Evaluación del acceso al tratamiento oportuno del cáncer de cérvix según clase social, en efectores de atención médica de provincias argentinas / Evaluation of access to timely treatment of cervical cancer according to social class, in health care providers from Argentine provinces

INTRODUCCIÓN El cáncer de cérvix tiene relevancia sanitaria por su morbilidad, mortalidad e impacto económico. La problematización sobre las determinaciones del acceso puede ayudar a disminuir el daño. OBJETIVOS Contribuir a la problematización sobre determinaciones del acceso al diagnóstico y tratamiento (DyT) y sus diferencias en medio público y privado (PyP), y en provincias de distintas regiones de Argentina. MÉTODOS Se trató de un estudio cualitativo, descriptivo-analítico de corte transversal, en el que la muestra se conformó con un hospital y una clínica por provincia, en cinco provincias argentinas. Los datos provinieron de entrevistas semiestructuradas y observación participante; en cuanto al análisis, se realizó con evaluación del discurso sobre percepción de las pacientes y del personal de salud, acerca de las determinaciones de acceso. RESULTADOS En el sector público se afronta la situación con mayor compromiso emocional, lo cual dificulta el tratamiento. No hay grandes diferencias de conocimiento técnico sobre prevención del cáncer de cérvix entre medios PyP, pero en el público existe menor adherencia a prácticas preventivas debido a problemas familiares, laborales y a mecanismos inadecuados de acceso. La comunicación médico-paciente sobre el proceso DyT es siempre deficiente, pero alcanza situaciones de maltrato en el medio público con mayor frecuencia. El manejo del pudor y la exposición corporal es muy deficiente en ambos medios. En el sector público se produce durante el DyT, un impacto grave en las familias por ruptura de vínculos de pareja, fracasos escolares en los hijos y catástrofes de la economía doméstica, hechos que a su vez influyen en el acceso. DISCUSIÓN En todos los aspectos estudiados existen desventajas claras de las pacientes del medio público, atribuibles a la situación socio-económica-laboral de las familias y al funcionamiento de los hospitales, más que a cuestiones culturales. Las diferencias entre provincias no son relevantes. Existe un profundo déficit de la función protectora del Estado sobre la población aludida

Multiregion whole-exome sequencing of matched primary and metastatic tumors revealed genomic heterogeneity and suggested polyclonal seeding in colorectal cancer metastasis.

BACKGROUND: Distant metastasis accounts for 90% of deaths from colorectal cancer (CRC). Genomic heterogeneity has been reported in various solid malignancies, but remains largely under-explored in metastatic CRC tumors, especially in primary to metastatic tumor evolution. PATIENTS AND METHODS: We conducted high-depth whole-exome sequencing in multiple regions of matched primary and metastatic CRC tumors. Using a total of 28 tumor, normal, and lymph node tissues, we analyzed inter- and intra-individual heterogeneity, inferred the tumor subclonal architectures, and depicted the subclonal evolutionary routes from primary to metastatic tumors. RESULTS: CRC has significant inter-individual but relatively limited intra-individual heterogeneity. Genomic landscapes were more similar within primary, metastatic, or lymph node tumors than across these types. Metastatic tumors exhibited less intratumor heterogeneity than primary tumors, indicating that single-region sequencing may be adequate to identify important metastasis mutations to guide treatment. Remarkably, all metastatic tumors inherited multiple genetically distinct subclones from primary tumors, supporting a possible polyclonal seeding mechanism for metastasis. Analysis of one patient with the trio samples of primary, metastatic, and lymph node tumors supported a mechanism of synchronous parallel dissemination from the primary to metastatic tumors that was not mediated through lymph nodes. CONCLUSIONS: In CRC, metastatic tumors have different but less heterogeneous genomic landscapes than primary tumors. It is possible that CRC metastasis is, at least partly, mediated through a polyclonal seeding mechanism. These findings demonstrated the rationale and feasibility for identifying and targeting primary tumor-derived metastasis-potent subclones for the prediction, prevention, and treatment of CRC metastasis.

Cervical metastasis on level IV in laryngeal cancer.

