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Renal medullary carcinoma (RMC) is a highly aggressive renal cell carcinoma arising in the collecting system and requiring careful correlation with status of sickle cell trait. A panel of international experts has recently proposed provisional diagnostic terminology, renal cell carcinoma, unclassified, with medullary phenotype, based on encountering an extraordinarily rare tumor with RMC morphology and immunophenotype in an individual proven not to have a hemoglobinopathy. Herein, we extend this observation to a cohort of 5 such tumors, morphologically similar to RMC, lacking SMARCB1 expression by immunohistochemistry, but each without evidence of a hemoglobinopathy. The tumors arose in 4 men and 1 woman with a mean age of 44 years, occurring in 3 left and 2 right kidneys. Clinically, aggression was apparent with involvement of perinephric adipose tissue in all 5 cases, nodal metastasis in 4 of 5 cases, and death of disease in 4 of 5 cases within 3-27 months. Histologic sections showed poorly differentiated adenocarcinoma, often with solid and nested growth patterns, as well as infiltrative glandular, tubulopapillary, cribriform, or reticular growth. Rhabdoid and sarcomatoid cytomorphology was seen in a subset. All tumors showed PAX8 nuclear positivity and SMARCB1 loss, with OCT3/4 expression in 4 of 5 cases. In summary, this first series of renal cell carcinoma, unclassified, with medullary phenotype documents tumors with morphologic, immunophenotypic, and prognostic features of RMC occurring in individuals without sickle cell trait. Although greater biologic and molecular understanding is needed, the available evidence points to these cases representing a sporadic counterpart to sickle cell trait-associated RMC., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Colorectal medullary carcinoma, recognized by the World Health Organization as a distinct histologic subtype, is commonly regarded as a specific entity with an improved prognosis and unique molecular pathogenesis. A fundamental but as yet unaddressed question, however, is whether it can be diagnosed reproducibly. In this study, by analyzing 80 colorectal adenocarcinomas whose dominant growth pattern was solid (thus encompassing medullary carcinoma and its mimics), we provided a detailed description of the morphological spectrum from "classic medullary histology" to nonmedullary poorly differentiated histologies and demonstrated significant overlapping between categories. By assessing a selected subset (n=30) that represented the spectrum of histologies, we showed that the interobserver agreement for diagnosing medullary carcinoma by using 2010 World Health Organization criteria was poor; the κ value among 5 gastrointestinal pathologists was only 0.157 (95% confidence interval, 0.127-0.263; P=.001). When we arbitrarily classified the entire cohort into "classic" and "indeterminate" medullary tumors (group 1, n=19; group 2, n=26, respectively) and nonmedullary poorly differentiated tumors (group 3, n=35), groups 1 and 2 were more likely to exhibit mismatch repair protein deficiency than group 3 (P<.001); however, improved survival could not be detected in either group compared with group 3. Our findings suggest that the diagnosis of medullary carcinoma, as currently applied, may only serve as a morphological descriptor indicating an increased likelihood of mismatch-repair deficiency. Additional evidence including a more objective classification system is needed before medullary carcinoma can be regarded as a distinct entity with prognostic relevance. Until such evidence becomes available, caution should be exercised when making this diagnosis, as well as when comparing results across different studies., (Copyright © 2016 Elsevier Inc. All rights reserved.)

A third to half of penile invasive squamous cell carcinomas are human papillomavirus (HPV) related. Warty (condylomatous), warty-basaloid, and basaloid carcinomas are the most common subtypes associated with HPV. Less frequent are clear cell and lymphoepithelioma-like carcinomas. Here we report a novel penile tumor associated with HPV. Twelve cases were selected from 1010 penile carcinomas, part of an international HPV detection study conducted at the Institut Català d'Oncologia, Barcelona, Spain. Immunostaining with p16 was performed on all cases, and HPV-mRNA detection was also performed. En bloc full tumor staining was the utilized criteria for positivity of p16. For HPV-DNA detection, whole-tissue section polymerase chain reaction analysis was performed by SPF10-DEIA-LiPA25 (version 1). The patients' ages ranged from 42 to 92 years (average, 71 y). The tumor was most commonly located in the glans. A characteristic microscopic finding was the presence of a moderate to dense tumor-associated inflammatory cell infiltrate composed of neutrophils, lymphocytes, plasma cells, or eosinophils. Tumors grew in large solid sheets, nests, or had a trabecular pattern. Cells were large and poorly differentiated or anaplastic. Keratinization was minimal or absent. Nuclei were large with prominent nucleoli. Mitoses were numerous. Tumor necrosis was common. Deep invasion of the corpora cavernosa was frequent. p16 and HPV-DNA were positive in all cases, whereas mRNA detection was positive in 9 cases only. The prevalent genotype was HPV16 (9 cases, 75%). Other genotypes were HPVs 58, 33, and 66. Medullary carcinomas of the penis are morphologically distinctive HPV-related high-grade neoplasms affecting older individuals. More studies are necessary to delineate the epidemiological, clinical, and molecular features of this unusual penile neoplasm.

Objectives: To analyze the relationship between clinical features, hormonal receptor status, and survival in patients who were diagnosed with medullary breast cancer (MBC). Methods: Demographic characteristics, histopathological features, and survival statuses of 201 patients diagnosed with MBC between 1995 and 2015 were retrospectively recorded. Survival analyses were conducted with uni- and multivariate cox regression analysis., Results: Median follow-up time was 54 (4-272) months. Median patient age at the time of diagnosis was 47 years old (26-90). Of the patients, 91.5% were triple negative. Five-year recurrence free survival time (RFS) rate was 87.4% and overalll survival (OS) rate 95.7%. For RFS, progesterone receptor (PR) negativity, atypical histopathological evaluation, absence of lymphovascular invasion, smaller tumor, lower nodal involvement were found to be favourable prognostic factors by univariate analysis (p less than 0.05). The PR negativity and smaller tumor were found to be favourable factors by univariate analysis (p less than 0.05). However, none of these factors were determined as significant independent prognostic factors for OS (p greater than 0.05).  Conclusion: Turkish MBC patients exhibited good prognosis, which was comparable with survival outcomes achieved in the literature. The PR negativity was related to a better RFS and OS rates.

