 8% (95% CI: 4-12) in persons ≥15 years. Compared with the referent population, those ≥15 years, recurrent infections were significantly more likely in children <5 years (odds ratios [OR] 2.7, 95% CI: 1.2-5.8) and 5-9 years (OR 2.7, 95% CI: 1.4-5.1).
INTERPRETATION: Children <10 years had high H. pylori recurrence rates following a population-based screen and treat program; this H. pylori eradication strategy may not be feasible in high-prevalence, low-income settings.

Spitz nevi are acquired melanocytic lesions with a wide histomorphological spectrum; reliable distinction from spitzoid melanoma is often difficult. Misdiagnoses of benign spitzoid tumors as spitzoid melanomas and vice versa are attributable to a frequently disturbing morphology and inconsistent or poorly defined histological criteria for diagnosis. Many recognized histological variants of Spitz nevi have been described, including the intradermal Spitz. Histopathologic descriptions of intradermal Spitz nevi have been done in the past; however, large studies addressing their histological spectrum have been lacking. We have retrospectively assessed the morphological features in 74 cases of intradermal Spitz nevi, excluding tumors clearly defined as atypical Spitz nevi and Spitzoid melanomas, to further delineate their histological spectrum. The patients' ages ranged from 5 to 81 years (median: 27). Anatomic location included: the upper extremities (27 cases), followed by head and neck (22 cases), lower extremities (9 cases), back (8 cases), buttock (5 cases), chest (1 case), and vulva (1 case). In 1 case, the anatomic location of the lesion was not available. Different histological variants were observed including hyalinized, polypoid, desmoplastic, angiomatoid, and halo Spitz. Morphological features evaluated included symmetry (100%), cell type (epithelioid 42%, spindle 16%, mixed 42%), maturation (85%), pigmentation (26%), chronic inflammation (24%), and mitotic activity (38%). Mild atypia was seen in 36 cases (49%), moderate atypia was seen in 28 cases (38%), and severe atypia was seen in 10 cases (14%). Intradermal Spitz nevus is a distinctive type of Spitz nevus that sometimes can be difficult to define given the unusual features that these lesions can show; thus, strict application of well-defined histological criteria and awareness of their morphological spectrum will facilitate definitive diagnosis.

BACKGROUND: Localized lymphedema is a nonneoplastic condition associated with obesity and predominantly involving the legs. This condition has distinctive clinical and histologic features and only rarely has been mentioned in the dermatologic literature.
OBJECTIVE: We sought to evaluate the clinical and histopathologic features.
METHODS: The clinicopathologic features in patients with localized lymphedema of the genital region were studied.
RESULTS: We identified 18 patients with localized lymphedema clinically presenting as large polypoid or verrucous lesions. The patients were 5 men and 13 women with a mean age of 46.5 years. Twelve patients were obese at diagnosis. Thirteen patients presented with tumors involving the vulva, 4 patients with tumors in the penis and scrotum, and 1 patient with scrotal and pubic lesions. Histologically, all cases showed marked dermal edema along with dilated lymphatic spaces, fibroplasia, and verrucous epidermal changes (papillomatous and hyperplastic epidermis).
LIMITATIONS: Only 18 cases were included in our study.
CONCLUSIONS: This condition is an uncommon and recently described entity that could potentially be clinically and histologically misdiagnosed as a neoplasm; thus, it needs to be included in the differential diagnosis of polypoid and verrucous skin tumors with extensive dermal edema and fibroplasia.

Low-grade B-cell lymphomas of the skin, especially, primary cutaneous follicle center cell lymphoma has several distinctive features when compared with nodal/systemic follicular lymphomas, as they are frequently negative for bcl-2 and CD10, and only fewer than 25% of the cases show a bcl-2 rearrangement. The risk of transformation of a cutaneous low-grade B-cell lymphoma, such as primary cutaneous follicle center cell lymphoma, to primary cutaneous diffuse large B-cell lymphomas (PCDLBCL) has not been clearly delineated in the literature. Transformation of systemic/nodal follicular lymphoma into aggressive DLBCL is associated with rapid disease progression, refractoriness to treatment, and poor prognosis. The authors studied 82 cases of primary cutaneous DLBCL using antibodies for follicular dendritic cells (FDCs), CD21, and CD35 to detect networks of FDCs that could possibly indicate transformation of preexisting low-grade B-cell lymphoma to PCDLBCL. All cases were classified as PCDLBCL using strict histologic and immunophenotypic criteria. Fifty-three cases were classified as primary cutaneous DLBCL of "leg type," and 29 cases were classified as primary cutaneous DLBCL, "NOS" category. Immunohistochemical studies were performed in all 82 cases; in 15 cases, a CD21/CD35+ network of FDCs was noted within the tumor, indicating the presence of remnants of residual germinal centers, suggesting the possibility of a transformed low-grade B-cell lymphoma. In summary, the authors' findings seem to indicate that some cases of primary cutaneous DLBCL may result from transformation of a low-grade B-cell lymphoma. Further studies are necessary to evaluate the significance of their findings by using ancillary techniques including genetic analysis.

BACKGROUND: Fibrolipomatous hamartoma of the nerve is a rare benign infiltrating condition of peripheral nerves with prominent cutaneous findings that has not being well described in the dermatologic and dermatopathologic literature.
OBJECTIVE: We sought to evaluate the clinical and histopathological features of this rare condition.
METHODS: We reviewed the clinicopathologic features of 13 cases to delineate their clinical presentation and histopathologic spectrum.
RESULTS: All patients presented with unilateral lesions on the thenar areas, fingers, or both. In 7 cases the lesions presented congenitally and in 6 cases the lesions presented sporadically. Histologically, we found 2 patterns that have only been rarely mentioned before including cases with intraneural perineurioma-like features and cases with marked nerve hyperplasia.
LIMITATIONS: Only 13 cases were included in our study.
CONCLUSIONS: This condition is an uncommon entity. The diagnosis of this disorder can be highly suspected on its macroscopic features. Predilection of the median nerve and the frequent association with macrodactyly are characteristic clinical findings.

PURPOSE: Abdominal cerebrospinal fluid (CSF) pseudocyst is a rare but important complication in patients with ventriculoperitoneal shunt (VPS). In addition to presenting our experience, we performed a comparative analysis between children and adults with this entity. To the author's knowledge, there are no studies in which this condition has been compared.
METHODS: The PubMed database was searched for all relevant reports published from 1954 to 2012. The differences were statistically compared, especially regarding clinical investigations, etiology of the hydrocephalus, shunt revision, CSF infection, treatment, and recurrence. Chi-square test or Fisher's exact test was used to find associations among the variables.
RESULTS: Compiled from literature, we found 393 cases of abdominal pseudocyst: 295 children, including our cases, and 55 adults, with age not informed in 43 cases. In children, 33 % of the patients have a positive culture on presentation, with higher incidence in children younger than 10 years. In contrast, only 15 % among adults were positive CSF culture. In total, 287 abdominal pseudocyst cases who underwent shunt revision have been reported; 78.4 % of children and 62.2 % of adults. The main occurrence of this complication according to the etiology of hydrocephalus in children was different from adults. The recurrence of pseudocyst occurred in 19.8 and 24.2 % of children and adults, respectively.
CONCLUSIONS: The differences between children and adults might represent distinct trends on the etiology and treatment of this entity. Hence, additional well-designed cohort studies will be necessary to strengthen our findings.