The presence of cervical metastasis has substantial negative impact on survival of patients with laryngeal cancer. Bilateral elective selective neck dissection of levels II, III and IV is usually the chosen approach in these patients. However, there is significant morbidity associated with level IV dissection, such as phrenic nerve injury and lymphatic fistula. The objective of the present study was to evaluate the frequency of metastatic nodes in level IV in clinically T3/T4N0 patients with laryngeal cancer. The pathological reports of 77 patients with clinically T3/T4N0 laryngeal squamous cell carcinoma were reviewed. Patients underwent bilateral lateral neck dissection from January 2007 to November 2012. The surgical specimens were subdivided in levels before evaluation. There were 12 patients with neck metastasis (15.58%). In 3 cases (3.89%), there were metastatic lymph nodes in level IV, all T4 and with ipsilateral metastasis. In conclusion, the incidence of level IV metastasis was 3.89%, an in all patients was staged as T4.

Tricuspid valve injury after heart transplantation due to endomyocardial biopsy: an analysis of 3550 biopsies.

INTRODUCTION: Tricuspid regurgitation (TR) is the most commonly valvular dysfunction found after heart transplantation (HTx). It may be related to endomyocardial biopsy (EMB) performed for allograft rejection surveillance. OBJECTIVE: This investigation evaluated the presence of tricuspid valve tissue fragments obtained during routine EMB performed after HTx and its possible effect on short-term and long-term hemodynamic status. METHOD: This single-center review included prospectively collected and retrospectively analyzed data. From 1985 to 2010, 417 patients underwent 3550 EMB after HTx. All myocardial specimens were reviewed to identify the presence of tricuspid valve tissue by 2 observers initially and in doubtful cases by a third observer. The echocardiographic and hemodynamic parameters were only considered for valvular functional damage analysis in cases of tricuspid tissue inadvertently removed during EMB. RESULTS: The 417 HTx patients to 3550 EMB, including 17,550 myocardial specimens. Tricuspid valve tissue was observed in 12 (2.9%) patients corresponding to 0.07% of the removed fragments. The echocardiographic and hemodynamic parameters of these patients before versus after the biopsy showed increased TR in 2 cases (2/12; 16.7%) quantified as moderate without progression in the long term. Only the right atrial pressure showed a significant increase (P = .0420) after tricuspid injury; however, the worsening of the functional class was not significant enough in any of the subjects. Thus, surgical intervention was not required. CONCLUSIONS: Histological evidence of chordal tissue in EMB specimens is a real-world problem of relatively low frequency. Traumatic tricuspid valve injury due to EMB rarely leads to severe valvular regurgitation; only a minority of patients develop significant clinical symptoms. Hemodynamic and echocardiographic alterations are also less often observed in most patients.

Comparative analysis of the complications of 5347 endomyocardial biopsies applied to patients after heart transplantation and with cardiomyopathies: a single-center study.

INTRODUCTION: Endomyocardial biopsy (EMB) plays an important role in allograft surveillance to screen an acute rejection episode after heart transplantation (HT), to diagnose an unknown cause of cardiomyopathies (CMP) or to reveal a cardiac tumor. However, the procedure is not risk free. OBJECTIVE: The main objective of this research was to describe our experience with EMB during the last 33 years comparing surgical risk between HT versus no-HT patients. METHOD: We analyzed retrospectively the data of 5347 EMBs performed from 1978 to 2011 (33 years). For surveillance of acute rejection episodes after HT we performed 3564 (66.7%), whereas 1777 (33.2%) for CMP diagnosis, and 6 (1.0%) for cardiac tumor identification. RESULTS: The main complications due to EMB were divided into 2 groups to facilitate analysis: major complications associated with potential death risk, and minor complications. The variables that showed a significant difference in the HT group were as follows: tricuspid injury (.0490) and coronary fistula (.0000). Among the no-HT cohort they were insufficient fragment (.0000), major complications (.0000) and total complications (.0000). CONCLUSIONS: EMB can be accomplished with a low risk of complications and high effectiveness to diagnose CMP and rejection after HT. However, the risk is great among patients with CMP due to their anatomic characteristics. Children also constitute a risk group for EMB due to their small size in addition to the heart disease. The risk of injury to the tricuspid valve was higher among the HT group.