Medullary carcinoma (MC) is a very rare variant of colorectal carcinoma (CRC). Its clinicopathologic findings are not fully elucidated. The aim of this study was to investigate the clinicopathological characteristics of MC in the colorectum through a systematic review and meta-analysis. The meta-analysis examined the incidence, age, sex, site, mismatch repair deficiency (MMRd), MMR protein expression, ARID1A expression, BRAF(V600E) mutation, KRAS mutation, and survival rate of MC. The 21469 CRCs included 462 MCs in 16 eligible studies, representing an estimated incidence of MC of 0.027 (95% confidence interval [CI] 26 0.016-0.045). MC frequently occurred in female patients and in the right colon. Lymph node metastasis of MC was significantly lower than that of poorly differentiated adenocarcinoma/undifferentiated adenocarcinoma (PDA/UDA). In addition, MC had a higher MMRd rate (0.892, 95% CI 0.758-0.956), higher BRAF(V600E) mutation rate (0.652, 95% CI 0.143-0.954) and lower KRAS mutation rate (0.171, 95% CI 0.065-0.378) than PDA/UDA and conventional adenocarcinoma. Patients with MC had significantly better overall survival rate compared to patients with PDA/UDA (hazard ratio 0.441, 95% CI 0.262-0.742). However, there was no significant difference of overall survival rate between MC and conventional adenocarcinoma patients. MC predominantly occurred in females and in the right colon, and had different molecular characteristics and behaviors compared to PDA/UDA and conventional adenocarcinoma., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Medullary carcinoma (MC) of the colorectum is known as a rare variant with favorable prognosis despite its poorly differentiated morphology. The mechanism of its favorable behavior has been unclear. Here, we compared the expressions of adhesion molecules and epithelial-mesenchymal transition (EMT)-related proteins in the central portion and invasive front between 43 MCs and 30 poorly differentiated adenocarcinomas (PDAs). The expressions of membranous E-cadherin (P < .0001), β-catenin (P < .0001) and claudin 1 (P = .0036) were significantly preserved in the invasive front of the MCs compared to those in the invasive front of the PDAs. E-cadherin membranous expression was also significantly preserved in the central portion of the MCs (P = .0178). Nuclear β-catenin expression in both the central portion (P = .0463) and invasive front (P = .0346) of the MCs was significantly less frequent compared to that in the PDAs. Snail (P = .0035) and Twist1 (P = .0463) expressions in the invasive front of the MCs were significantly less frequent compared to the PDAs, suggesting that the EMT phenomenon may occur rarely in colorectal MC. Reduced membranous E-cadherin expression in the MC central portion was significantly correlated with poor clinical outcome (P = .0086). Our immunohistochemical results indicate that preserved adhesion molecule protein and less frequent expression of EMT-related transcription factors in the invasive front contribute to the favorable prognosis of colorectal MCs. We suggest that a reduced expression of E-cadherin in the central portion might be a good biomarker for an unfavorable prognosis in cases of MC., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: Medullary breast carcinoma is a rare breast carcinoma with good prognosis. Although it has been established that axillary lymph node metastasis is a poor prognostic factor, little is known about the relationship between axillary lymph node metastasis and clinicopathological characteristics of medullary breast carcinoma patients. The aim of this study was to identify factors that predict occurrence of axillary lymph node metastasis in medullary breast carcinoma patients., Methods: We performed a retrospective study of axillary lymph node status and the relevant clinicopathological characteristics in 49 triple-negative medullary breast carcinoma patients with axillary lymph node dissection between November 2004 and July 2011., Results: A total of 49 patients were enrolled in the study. Fourteen patients (28.6%) had axillary lymph node metastasis that was confirmed pathologically. Axillary lymph node metastasis was not associated with age, menopausal status, primary tumor size or its location, the degree of inflammation within the tumor or mitotic count. However, we found a statistically significant association between axillary lymph node metastasis and Ki67 labeling index in primary tumors (P < 0.001)., Conclusions: There is a positive association between Ki67 labeling index in the primary tumor and axillary lymph node metastasis in triple-negative medullary breast carcinoma patients., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

This paper updates the histopathology and cytopathology of thyroid tumors and proliferations derived from the para-follicular or C cells. Beginning with an historical over view, including the recognition of medullary thyroid carcinoma as a distinct histologic entity, its relationship to the hormone, calcitonin, (which was discovered in the same decade) and to thyroid C cells, medullary carcinoma and its variants are reviewed. The molecular biology of the tumors and the associated mutations in the tumors (somatic mutations) are discussed. Additionally the genetic features (germline mutations) including familial clusters and associations with other endocrine and neuroendocrine lesions are reviewed. Screening for the tumor and its precursors is included with a review of the latest American Thyroid Association guidelines for treatment as well as timing and approach to surgery. Tabular data of specific germline mutations and their relationships to tumor virulence, and prognosis are illustrated. Precursor and early C cell lesions such as C-cell hyperplasia and micro-medullary carcinoma are discussed. Difficulties and controversies in the definition of C-cell proliferations which are neoplastic and those which are "reactive" are reviewed. The entity of medullary microcarcinoma or medullary microcarcinoma is illustrated and the distinction between C cell nodules and microcarcinoma is defined using the latest available criteria. Finally the latest approved chemotherapeutic agents and their results in metastatic medullary thyroid carcinoma are included.

Medullary carcinoma (MC) of the colon and rectum is a rare entity, accounting for less than 0.1% of colonic adenocarcinoma that poses a diagnostic challenge for the practicing pathologist. Poorly differentiated or undifferentiated MC with an unusual histological appearance and immunoprofile in addition to heavy lymphoid infiltrate could make it problematic when differentiating it from a high grade lymphoma, in particular anaplastic large B- or T-cell lymphoma, plasmablastic lymphoma, and other undifferentiated neoplasms. Here we reported a unique case of an 81 y/o woman presenting with a 7.0 cm colon mass detected by computed tomography (CT) scan. A partial transverse and ileum resection with appendectomy were performed. Microscopic examination revealed sheets of large, pleomorphic, mitotically-active cells with abundant eosinophilic cytoplasm and multiple prominent nucleoli, growing with a pushing border and poor glandular formation in a background of intratumoral lymphocytes. The neoplastic cells were only focally positive for keratins (<10%); diffusely and strongly positive for vimentin and CD10 with high proliferative index (Ki-67, 90%). The tumor cells were also aberrantly positive for CD30, CD79a and CD43 (diffusely or focally), resulting in a diagnostic dilemma between colonic MC and high grade lymphoma. Careful examination and additional immunohistochemical stains performed proved there was no evidence of T or B-cell lymphoma, melanoma, or other types of primary colon or metastatic carcinomas. This case highlights the difficulty in distinguishing a high grade lymphoma and poorly differentiated colonic MC, and, also the aberrant expression of CD10 and a significant loss of pancytokeratin could result in a diagnostic pitfall.

Aims and Background: The aims of this study were to investigate the correlation between topoisomerase II alpha (TOP2A), microtubule-associated protein-tau (MAP-tau) and other prognostic factors in breast cancer and to evaluate the predictive value of TOP2A and MAP-tau in breast cancer patients who received anthracycline and taxane-containing adjuvant chemotherapy., Methods and Study Design: Seventy patients with axillary lymph node positive breast cancer who underwent curative surgery between January 2000 and December 2005 were evaluated retrospectively. The levels of protein expression of TOP2A and MAP-tau were assessed using immunohistochemistry., Results: Among the 70 patients, 43 (61.4%) showed TOP2A overexpression and 30 (42.9%) showed MAP-tau positivity. TOP2A overexpression was associated with p53 positivity and high histological grade. MAP-tau positivity was associated with a lower positive lymph node ratio, lower proliferative activity, and hormone receptor positivity. Based on the TOP2A and MAP-tau expression, there was no significant difference in disease-free survival in the breast cancer patients who received anthracycline and taxane-containing adjuvant chemotherapy., Conclusions: We conclude that immunohistochemical analysis of TOP2A and MAP-tau protein expression may not predict the benefits of adjuvant anthracycline and taxane chemotherapy in axillary node positive breast cancer.

Background: Medullary breast cancer is a rare type, considered of good prognosis., Objective: To know the epidemiological and clinical characteristics of the population attended in the Hospital Juarez de Mexico, to know if they are alike to described worldwide and if the treatments proposed internationally are applicable for this hospitable center., Methods: We performed a retrospective analysis. Reviewing the records with histopathologic diagnosis of medullary breast cancer from February 1993 to February 2011. Finding 41 patients in the oncology unit of the institution., Results: We report an incidence of 3.04%, originating in 11 Mexican States, with a low to middle socioeconomic level in 39.02%. The average age at the time of diagnosis was 50 years. No family history was reported but some patients had medical history for type 2 diabetes, hypertension and previous breast cancer. 63.41% were menopausal. The average clinical size of the tumor was 58 mm. The 63% of the cases were located in the left breast. The 53.1% were clinical stages I and II, 46.3% were clinical stages III and in 9.6% of the cases primary tumor could not be assessed. Only 47% of the patients had positive axillary lynph nodes at diagnosis. The inmunohistochemestry was only reported in 14 of the 41 patients, according to the molecular classification of breast cancer: 8 were triple negative, 2 luminal A, 1 luminal B and 3 Her2neu., Conclusions: The Mexican population presents epidemiological and clinical characteristics similar to those patients described in other studies worldwide.