Prognostic significance of high-grade dysplasia in colorectal adenomas.

AIM: Colonoscopy to detect and remove polyps has contributed to a reduction in colorectal carcinoma. Three-year follow up is recommended for patients considered to be at high risk (at least three adenomas, adenoma ≥ 1 cm, villous or high-grade features). Our study focused on patients diagnosed with high-grade dysplasia with regard to initial management and follow up. METHOD: A search of patients who had had endoscopic removal of a high-grade adenoma was carried out. Patients with the following were excluded: follow up of < 1 year, polyposis syndromes, prior colon cancer and a diagnosis of adenocarcinoma within 6 months following initial diagnosis. RESULTS: Eighty-three patients treated between 1999 and 2007 for high-grade dysplasia (HGD) in a colorectal adenoma were identified. Over a median follow-up period of 4 years, 53 (64%) developed further adenomatous polyps. Among these, 7% had an adenoma with HGD or an adenocarcinoma. In all these patients, the initial high-grade adenoma was > 1 cm in diameter. Initial follow-up colonoscopy was performed on average 7 months following the initial diagnosis. Ten per cent of patients underwent prophylactic segmental resection, and 6% received argon laser therapy. CONCLUSION: The study demonstrates that patients who have a colorectal adenoma > 1 cm with HGD may be at high risk of developing further adenomas with HGD or carcinoma. Close follow up is warranted.

MITOSTATIN, a putative tumor suppressor on chromosome 12q24.1, is downregulated in human bladder and breast cancer.

Allelic deletions on human chromosome 12q24 are frequently reported in a variety of malignant neoplasms, indicating the presence of a tumor suppressor gene(s) in this chromosomal region. However, no reasonable candidate has been identified so far. In this study, we report the cloning and functional characterization of a novel mitochondrial protein with tumor suppressor activity, henceforth designated MITOSTATIN. Human MITOSTATIN was found within a 3.2-kb transcript, which encoded a approximately 62 kDa, ubiquitously expressed protein with little homology to any known protein. We found homozygous deletions and mutations of MITOSTATIN gene in approximately 5 and approximately 11% of various cancer-derived cells and solid tumors, respectively. When transiently overexpressed, MITOSTATIN inhibited colony formation, tumor cell growth and was proapoptotic, all features shared by established tumor suppressor genes. We discovered a specific link between MITOSTATIN overexpression and downregulation of Hsp27. Conversely, MITOSTATIN knockdown cells showed an increase in cell growth and cell survival rates. Finally, MITOSTATIN expression was significantly reduced in primary bladder and breast tumors, and its reduction was associated with advanced tumor stages. Our findings support the hypothesis that MITOSTATIN has many hallmarks of a classical tumor suppressor in solid tumors and may play an important role in cancer development and progression.

Cytokeratin profiles of male breast cancers.

AIMS: The prognostic factors and expression of molecular markers in male breast carcinomas are similar to those in female breast cancers. The identification of distinct cytokeratin (CK) profiles (basal as opposed to luminal cells) helps to identify subsets of tumours with different clinical behaviour. The aim of this study was to investigate CK expression in male breast cancer. METHODS AND RESULTS: Thirty-two cases of male breast cancer were studied. The panel of CKs studied by immunohistochemistry included: 5/6, 14, 17, 18 and 19. Pathological findings and CK expression were analysed in all cases. Histological patterns included ductal carcinoma in situ, invasive ductal carcinoma and mixed patterns. Four cases were positive for CK5/6 and CK14, identifying a basal-like phenotype. CK17 was negative in all but two cases. All cases expressing either CK5/6 or CK14 were invasive carcinomas of high nuclear and histological grade and were also larger compared with the tumours not expressing CK5/6 and CK14. All tumours except three (also negative for CK5/6) expressed CK18 and CK19. The four basal-like tumours were negative for Her-2 expression. CONCLUSIONS: Male breast carcinomas have a basal-like phenotype that is similar in frequency to that of female breast carcinomas. The expression of CK5/6 and CK14 identifies a subset of pathologically aggressive male breast cancers.