Background: Triple negative breast cancer (TNBC) is heterogeneous and considered as an aggressive tumor. This study was to evaluate the associated classification and its correlations with prognosis and the response to chemotherapy in Chinese women., Methods: Four hundred and twenty-eight cases of invasive TNBC were involved in this study. The expression of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR), and cytokeratin 5/6 (CK5/6), Ki67 and p53 were analyzed by immunohistochemistry and compared with patient outcome, and its implications and chemotherapy response were evaluated in four subgroups: typical medullary carcinoma (TMC), atypical medullary carcinoma (AMC), non-specific invasive ductal carcinoma (IDC) and other types., Results: The factors of tumor grade, tumor stage, lymph node status, EGFR/CK5/6 status and p53 labeling index were different among the groups. TMC tumors had the lowest rate of relapse (5.8%), while AMC, IDC and other types were associated with an increased risk of relapse (19.1%, 26.7% and 38.2% respectively). Many factors were risk predictors of relapse for TNBC and IDC, while only positive lymph node was for AMC. For MC tumors, adjunctive chemotherapy decreased the risk of relapse in lymph node positive subgroup (36.8% and 66.7%), while not significant in lymph node negative one (8.1% and 10.0%)., Conclusion: The classification based on histologic and IHC findings may be a significant improvement in predicting outcome in TNBC. The different chemotherapy response in subgroups may contribute to guiding the treatment of TNBC.

Calcitonin (CT) measurement on fine-needle aspiration cytology (FNAC) washouts (FNAC-CT) is a promising tool in the diagnosis of medullary thyroid carcinoma (MTC). Guidelines for the method with codified cut-off are needed to use this technique in clinical routine. This study was undertaken to assess the best pre-analytical procedure and to define a reliable reference value for FNAC-CT. Fifty-four patients underwent thyroid surgery, so MTC was excluded by surgical pathology examination and CT immunostains. Before surgery, FNAC-CT was measured on 78 thyroid nodules from such 54 patients. Needles were rinsed by normal saline and specific CT-free dilution buffer, and CT was measured by a fully automated immunochemiluminometric assay. FNAC-CT levels were not significantly different in normal saline or specific buffer. The calculated 97.5th upper FNAC-CT value was 8.5 pg/mL (saline) and 7.43 pg/mL (buffer), respectively. Seeing its relatively large sample size, rigorous selection criteria and inclusion of CT immunostaining of thyroid nodules, the present study provides a reliable guideline and a clinically relevant reference value for FNAC-CT measurement in thyroid nodules., (Copyright © 2011 Wiley Periodicals, Inc.)

Breast carcinoma may be classified into distinct molecular subtypes based on immunohistochemical markers for estrogen, progesterone and Her-2/neu receptors. The aim of the study was to identify the clinicopathological features of the molecular subtypes of breast carcinoma in our locality. A total of 274 surgically resected breast carcinomas were selected from the files of the Dr. KRZ referral pathology laboratory, Mansoura, Egypt, and the Pathology Department of Mansoura University. Molecular subtypes were classified into luminal A, luminal B, Her-2/neu-expressing and triple-negative. Clinicopathological and histological features of molecular subtypes were analyzed. Luminal A subtype was the most prevalent (41.2%), followed by triple-negative subtype (28.5%), then Her2-expressing subtype (19.4%) and luminal B subtype (13.9%). The commonest histological type was infiltrating duct carcinoma (83.2%), followed by infiltrating lobular carcinoma (9.1%) and medullary carcinoma (3.2%). The luminal A subtype was significantly correlated to low tumor grade, lower number of positive lymph nodes metastasis, absence of both necrosis and syncytial growth pattern. We concluded that the commonest molecular subtype of invasive breast carcinoma among Egyptian women is luminal subtype A, which displayed favorable features. Triple-negative subtype and medullary carcinomas are present in a ratio higher than in western countries., (Copyright © 2012 Elsevier GmbH. All rights reserved.)

Background: Medullary carcinomas of the breast account for fewer than 7% of all invasive breast cancers. Some investigators include medullary carcinomas in the favourable histologic subtype, despite its aggressive histologic appearance. However, others fail to confirm its favourable prognosis., Methods: This was a retrospective analysis of sixty-one (61) cases of breast cancer cases diagnosed with Medullary Carcinoma, presenting to the Kuwait Cancer Control Center between 1995 and 2005., Results: Median survival time was 122 months and the seven-year disease free survival was 82%. Overall survival rate was not assessed as no cases died during the study period. No cases were metastatic from the start and only eight cases developed metastases, local recurrence or contralateral breast primary. 68.8% of the cases were Stage I or IIA (i.e. no lymph node affection)., Conclusion: There is no overt favourable prognosis of medullary carcinoma when compared to invasive ductal carcinoma. Prognosis is more related to stage than histologic subtyping. The majority of cases were negative estrogen and progesterone receptor status and node negative.

Tumor localization is difficult in patients with medullary thyroid carcinoma (MTC) that have persistent hypercalcitoninemia after thyroidectomy. In this study, the (11)C-methionine positron emission tomography/computed tomography (PET/CT) was compared with the (18)F-FDG PET/CT for diagnostic sensitivity in detecting residual or metastatic disease. (11)C-methionine PET/CT and (18)F-FDG PET/CT were performed on 16 consecutive patients with MTC that had persistent hypercalcitoninemia after surgery in this prospective, single-center study. Patient- and lesion-based analyses were performed using a composite reference standard which was the sum of the lesions confirmed by all combined modalities, including neck ultrasonography (US) with or without fine needle aspiration cytology, CT, bone scan, magnetic resonance imaging (MRI), and surgery. By patient-based analysis, the sensitivities of (11)C-methionine PET/CT and (18)F-FDG PET/CT were both 63%. By lesion-based analysis, the sensitivity of (11)C-methionine PET/CT was similar to (18)F-FDG PET/CT (73% vs. 80%). Excluding hepatic lesions, which could not be detected because of physiological uptake of methionine by the liver, the sensitivity of (11)C-methionine PET/CT was better than (18)F-FDG PET/CT especially for detecting cervical lymph node lesions; however, it was not superior to US. All patients with serum calcitonin levels ≥370 pg/mL showed uptake by (11)C-methionine PET/CT and (18)F-FDG PET/CT. This preliminary data showed that despite its similar sensitivity to (18)F-FDG PET/CT for detecting residual or metastatic MTC, (11)C-methionine PET/CT provided minimal additional information compared to combined (18)F-FDG PET/CT and neck US.

A diagnosis of sporadic medullary thyroid carcinoma (MTC) is complicated. On first diagnosis it may present with distant metastasis. There has been inconsistency regarding metastatic MTC tissue expression of calcitonin, its tumor marker. Adding to the difficulty is the fact that the radiographic pattern of pulmonary metastasis from MTC may vary substantially among patients. Herein is reported the case of a 73-year-old man who presented with two ill-defined pulmonary opacities, clinically resembling primary lung carcinoma. MTC was diagnosed on histopathology of tissue obtained from a total thyroidectomy. The pulmonary biopsy specimens were confirmed to be MTC metastasis on positive immunohistochemical staining of chromogranin-A and synaptophysin, even though only a few cells were stained for calcitonin. To the authors' knowledge this is the first reported case of MTC presenting initially as complex pulmonary metastasis with weakened expression of calcitonin in the metastatic lesion.

Tenascin C (Tn-C) is an extracellular matrix glycoprotein that is expressed early in carcinogenesis including intraepithelial neoplastic lesions of different organs. In this study, we analyze whether stroma reaction seen by Tn-C expression is detected early in tumorigenesis of medullary thyroid carcinoma (MTC) including medullary microcarcinoma and C-cell hyperplasia (CCH), which is accepted to be a precursor lesion of MTC in the setting of RET oncogene germ-line mutation. Tn-C was expressed in the stroma of all medullary microcarcinoma and in the stroma next to CCH. Stromal Tn-C expression was significantly more often seen in CCH with concomitant MTC than in isolated CCH of hereditary as well as nonhereditary cases (p = 0.001 and p = 0.016, respectively). We conclude that Tn-C expression and thus early stroma remodeling is seen in medullary microcarcinoma and CCH. Stromal Tn-C expression seems to be an indicator of a further step in carcinogenesis of MTC irrespective of a RET oncogene germ-line mutation.