Fibroblast growth factor-binding protein expression changes with disease progression in clinical and experimental human squamous epithelium.

Basic fibroblast growth factor (bFGF) is synthesized by a wide variety of normal and malignant cells. However, bFGF cannot exert its effects unless it gets outside of the cell. Since it lacks a signal sequence to direct secretion, the method by which cells release it remains unclear. A 17 kDa secreted binding protein for bFGF (FGF-BP, HBp-17) is expressed at high levels in squamous cell carcinoma (SCC) and transformed keratinocytes and may act as a chaperone to transport bFGF outside of the cell. In our study, FGF-BP mRNA expression in normal keratinocytes was higher than in 5/5 SCCs. Using a new monoclonal antibody, we demonstrate that FGF-BP can dimerize. Immunoassays demonstrate that normal keratinocytes have a higher level of FGF-BP than SCCs. In normal human squamous epithelium, we observed diffuse, moderate to intense cytoplasmic and membranous expression of FGF-BP. Expression decreased and became focal with disease progression to invasive cancer. Injection of immortalized but non-tumorigenic HaCaT cells transduced with FGF-BP into normal human skin xenografts failed to result in tumors. Transfection of FGF-BP into the SCCs Det 562 and FaDu did not promote tumor growth more than controls, and peri-tumoral microvessel density was lower in FGF-BP-transfected than in control tumors. Taken together, these data suggest that FGF-BP expression in squamous epithelium does not play an important role in progression to invasive carcinoma.

p53 protein expression and gene mutation in phyllodes tumors of the breast.

The malignant potential of mammary phyllodes tumors is difficult to assess on initial pathologic examination. Studies on the p53 tumor suppressor gene have shown that it has an important role in the development of a variety of malignancies, yet the specific contribution to the pathogenesis and development of the malignant potential of phyllodes tumor is largely unknown. We studied p53 protein expression in 25 cases of phyllodes tumors histologically classified as either malignant (12 cases) or benign (13 cases). Using microdissection approach, we also analyzed the p53 gene sequence in a case that demonstrated progression from benign to malignant phenotype. Nuclear p53 staining was detected in various proportions (1-90%) of neoplastic stromal cells of malignant tumors. No staining was found in benign tumors. Progression from benign to malignant phenotype was associated with a significant increase in the accumulation of p53 (more than 20 times). This was caused by an underlying missense mutation in exon 7, resulting in a change from Arg248 to Trp248 in the malignant component of the tumor. Stromal p53 over-expression was observed only in neoplasms histologically classified as malignant and was associated with an increased proliferation index (MIB-1 staining). These two markers may be used as useful adjuncts in the diagnosis of malignancy in difficult cases or when only a limited sample size is available. Somatic mutation in exon 7 of p53 gene in malignant phyllodes tumor points toward the importance of p53 in the malignant transformation of phyllodes tumors.

Pathologic features of Hashimoto's-associated papillary thyroid carcinomas.

Some investigators have found an increased incidence of papillary carcinoma (PC) of the thyroid in patients with Hashimoto's (autoimmune) thyroiditis (HT), which raises the possibility that there may be more than an incidental association between these 2 diseases. In this study, we analyzed the pathology of Hashimoto's-associated thyroid carcinomas to see if these tumors showed any distinctive features. The possible significance of solid cellular nodules as preneoplastic lesions in patients with HT was investigated. A review of all the cases of HT during a 16-year period yielded 30 PC and 3 follicular carcinomas (FC). Within the PC there were 7 (23%) follicular variants. Twenty (67%) of the PC showed various degree of intratumoral fibrosis, ranging from thick fibrous septa separating tumor nodules to almost complete obliteration of the tumor by the fibrosis, with only microscopic residual tumor nests. In most of the cases, the desmoplastic response within the tumors was of the fibromatosis-like type with dense hyalinized collagen and bland-appearing spindle cells. All the tumors, independently of the degree of fibrosis, showed the nuclear features of PC. No correlation was found between the degree of fibrosis in the tumors and the thyroid gland outside the tumors. There were tumors with marked fibrosis without fibrosis outside the tumors. Four cases of PC (13%) showed a growth pattern characterized by cystic spaces with thick hyalinized walls and focal papillary hyperplasia lined by flat and cuboidal epithelium, reminiscent of a vascular neoplasm. There were 4 atypical solid microscopic nodules with confluent cellularity; 2 of them associated with a PC and the other 2 with diffuse HT without PC. These nodules were composed of cells with clear nuclei and occasional grooves without nuclear pseudoinclusions. By immunohistochemistry, 2 of 3 nodules showed cytoplasmic reactivity for cytokeratin 19, and 2 of 3 nodules were positive for the RET/PTC (rearranged during transfection, papillary thyroid carcinoma) antibody. In summary, HT-associated PC may frequently display prominent stromal desmoplasia and a pseudovascular pattern, both of which can present diagnostic difficulties if the cytologic features of PC are not recognized because of the marked obliteration of the tumor by the fibrosis. Atypical nodules may represent a precursor lesion of PC in patients with HT.

Follicular carcinoma of the thyroid with extensive clear-cell differentiation: a potential diagnostic pitfall.

Clear-cell features have been recognized in several different thyroid neoplasms. A case of thyroid follicular carcinoma with extensive clear- and Hurthle-cell features is described in a 37-yr-old white female, with cytochemical and immunohistochemical analysis. The tumor of the thyroid gland, with anterior neck soft-tissue extension, displayed clear cells on fine-needle aspiration, which were negative for thyroglobulin. The surgical specimen displayed predominately clear cells (80%), and only the nonclear-cell areas stained for thyroglobulin. Proper categorization of clear-cell lesions of the thyroid and soft tissues requires a multimodality approach, involving clinical/pathological correlation, morphological analysis, and ancillary tissue studies. Immunohistochemical stains for thyroglobulin are quite definitive in making the distinction between primary clear-cell thyroid tumors vs. metastatic clear-cell tumors. Cytologists should be aware, however, that the clear-cell areas of thyroid tumors might not stain for thyroglobulin.

Overexpression of p21WAF1/CIP1 and MDM2 characterizes serous borderline ovarian tumors.

Ovarian epithelial tumors are classically divided into benign, malignant, and borderline or of low malignant potential. It is controversial whether this last group of tumors should be considered benign or malignant. Expression of cell cycle markers has recently been linked to tumor behavior and response to treatment. It has been shown that one of the pathways through which the p53 gene controls the cell cycle is by transactivating p21WAF1/CIP1, a cyclin-dependent kinase (cdk) inhibitor. By inhibiting cdks, p21WAF1/CIP1 blocks the G-1 to S-phase transition in the cell cycle. p53 can be regulated by MDM2 (murine double minute-2) through direct inactivation or promotion of its cytoplasmic degradation. In an attempt to investigate the cell cycle checkpoint mechanisms of these tumors, we studied the expression of p53, Ki-67, MDM2, and p21WAF1/CIP1 by immunohistochemistry. We analyzed the expression of these proteins in 19 cystadenomas (8 serous and 11 mucinous), 40 borderline tumors (31 serous and 9 mucinous), and 18 serous carcinomas of the ovary. p21WAF1/CIP1 was expressed in 7 of 19 (37%) benign cystadenomas, 32 of 40 (80%) borderline tumors (93.5% of serous and 33% of mucinous), and in 9 of 18 (50%) serous carcinomas. Ki-67 was only weakly expressed in 8 of 19 (42%) benign cystadenomas, all borderline tumors showed Ki-67 staining in less than 50% of the cells, and 55% of serous carcinomas stained in more than 50% of tumor cells. p53 was absent in all but 1 of the cystadenomas, was expressed in 9 of 40 (22.5%) borderline tumors (25.8% of serous and 11% of mucinous), and in 10 of 18 (55%) carcinomas. All 11 implants of serous borderline tumors expressed p21WAF1/CIP1. Most serous borderline tumors expressed higher levels of MDM2 compared with the benign cystadenomas and carcinomas. Four of the serous borderline implants (40%) expressed MDM2. Coexpression of p21WAF1/CIP1 and MDM2 characterizes serous borderline tumors of the ovary and their implants, which suggests that these cell cycle control proteins are important in these tumors and may be related to tumor progression. Low expression of p53 protein in serous borderline tumors might be in part mediated by MDM2. This suggests that the p53 pathway is intact in most of these tumors, in contrast with carcinomas, in which high expression of p53 has been related to mutations of this gene.