Background: Breast cancer is the commonest cancer among Sri Lankan women. The aim of this study was to document the breast cancer profile of a group of Sri Lankan women and compare it with regional data. Patient-tumor characteristics and predicted prognosis are compared with the immune profile., Methods: A total of 814 Sri Lankan women with breast cancer were studied, with their information retrieved from patient records. Tumor type and grade were reassessed on routine tissue sections. The Nottingham Prognostic Index (NPI) was calculated. Estrogen receptors (ER) and human epidermal receptor 2 (HER2) were assessed using Dako antibodies. Strong nuclear staining for ER in >10% of tumor cells and strong, complete cell membrane staining (3+) for HER2 were regarded as positive. An SPSS-16 software program and the chi-squared test were used for statistical analysis., Results: The highest prevalence (32%) was in the 50- to 59-year age cohort (mean +/- SD 51.88 +/- 11.939 years). In all, 58% of the tumors measured between 2 and 5 cm. Most (52%) were moderately differentiated and were invasive ductal carcinomas (86.3%). Regional lymph node metastasis was present in 41% of the patients. ER was expressed in 31.7% and was more frequent in women >35 years (p < 0.024). HER2 was found in 14.5% of tumors. Its expression was lower in ER-positive tumors (p < 0.000). Well-differentiated tumors were frequently ER-positive (p < 0.000) and HER2-negative (p < 0.001). The NPI was better for ER-positive (p < 0.000) and HER2-negative tumors (p < 0.028)., Conclusions: The overall profile of breast cancer and immune characteristics of Sri Lankan women in this study was largely comparable to profiles documented elsewhere in the region despite the lower prevalence of ER.

Neuroendocrine tumors (NET) are relatively rare diverse group of tumors that possess several unique characteristics and occur most commonly in the gastrointestinal tract. An important feature of these tumors is that they express somatostatin (SST) receptors, and thus can be successfully targeted with specific radiolabeled SST receptor related compounds. This has led to the introduction of multitude of single photon emission computed tomography (SPECT) and positron emission tomography (PET) tracers, which have significantly improved the ability for imaging these neoplastic lesions with high spatial resolution in the abdomen and elsewhere in the body. The introduction of Gallium-68 labeled radiopharmaceuticals as viable PET agents have added a new dimension to the management of patients with NET by providing high quality images compared with planar or SPECT with single photon emitting preparations. (18)F-labeled DOPA has demonstrated impressive results in differentiating between focal and diffuse disease in hyperinsulinism of the newborn which appears to be of crucial clinical benefit and has altered the management of these patients significantly. With regard to other types of NET, the current experience with such agents is relatively limited and therefore prospective studies are required to further define the role of PET in this complicated group of patients.

The basal molecular subtype of breast cancer (BC) is defined by the mRNA expression pattern of an intrinsic approximately 500-gene set. It is the most homogeneous subtype in transcriptional terms, and one of the most aggressive in prognostic terms. Clinical trials testing new systemic therapeutic strategies have been launched in basal BCs. Although no proof of evidence has yet been reported, basal tumors are currently assimilated to and selected as triple-negative (TN) BCs in these trials because of their frequent immunohistochemical (IHC) negativity for hormone and ERBB2 receptors. Here, we have assessed the degrees of correlation and of homogeneity of the TN phenotype (IHC-based definition) and the basal subtype (gene expression-based definition). We analyzed 172 TN BCs defined by gene expression profile as basal (123 cases) and nonbasal (49 cases). Conversely, 160 tumors were defined as basal by their gene expression profile and included 123 TN and 37 non-TN samples. Uni- and multivariate analyses revealed that TN BCs represent a more heterogeneous group than basal BCs, including basal and nonbasal tumors very different both at the histoclinical and molecular level, notably for mRNA expression of molecules targeted by specific therapies under evaluation in clinical trials. These results call for caution in the interpretation of ongoing trials and selection of patients in future trials. They also warrant the identification of molecular markers for basal BCs more clinically applicable than gene expression profiles., ((c) 2008 Wiley-Liss, Inc.)

We present a case of metastatic medullary thyroid carcinoma involving the pituitary gland of a 23-year-old woman with multiple endocrine neoplasia type 2b who presented with diabetes insipidus and visual loss. The diagnostic features, including cytomorphology and immunohistochemistry, used to differentiate pituitary adenoma from metastatic medullary carcinoma are discussed. Pituitary metastases and tumor-to-tumor metastases in this region are also highlighted.

A 38-year-old woman with RET gene mutation presented with tumors in her thyroid and bilateral adrenal glands. I-metaiodobenzylguanidine scintigraphy revealed accumulation of the radioisotope in both adrenal glands. Both plasma adrenaline and noradrenaline levels were elevated. The circadian rhythms for plasma adrenocorticotropic hormone (ACTH) and cortisol levels were disturbed. Plasma ACTH and cortisol levels failed to be suppressed by an overnight dexamethasone test, suggesting autonomic secretion of ACTH and cortisol, although the patient had no typical Cushingoid features, hypertension, or impaired glucose tolerance. Pathological examination showed that these tumors were pheochromocytoma and thyroid medullary carcinoma, respectively, both of which highly expressed corticotropin-releasing factor, urocortin1, and urocortin3. Together with the endocrinological and pathological observations, the patient was diagnosed as multiple endocrine neoplasia type II with corticotropin-releasing factor- and urocortin-producing tumors that stimulated ACTH and glucocorticoid secretion.

Claudins and occludin are integral constituents of tight junctions and are deregulated in a variety of malignancies. Their role in thyroid carcinogenesis has not yet been elucidated. This study investigates the expression of occludin and claudin-1, -4 and -7 in thyroid neoplasms. Ninety-one thyroid neoplasms (15 follicular adenomas, 15 follicular carcinomas, 26 papillary carcinomas, 16 papillary microcarcinomas, 8 medullary carcinomas, 3 poorly differentiated carcinomas, 8 undifferentiated carcinomas) were immunostained with antibodies against occludin and claudin-1, -4 and -7. Occludin was mainly expressed in the form of intracytoplasmic vesicles, whereas all claudins tested exhibited membranous immunostaining. Thirteen out of 15 follicular adenomas, 10/15 follicular carcinomas, 24/26 papillary carcinomas, 15/16 papillary microcarcinomas, 1/8 medullary carcinomas, 2/3 poorly differentiated carcinomas and 2/8 undifferentiated carcinomas exhibited claudin-1 expression, whereas claudin-4 was expressed in 13/15, 12/15, 23/26, 13/16, 7/8, 2/3 and 2/8 of the tumors, respectively, and claudin-7 expression was found in 67, 33, 73, 69, 25, 0 and 13% of the cases, respectively. Occludin was expressed in 100% follicular adenomas, 80% follicular carcinomas, 96% papillary carcinomas, 50% papillary microcarcinomas, 50% medullary carcinomas, 33% poorly differentiated carcinomas and 88% undifferentiated carcinomas. Occludin expression was reduced in papillary microcarcinomas, medullary carcinomas and poorly differentiated carcinomas. All claudins exhibited reduced expression in undifferentiated carcinomas. Claudin-1 was additionally reduced in medullary carcinomas and claudin-7 in follicular, medullary and poorly differentiated carcinomas. A correlation between loss of claudin-1 expression and worse disease-free survival was noted on univariate analysis. Dedifferentiation of the thyroid carcinomas is accompanied by reduction in claudin-1, -4 and -7 expression. A differential expression of tight junction proteins in the different histologic types of thyroid gland is noted. Additionally, claudin-1 expression may be an important prognostic indicator of recurrence in thyroid carcinomas.

We report seven cases of renal medullary carcinoma collected from several institutions in Brazil. In spite of a relatively high incidence of sickle cell trait in Brazil, this is a rare tumor. All patients were males between the ages of 8 and 69 years (mean 22 years). From the collected information, the most frequent presenting symptoms were gross hematuria and flank or abdominal pain. The duration of symptoms ranged from 1 week to 5 months. Most of the tumors were poorly circumscribed arising centrally in the renal medulla. Size ranged from 4 to 12 cm (mean 7 cm) and hemorrhage and necrosis were common findings. All seven cases described showed sickled red blood cells in the tissue and six patients were confirmed to have sickle cell trait. All cases disclosed the characteristic reticular pattern consisting of tumor cell aggregates forming spaces of varied size, reminiscent of yolk sac testicular tumors of reticular type. Other findings included microcystic, tubular, trabecular, solid and adenoid-cystic patterns, rhabdoid-like cells and stromal desmoplasia. A peculiar feature was suppurative necrosis typically resembling microabscesses within epithelial aggregates. The medullary carcinoma of the 69-year-old patient was associated with a conventional clear cell carcinoma. To our knowledge, this association has not been previously reported and the patient is the oldest in the literature. The survival after diagnosis or admission ranged from 4 days to 9 months. The 8-year-old African-Brazilian patient with a circumscribed mass is alive and free of recurrence 8 years after diagnosis. This case raises the question whether a periodic search for renal medullary carcinoma in young patients who have known abnormalities of the hemoglobin gene and hematuria could result in an early diagnosis and a better survival.

Medullary thyroid carcinomas are aggressive neoplasias that metastasize very early to loco-regional lymph nodes, and tumors with a desmoplastic stromal reaction have a higher incidence of lymph node metastasis. In order to characterize the desmoplastic response in thyroid cancers, we evaluated the expression pattern of three molecular markers of activated fibroblasts/myofibroblasts, namely, fibroblast activation protein alpha (FAPalpha), tenascin-C (Tn-C), and alpha-smooth muscle actin (alpha-SMA), as well as the endothelial markers endoglyx-1, CD34 and CD31 in a series of 28 metastatic and non-metastatic medullary thyroid cancers. Immunohistochemical studies demonstrated that the three fibroblast activation markers (FAPalpha, Tn-C, alpha-SMA) are consistently expressed in the peritumoral and intratumoral stromal compartment of medullary thyroid carcinomas and expression of FAPalpha and Tn-C correlated with the degree of desmoplasia determined histologically (p=0.001 for FAPalpha and p<0.001 for Tn-C). Moreover, the extent of desmoplasia as well as the expression of FAPalpha and Tn-C correlated with the presence of lymph node (LN) metastases (p=0.002, p=0.005 and p=0.002, respectively). No correlation was found between the microvessel density (neoangiogenesis) in the tumor stroma, assessed with the endoglyx-1, CD34 and CD31 markers, and the degree of desmoplasia or incidence of LN metastases. Using a bioinformatics-based search of the BioExpresstrade mark database we found in a series of 48 thyroid cancers a significant correlation between FAPalpha RNA expression and incidence of LN metastases also in papillary cancers. These findings suggest that the link between specific molecular markers of tumor stromal reaction and locoregional metastasis extends from medullary to other thyroid cancer types.

Medullary thyroid carcinoma (MTC) is a rare neuroendocrine thyroid malignancy. This study retrospectively reviewed 10 fine-needle aspiration samples from six MTC patients. Aspirated specimens were from thyroid (3), cervical lymph nodes (5), left lung (1), and anterior chest wall (1). Cytomorphology consisted predominantly of plasmacytoid cells (3 cases), spindle cells (2 cases), and epithelioid cells (1 case). However, all specimens had a mixture of other cell types and "salt and pepper" chromatin. Only one specimen showed Congo-red-positive amyloid. Calcitonin was expressed in 7/7 specimens. Four patients underwent surgical excision and MTC was confirmed in all four. Follow-up studies included serum calcitonin (3/6 cases) and imaging (2/6 cases). One patient had MTC associated with multiple endocrine neoplasia IIA syndrome and one had familial MTC with a history of MTC in mother. In conclusion, the cytomorphology of MTC is typical and calcitonin immunostain is a reliable method for confirming primary or metastatic MTC. Early cytological diagnosis of MTC positively impacted patient management. Follow-up with serum calcitonin and imaging is helpful in the early detection of recurrences., ((c) 2007 Wiley-Liss, Inc.)

A 7-year-old boy presented with midline swelling in the neck. On fine-needle aspiration cytology it was diagnosed as papillary carcinoma of the thyroid. The patient underwent total thyroidectomy. Histopathological examination, immunohistochemistry and electron microscopy revealed the presence of two intermingled components: medullary carcinoma and papillary carcinoma. One of the submandibular lymph nodes had metastasis of both the components. The case was diagnosed as 'mixed medullary and follicular cell carcinoma' with papillary carcinoma pattern and lymph node metastasis. Mixed medullary and follicular cell carcinoma with intermingling of medullary and papillary carcinoma components is a rare tumor. In adults, only eight such cases with lymph node metastasis have been published. To the best of the authors' knowledge no pediatric case has previously been reported in the English-language literature.

Aims: Immunohistochemistry (IHC) and fluorescence in-situ hybridization (FISH) are both commonly used assays for evaluation of HER-2/neu status in breast cancer. However, there is still no consensus on which method is most predictive of patient response to Herceptin. Recently, the automated cellular imaging system (ACIS) has been shown to improve the accuracy and reproducibility in scoring IHC. Our aim was to compare the results of HER-2/neu expression and gene amplification in the same patients by IHC using the ACIS system and by FISH., Methods and Results: Two hundred and forty-seven breast cancer cases were studied. The concordance rate between IHC-ACIS (> or = 2.2) and FISH (> or = 2.0) was 94%. Fifteen patients were discordant; three had borderline FISH values and three had borderline IHC values. The other nine discordant cases consisted of five IHC-ACIS+, FISH- and six IHC-ACIS-, FISH+. HER-2/neu overexpression was more common in tumours that were high-grade, aneuploid, progesterone receptor and bcl-2 negative, with MIB-1 > 10%., Conclusion: HER-2/neu assessment by the ACIS is reliable, rapid and inexpensive, and correlates highly with results obtained by FISH.

Tumors and metastases that express the somatostatin receptor subtypes sst2 sst3 or sst5 can be visualized in vivo after injection of radiolabeled octapeptide somatostatin analogs, like (111)In-pentetreotide. (111)In-pentetreotide scintigraphy also allows for more accurate staging of the disease by demonstrating tumor sites, which were not shown by conventional imaging. (111)In-pentetreotide scintigraphy may also detect resectable tumors that would have remained unrecognized using conventional radiological imaging techniques; it may prevent surgery with curative intent in those patients whose tumors have metastasized to a greater extend than could be detected with conventional radiological imaging and it may be used to select patients for treatment with the currently available octapeptide somatostatin analogs or with tumor targeted radioactive treatment with radiolabelled somatostatin analogs. (111)In-pentetreotide scintigraphy has also been used to select patients with pituitary tumors for medical treatment with octapeptide analogs, but its clinical usefulness for this purpose seems to be limited. It further allows scar tissue to be differentiated from tumor recurrence after the pituitary surgery or radiotherapy. However, a large variety of lesions in and around the pituitary region also express somatostatin receptors and, therefore, can be visualized by (111)In-pentetreotide scintigraphy.