Treatment of inflammatory bowel disease in a rodent model with the intestinal growth factor glucagon-like peptide-2.

BACKGROUND/PURPOSE: Microinjection of a Fisher (F344) rat zygote with human HLA-B27 and beta2-microglobulin genes induces spontaneous chronic gastrointestinal (GI) inflammation similar to lesions seen in patients with inflammatory bowel disease (IBD). This study was designed to evaluate the potential therapeutic benefit of GLP-2, an intestinal growth factor, in this transgenic rat model of IBD. METHODS: Five F344 (control) and 10 HLA-B27 (on a F344 background) rats at 25 weeks of age were used. Rats were divided into the following 3 groups: group 1, F344 rats, no treatment (n = 5); group 2, HLA-B27, no treatment (n = 5); and group 3, HLA-B27, treated with a 14-day systemic infusion (via the jugular vein) of GLP-2 at 50 microg/kg/d (n = 5). After infusion, all rats underwent laparotomy, and the intestine from the ligament of Treitz to the rectum was harvested. Total mucosal damage (percent surface area) was measured using image analysis software (Sigmascan 2.0). Microscopic analysis was performed by a blinded reviewer and scored as follows: 0, no inflammation; 1, mild inflammation; 2, moderate inflammation; and 3, severe inflammation. Colonic mucosal total RNA was assayed for tumor necrosis factor alpha (TNF-alpha), interferon-gamma (IFN-gamma), interleukin-2 (IL-2), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), internal standard, mRNA by reverse transcriptase polymerase chain reaction. Statistical analysis was performed using analysis of variance (ANOVA) and expressed as mean +/- SEM. RESULTS: Normal F344 rats did not show evidence of gross or histological lesions in the small or large intestine. GLP-2 reduced total mucosal damage from 9.0% +/- 0.7% in group 2 to 0.9% +/- 0.5% in group 3 (P < .01). The histological lesion score was reduced from 7.0 +/- 0.6 in group 2 to 4.4 +/- 0.8 in group 3 (P < .01). Furthermore, GLP-2 reduced the mean band intensity (MBI) of TNF-alpha (0.4 +/- 0.04 in group 2 to 0 in group 3, P < .01) and IFN-gamma (0.3 +/- 0.02 in group 2 to 0 in group 3, P < .01). CONCLUSIONS: These data show for the first time that GLP-2 significantly reduces gross (90% decrease) and histological (40% decrease) lesions in this rat model of IBD. This is further supported by a significant decrease in gene expression of the inflammatory mediators TNF-alpha (100% decrease) and IFN-gamma (100% decrease). These data suggest a potential therapeutic role for GLP-2 in IBD.

Neoplastic progression occurs through mutator pathways in hyperplastic polyposis of the colorectum.