Objective: Ghrelin is a novel gastrointestinal hormone involved in several metabolic functions. It has been identified previously in several normal and tumoral neuroendocrine tissues, including human medullary thyroid carcinomas (MTCs). The aim of the study was to evaluate ghrelin levels in patients with MTC and nontoxic goitre (NTG) with elevated calcitonin (CT) levels, as an additional marker of the disease., Patients and Design: The study included 22 patients with MTC (four before and 18 after thyroidectomy), 12 patients with NTG with basal CT levels exceeding 10 ng/l and 15 healthy subjects matched for age, sex and body mass index (BMI). After thyroidectomy, MTC patients were considered cured when basal and pentagastrin-stimulated CT levels were < 0.2 and < 10 ng/l, respectively. A pentagastrin-induced CT peak over 50 ng/l was considered as an abnormal response while 100 ng/l was the cut-off accepted for the diagnosis of C-cell hyperplasia or tumour. Circulating ghrelin and CT levels were evaluated at baseline in patients and controls and at -10, 0, 1, 2, 5 and 15 min after pentagastrin injection (0.5 microg/kg body weight) in 12 patients with MTC and nine with NTG. Four surgically removed MTCs were tested for ghrelin expression., Measurements: Total plasma ghrelin and CT levels were measured with a commercially available radioimmunoassay (RIA) and two-site chemiluminescence immunometric assays, respectively. In paraffin-embedded MTC samples ghrelin immunostaining was performed with a polyclonal antibody (1:1000) and the reaction visualized by an indirect immunoperoxidase system., Results: Plasma ghrelin levels found in cured or not cured MTC and in NTG patients were similar to those of BMI-matched healthy controls. No correlation between ghrelin and CT levels, thyroid disease or previous thyroidectomy was observed. The administration of pentagastrin caused a 17% increase in ghrelin levels (basal ghrelin vs. peak: 162 +/- 62 pmol/l vs. 189 +/- 58 pmol/l, P < 0.05) that was particularly evident (33% increase) in patients with an abnormal CT response to the test (CT > 50 ng/l). Immunohistochemistry showed positivity for ghrelin in a small proportion of CT positive cells from the four MTCs removed., Conclusions: Patients with MTC, NTG and controls showed similar ghrelin levels, ruling out this parameter as a marker of MTC. The increase in ghrelin levels in patients with a positive CT response to pentagastrin, together with the immunopositivity for ghrelin in some MTC cells, suggests C cells as minor source of ghrelin production.

The potential tumor-recognizing capacity of B cells infiltrating human breast carcinoma is an important aspect of breast cancer biology. As an experimental system, we used human medullary breast carcinoma because of its heavy B lymphocytic infiltration paralleled to a relatively better prognosis. Ig-rearranged V region V(H)-J(H), Vkappa-Jkappa, and Vlambda-Jlambda genes, amplified by RT-PCR of the infiltrating B cells, were cloned, sequenced, and subjected to a comparative DNA analysis. A combinatorial single-chain variable fragment Ab minilibrary was constructed out of randomly selected V(H) and Vkappa clones and tested for binding activity. Our data analysis revealed that some of the V(H)-J(H), Vkappa-Jkappa, and Vlambda-Jlambda region sequences were being assigned to clusters with oligoclonal predominance, while other characteristics of the Ab repertoire were defined also. A tumor-restricted binder clone could be selected out of the single-chain variable fragment kappa minilibrary tested against membrane fractions of primary breast tumor cells and tumor cell lines, the V(H) of which proved to be the overexpressed V(H)3-1 cluster. The specific binding was confirmed by FACS analysis with primary breast carcinoma cells and MDA-MB 231 cell line. ELISA and thin layer chromatography dot-blot experiments showed this target Ag to be a ganglioside D3 (GD3). Our results are a proof of principle about the capacity of B cells infiltrating breast carcinomas to reveal key cancer-related Ags, such as the GD3. GD3-specific Abs may influence tumor cell progression and could be used for further development of diagnostic and/or therapeutic purposes.

We studied 68 sporadic colorectal carcinomas (CRCs) with medullary features (MCRCs) and compared them with 35 poorly differentiated purely "enteric" CRCs (ECRCs) and 15 purely neuroendocrine carcinomas (NECs) of grades II and III, all in patients lacking a family history of CRC. Potential clinicopathologic differences between the study groups were assessed. MCRCs were significantly more common in the ascending colon than were ECRCs, but there was no significant dissimilarity to NECs. ECRCs occurred more often in the rectosigmoid than MCRCs or NECs. MCRCs arose in older patients, and a marked sex difference also was noted. Despite an infiltrative growth pattern, MCRC was less likely than ECRC to manifest with stage III or IV disease, but there was no stage-related difference from NECs. Although the histologic images of MCRCs were evocative of neuroendocrine differentiation, chromogranin positivity and synaptophysin reactivity in that group did not differ meaningfully from that of ECRCs but was dissimilar to the 100% labeling of NECs. p53 immunolabeling was similar in the 3 tumor groups. Follow-up data in the study cases showed that 5-year mortality was 40% (27/68) for MCRC, 59% (19/32) for ECRC, and 93% (14/15) for NEC. Medullary CRC seems to be a distinct clinicopathologic variant of CRC, which does not have a neuroendocrine lineage. The biologic behavior of MCRC was better than that of ECRC or NEC.

Fine-needle aspiration biopsy of cervical lymph nodes was carried out in 22 patients with suspected metastatic involvement with medullary thyroid carcinoma (MTS). It was followed by cytopathological examination of aspirates and assay of of thyrocalcitonin (TCT) in fine-needle washings. TCT determinations proved highly informative as well as significantly high in all seven cases of MTS involvement (26-8,484.87 pg/ml, mean 2,208 +/- 1,722 pg/ml).

We report a case of a simultaneous occurrence of medullary and papillary carcinomas of the thyroid gland with metastases of a papillary carcinoma to the cervical lymph nodes and a concurrent small B-cell lymphocytic lymphoma revealed in the lymph nodes examined in a 71-year-old woman. The diagnosis was based on microscopic examination of surgical specimens and supported by immunohistochemistry. Additionally, P53 and RET mutation analysis was performed. In this case, the coincidence of medullary and papillary carcinomas of the thyroid gland may account for a true composite tumor. The coexistence of a small B-cell lymphoma in our patient may be explained by irradiation treatment undergone during the adolescence.

Medullary thyroid carcinoma (MTC) rarely causes ectopic ACTH syndrome. We describe a 38-yr-old man with renal stones who had a 5-cm MTC removed in 1992. He was RET-protooncogene positive (codon 618). Serum calcitonin was 1597 pg/ml postoperatively. In 1996 he had rib fractures, bruising, weakness, and three to four stools per day. Laboratory studies revealed an elevated 24-h urine-free cortisol (780 micro g/d), epinephrine (66 micro g/d), and calcium (558 mg/d). Baseline serum cortisol was 23.9 micro g/dl and decreased to 12.9 and 4.5 micro g/dl after 2 mg and 8 mg dexamethasone suppression, respectively. Plasma ACTH was 170 pg/ml and decreased to 75 and 24 pg/ml after dexamethasone. Bone density t-score was -4.3 (trochanter). Computed tomography scans showed multiple cervical nodes and 2-cm right adrenal nodule. Magnetic resonance imaging (MRI) scan showed a prominent, homogeneous pituitary; the adrenal MRI scan was not typical for a pheochromocytoma. Serum CRH was less than 6.6 pg/ml. Bilateral adrenalectomy revealed two adjacent right adrenal pheochromocytomas and corrected the elevated urine cortisol (30 micro g/d), epinephrine (0 micro g/d), and calcium (281 mg/d) but not plasma ACTH (125 pg/ml). Neck dissection reduced calcitonin by 96% (5300 to 120 pg/ml) and ACTH by 91% (125 to 11 pg/ml). Carcinoembryonic antigen was reduced from 32.0 to 2.3 ng/ml. Immunohistochemical stain was negative for ACTH in the MTC-positive lymph nodes and the pheochromocytoma. Proopiomelanocortin mRNA by in situ hybridization was positive in the MTC but not in the pheochromocytoma. A repeat pituitary MRI scan was normal. The differential diagnosis of ACTH-dependent Cushing's syndrome in this case included pituitary disease or ectopic ACTH, either from medullary thyroid carcinoma or pheochromocytoma. ACTH stains were unrevealing, but proopiomelanocortin mRNA in situ hybridization in MTC tissue and plasma ACTH response to neck dissection confirmed MTC as the source of ectopic ACTH.