AIM: Colorectal cancer has been described in association with hyperplastic polyposis but the mechanism underlying this observation is unknown. The aim of this study was to characterise foci of dysplasia developing in the polyps of subjects with hyperplastic polyposis on the basis of DNA microsatellite status and expression of the DNA mismatch repair proteins hMLH1, hMSH2, and hMSH6. MATERIALS AND METHODS: The material was derived from four patients with hyperplastic polyposis and between one and six synchronous colorectal cancers. Normal (four), hyperplastic (13), dysplastic (13), and malignant (11) samples were microdissected and a PCR based approach was used to identify mutations at 10 microsatellite loci, TGFbetaIIR, IGF2R, BAX, MSH3, and MSH6. Microsatellite instability-high (MSI-H) was diagnosed when 40% or more of the microsatellite loci showed mutational bandshifts. Serial sections were stained for hMLH1, hMSH2, and hMSH6. RESULTS: DNA microsatellite instability was found in 1/13 (8%) hyperplastic samples, in 7/13 (54%) dysplastic foci, and in 8/11 (73%) cancers. None of the MSI-low (MSI-L) samples (one hyperplastic, three dysplastic, two cancers) showed loss of hMLH1 expression. All four MSI-H dysplastic foci and six MSI-H cancers showed loss of hMLH1 expression. Loss of hMLH1 in MSI-H but not in MSI-L lesions showing dysplasia or cancer was significant (p<0.001, Fisher's exact test). Loss of hMSH6 occurred in one MSI-H cancer and one MSS focus of dysplasia which also showed loss of hMLH1 staining. CONCLUSION: Neoplastic changes in hyperplastic polyposis may occur within a hyperplastic polyp. Neoplasia may be driven by DNA instability that is present to a low (MSI-L) or high (MSI-H) degree. MSI-H but not MSI-L dysplastic foci are associated with loss of hMLH1 expression. At least two mutator pathways drive neoplasia in hyperplastic polyposis. The role of the hyperplastic polyp in the histogenesis of sporadic DNA microsatellite unstable colorectal cancer should be examined.

Follicular carcinoma of the thyroid with extensive clear-cell differentiation: a potential diagnostic pitfall.

Clear-cell features have been recognized in several different thyroid neoplasms. A case of thyroid follicular carcinoma with extensive clear- and Hurthle-cell features is described in a 37-yr-old white female, with cytochemical and immunohistochemical analysis. The tumor of the thyroid gland, with anterior neck soft-tissue extension, displayed clear cells on fine-needle aspiration, which were negative for thyroglobulin. The surgical specimen displayed predominately clear cells (80%), and only the nonclear-cell areas stained for thyroblobulin. Proper categorization of clear-cell lesions of the thyroid and soft tissues requires a multimodality approach, involving clinical/pathological correlation, morphological analysis, and ancillary tissue studies. Immunohistochemical stains for thyroglobulin are quite definitive in making the distinction between primary clear-cell thyroid tumors vs. metastatic clear-cell tumors. Cytologists should be aware, however, that the clear-cell areas of thyroid tumors might not stain for thyroglobulin.

Colorectal carcinomas with high microsatellite instability: defining a distinct immunologic and molecular entity with respect to prognostic markers.

Molecular analysis of hereditary nonpolyposis colorectal carcinomas (HNPCC) has identified DNA mismatch repair deficiencies with resulting microsatellite instability (MSI) as a pathway of carcinogenesis that appears to be relevant for prognosis, treatment, and possibly prevention. In this study, expression of cell cycle proteins and other known prognostic markers is correlated with the microsatellite status of colorectal cancers (CRC). One hundred consecutive cases from the CRC Registry at Thomas Jefferson University were analyzed for MSI. Immunohistochemistry was performed for the mismatch repair proteins hMLH1 and hMSH2, tumor suppressor p53, apoptosis inhibitor bcl-2, cell cycle proteins p21(WAF1/CIP1), and p27 and the proliferation markers Ki-67 and topoisomerase II. High MSI (MSI-H) is significantly correlated with loss of either hMLH1 or hMSH2, presence of bcl-2, and absence of p53. p21(WAF1/CIP1) is positive in all tumors with MSI-H. Previous findings of a lower proliferation rate were confirmed with a topoisomerase II stain. Microsatellite stable (MSS) tumors generally express both MSH2 and MLH1. Other highly significant differences are positive p53 in 56% of MSS cases and negative bcl-2 in 98% of MSS cases. p27 expression is found in approximately 50% of all CRCs irrespective of the microsatellite status. MSI-H tumors follow the mutator pathway, with loss of expression of one mismatch repair protein, wild-type p53, lower proliferation, and positivity for p21(WAF1/CIP1). MSS tumors follow the suppressor pathway, characterized by p53 overexpression, higher proliferation, and absence of bcl-2 expression; p21(WAF1/CIP1) expression can be variable. These data provide a molecular basis for the clinical observation that patients with HNPCC appear to have a more favorable prognosis. HUM PATHOL 31:1506-1514.