Background: In medullary thyroid carcinoma (MTC), mutations in the RET protooncogene lead to oncogenic transformation. RET activation in other cell types has been shown to cause phosphorylation of the focal adhesion-associated proteins focal adhesion kinase (FAK), paxillin, and p130(CAS). We hypothesized that adhesion-dependent signaling might be deranged in MTC cells., Methods: Indirect immunofluorescence was used to label beta(1) integrin, FAK, paxillin, and p130CAS. Rhodamine-labeled phalloidin was used to visualize actin microfilaments. Phosphorylated protein was detected by immunoprecipitation followed by Western blotting for phosphotyrosine. MTC cell invasiveness was quantified using a modified Boyden chamber assay., Results: Clustering of beta(1) integrin, FAK, paxillin, and p130(CAS) into focal adhesions were not detected in MTC cells under any conditions, although clustering was seen as expected in control HeLa cells. Despite this failure, FAK, paxillin and p130(CAS) were all found to be phosphorylated. Actin microfilaments were generally not seen although in a few cells, small, poorly formed microfilaments could be detected. MTC cells invaded poorly as compared with highly invasive cell lines. However a clear difference was noted between invasiveness on growth factor depleted Matrigel and regular Matrigel., Conclusions: In MTC cells, focal adhesions are not seen in response to interaction with extracellular matrix. Consistent with this failure, actin microfilaments are absent or poorly formed and invasion is weak. Despite the absence of focal adhesions, focal adhesion proteins remain phosphorylated, even though in normal cells their signaling activity is dependent on focal adhesion formation. Deranged adhesion-dependent signaling may contribute to MTC pathogenesis.

Medullary breast carcinoma (MBC) is a rare pathological type of breast cancer. The rate of p53 protein accumulation is higher in MBC than in common invasive ductal carcinoma. Whether this particular feature of MBC influences the outcome after treatment is unknown. We retrospectively analyzed the characteristics, treatment and outcome of 71 patients with MBC treated between 1981 and 1996. The median age was 51 years (range 27-81) and the median clinical tumor size was 25 mm (range 0-70 mm). Breast-conserving treatment was offered when possible: 55 patients had undergone a tumorectomy and radiotherapy while 16 patients had undergone a mastectomy. p53 protein accumulation was determined by immunohistochemistry on paraffin-embedded tumor specimens from 58/71 samples available for this study. The median follow-up for the 56 survivors was 113 months (range 30-241). The 10-year survival and metastasis-free survival rates were 81% and 81.4%, respectively. The local recurrence rate was 16.4%. The two factors predicting outcome were pathological axillary node involvement in the 60 patients who underwent axillary dissection and adjuvant chemotherapy. p53 accumulation was found in 33/58 patients (57%). p53 status was not predictive of survival nor of distant or local recurrences. We confirm that medullary breast carcinoma has a favorable prognosis despite its aggressive pathological features. p53 protein accumulation, found in the majority of MBCs, was not related to outcome.

Objectives: To investigate the pathologic, clinical, and genetic features of renal medullary carcinomas (RMCs) in search of clues to their pathogenesis., Methods: We analyzed 40 RMCs for clinical features, for immunohistochemical expression using a panel of markers, and for genetic changes using comparative genomic hybridization., Results: Patients presented at 5 to 32 years of age, and 82% were African American. All patients tested had sickle cell trait or disease. Seven patients presented with suspected renal abscess or urinary track infection without a clinically recognizable mass. Of the 15 tumors able to be analyzed, all were positive for epithelial markers CAM 5.2 and epithelial membrane antigen. All were negative for high-molecular-weight cytokeratin 34betaE12. Cytokeratins 7 and 20 and carcinoembryonic antigen were heterogeneous and variable. Ulex was focally positive in a minority of cases. Eight of 12 tumors showed significant positivity for TP53 protein (greater than 25% nuclear positivity). All tumor tested (n = 8) were strongly positive for vascular endothelial growth factor and hypoxia inducible factor. Of nine tumors analyzed for genetic gains and losses using comparative genomic hybridization, eight showed no changes and one showed loss of chromosome 22. Survival ranged from 2 weeks to 15 months (mean 4 months)., Conclusions: These findings suggest that RMC is clinically and pathologically distinct from collecting duct carcinoma. The hypothesis that chronic medullary hypoxia secondary to hemoglobinopathy may be involved in the pathogenesis of RMC is suggested by strong vascular endothelial growth factor and hypoxia inducible factor expression and positivity for TP53.

Data on the expression of interleukin 6 (IL-6)/interleukin 6 receptor (IL-6R) in thyroid nodules is scarce. Based on our recent data of CD30 ligand (CD30L)/CD30 receptor (CD30) in these nodules and on the knowledge that this signal stimulates IL-6 production in non-thyroid neoplasms, we wanted to evaluate the immunocytochemical expression of these 2 ligand/receptor systems in a large archival series of paraffin-embedded specimens. These specimens included 6 normal thyroids and 130 thyroid nodules. Co-expression of IL-6 and IL-6R in the epithelial (follicular) cells was observed solely in CD30L/CD30 positive nodules: 5/15 (33%) oncocytic adenomas; 6/30 (20%) follicular adenomas which belonged to 2 variants (4/4 microfollicular toxic and 2/2 hyalinizing trabecular); 9/30 (30%) papillary thyroid cancers (PTC), all belonging to the conventional variant. In PTC the proportion of tumor epithelial cells that were IL6 positive was inversely correlated with the pTNM staging (r=-0.549, p=0.01). All 15 follicular cancers (FTC), all 6 anaplastic cancers (ATC) were IL-6/lL-6R negative; 14/15 FTC and 5/6 ATC were CD30L/CD30 negative. In another oncocytic adenoma, another 4 conventional PTC and another 7 non-conventional PTC CD30L/CD30 expression was associated to expression of IL-6 only. IL-6 staining associated to absent expression of CD30L and CD30 was observed in 7 follicular adenomas (all belonging to variants different from toxic and hyalinizing trabecular), 2 oncocytic adenomas, 5 of the 30 colloid nodules and 2 normal thyroids. Of the 6 tumors arising from the parafollicular C cells (medullary thyroid cancer, MTC), all 3 that had metastasized were CD30L/CD30/IL-6 positive and IL-6R negative; only IL-6 expression was lost in both the local and distant metastases. This finding matched the loss of IL-6 expression in one PTC metastasis. All 3 non-metastasized MTC were IL-6/IL-6R negative, and 1/3 was CD30L positive/CD30 negative. We conclude that only in a subset of both benign and malignant thyroid nodules the IL-6/IL-6R signal could be induced by the CD30L/CD30. IL-6 expression is related with aggressiveness in both PTC and MTC. In the normal thyroid tissue, colloid nodules, and another subset of benign and malignant thyroid nodules, IL-6 expression is under control of signals other than CD30L/CD30.

Objective and Design: Galectin-3 is a beta-galactoside-binding protein that plays a role in cell adhesion and tumour progression. It was shown recently to diagnose malignant follicular thyroid lesions accurately. The reliability of this marker in the differential diagnosis between medullary thyroid carcinoma and C-cell hyperplasia was studied by immunohistochemistry., Patients: Tissue specimens were obtained from 34 patients belonging to families with medullary thyroid carcinoma who underwent prophylactic thyroidectomy for RET gene mutation and/or abnormally increased plasma calcitonin levels., Results: Galectin-3 was expressed in 23 of 25 cases of medullary thyroid carcinoma and in none of the nine cases of C-cell hyperplasia only, giving a sensitivity of 92% and a specificity of 100% for the diagnosis of carcinoma. A significant association was found between higher galectin-3 expression and occurrence of lymph node metastases (P < 0.05)., Conclusions: Galectin-3 is a reliable diagnostic marker of medullary thyroid carcinoma, and its use may provide relevant information for prognosis and therapy.

There has been much recent investigation of the cyclooxygenase (Cox) enzymes in tumor biology, but, to our knowledge, no study has yet been published describing Cox activity in medullary carcinoma of the thyroid (MTC). Nine cases of MTC from the past 10 yr were retrieved from our hospital archives. Slides cut from formalin-fixed paraffin-embedded tumor tissue from these cases were assessed for the activities of Cox-1 and Cox-2 enzymes by immunohistochemistry as well as by a battery of immunohistochemical stains for intermediate filaments, peptide hormone, and proliferation and promoter antigens. The staining reactions were semiquantitatively assessed and scored for comparison with each other as well as with each patient s clinical presentation and course. Staining for Cox-1 and Cox-2 enzymes was present only in tumorous tissue, not in nontumorous thyroid tissue or C-cells. Cox-2 staining was not consistently increased over Cox-1 staining; however, Cox-2 staining bore statistically significant correlations with the expression of low molecular weight keratin, thyroid-transforming factor-1, topoisomerase, and MIB1. Hyperplastic C-cells from patients with diverse physiologic conditions and from three patients with C-cell hyperplasia accompanying medullary carcinoma or multiple endocrine neoplasia type IIa showed no reactivity for the Cox antibodies. It appears that Cox enzyme immunoreactivity is present only in the neoplastic C-cells of medullary carcinoma, but with variable expression. A practical application of the preceding finding might involve the use of Cox staining to distinguish invasive medullary carcinoma cells from hyperplastic C-cells.

The high sensitivity of the pentagastrin stimulation test in detecting primary or metastatic medullary thyroid cancer (MTC) suggests a widespread expression of the corresponding receptor type on human MTC. Indeed, autoradiographic studies demonstrated cholecystokinin (CCK)-B/gastrin receptors not only in more than 90% of MTCs, but also in a high percentage of small-cell lung cancers, stromal ovarian tumors, and potentially a variety of other tumors, including gastrointestinal adenocarcinomas, neuroendocrine tumors, and malignant glioma. The aim of our work was to develop and systematically optimize suitable radioligands for targeting CCK-B receptors in vivo and to investigate their role in the staging and therapy of MTC and other CCK-B receptor expressing malignancies. For this purpose, a variety of CCK/gastrin-related peptides, all having in common the C-terminal CCK-receptor binding tetrapeptide sequence-Trp-Met-Asp-PheNH(2) or derivatives thereof, were investigated. They were members of the gastrin or cholecystokinin families or possessed characteristics of both, which differ by the intramolecular position of a tyrosyl moiety. Their stability and affinity were studied and optimized in vitro and in vivo; their biodistribution and therapeutic efficacy were tested in preclinical models. Best tumor uptake and tumor to nontumor ratios were obtained with members of the gastrin family, because of their superior selectivity and affinity for the CCK-B receptor subtype. Radiometal-labeled derivates of minigastrin showed excellent targeting of CCK-B receptor expressing tissues in animals and healthy human volunteers. Preclinical therapy experiments in MTC-bearing animals showed significant antitumor efficacy. In a subsequent clinical study, 45 MTC patients with metastatic MTC were investigated; 23 had known and 22 had occult disease. CCK-B receptor scintigraphy was performed with (111)In-diethylenetriamine pentaacetic acid-d-Glu(1)-minigastrin. The normal organ uptake was essentially confined to the stomach (and, to a lesser extent, to the gallbladder and, in premenopausal women, to normal breast tissue) as a result of CCK-B receptor specific binding and to the kidneys, as excretory organs. All tumor manifestations known from conventional imaging were visualized as early as 1 hour postinjection, with increasing tumor to background ratios over time; at least 1 lesion was detected in 20 of 22 patients with occult disease (patient-based sensitivity, 91%). Among them were local recurrences and lymph node, pulmonary, hepatic, splenic, and bone (marrow) metastases. Eight patients with advanced metastatic disease were injected in a dose-escalation study with potentially therapeutic activities of a (90)Y-labeled minigastrin derivative at 4 to 6-week intervals (30-50 mCi/m(2) per injection for a maximum of 4 injections). Hematologic and renal toxicities were identified as the dose-limiting toxicities at the 40 and 50 mCi/m(2) levels. Two patients experienced partial remissions, and 4 experienced stabilization of their previously rapidly progressing disease. These data suggest that CCK-B receptor ligands may be a useful new class of receptor-binding peptides for diagnosis and therapy of a variety of (CCK-B receptor expressing) tumor types. They allow for sensitive and reliable staging of patients with metastatic MTC. Initial therapeutic results are promising, but nephrotoxicity is a major concern to be solved., (Copyright 2002, Elsevier Science.)

By means of calcitonin screening programs, sporadic and hereditary medullary thyroid carcinoma (MTC) can be detected at an early stage. We investigated the histopathologic findings of 16 familial (mean age 32 +/- 21 years, female/male ratio 1.6:1) and 34 sporadic (mean age 58 +/- 15 years; female/male ratio 2.4:1) MTCs with stage T1 comparatively. Patients with hereditary tumors were younger. Hereditary tumors were more often found multifocal (13 of 16 vs 3 of 34; p < 0.001), bilateral (11 of 16 vs 3 of 34; p < 0.001), displaying desmoplastic stroma (14 of 16 vs 19 of 34; p = 0.02), and accompanied by C cell hyperplasia (16 of 16 vs 24 of 34; p = 0.01), but all of these factors were present in some sporadic patients. Only tumors with desmoplastic stroma showed lymph node metastasis, which was observed in eight of the 50 patients. After surgery all patients showed permanent normalization of calcitonin levels. We conclude that 1) morphologic parameters considered to indicate familial MTC risk are of no value in the individual patient, 2) many sporadic MTCs develop on the background of CCH, 3) tumors with desmoplastic stroma are more likely to develop lymph node metastasis, and 4) early detection of MTC permits curative surgery in the majority of patients.

RET/PTC oncogene expression is restricted to papillary thyroid carcinomas (PTC). At least three forms of this oncogene have been described. These are generated by the rearrangement of the 5'-terminal region of different expressed genes with the tyrosine-kinase (TK) domain of the ret proto-oncogene. Several studies showing the correlation between the expression of this oncogene, clinical outcome, and histological subtypes have been published. Thirty-five paraffin-embedded PTC samples from patients without a history of radiation exposure were studied. Immunohistochemistry (IHC) and in situ hybridization (ISH) were used to determine a possible correlation between RET activation, clinical outcome, and tumor subtype. Almost half of the studied cases presented with tumoral extension or metastases. Ret gene transcripts and protein were found in all PTC variants as well as in their corresponding metastases. In contrast, none of the follicular adenomas, goiters, or normal follicular cells from the thyroid gland showed evidence of ret activation. We observed a high frequency of ret expression in PTCs, suggesting that ret activation is a common event in nonradiation-related PTC from Mexican patients.

Background: We have analysed the distribution of the five somatostatin receptors (sst1-5) by immunohistochemistry in a large retrospective series of 51 medullary carcinoma of the thyroid (MCT) specimens and correlated the pattern of sst expression with expression of somatostatin (SRIF) peptide, tumour pathology and clinical outcome., Measurements: Immunohistochemistry was performed with rabbit polyclonal antipeptide antibodies directed against the extracellular domains or cytoplasmic tail of human (h) sst1-5. SRIF immunoreactivity was investigated in parallel paraffin sections., Results: Eighty-five percent of the tumours were positive for one or more sst, localized to both tumour cells as well as surrounding peritumoural structures, especially blood vessels. Forty-nine percent of the tumours were positive for sst1, 43% for sst2, 47% for sst3, 4% for sst4, and 57% for sst5. Fifty-one percent of tumours expressed one or two sst subtypes; 33% were positive for three or more sst isoforms. All five sst receptors were detected in only two cases. Tumours expressing octreotide sensitive subtypes (sst2,3,5) accounted for 75% of the series. 50% of the tumours co-expressed SRIF suggesting tumour cell regulation by endogenous SRIF via paracrine/autocrine circuits. There was no correlation between sst1-5 expression and age, sex, tumour size or stage, histological type or clinical outcome. Simultaneous analysis of primary tumour and lymph node metastases revealed a similar pattern of sst immunoreactivity indicating that sst expression is not modified in the course of disease progression., Conclusions: With the exception of sst4, medullary carcinoma of the thyroid display a rich but heterogeneous expression of sst subtypes. Immunohistochemical typing of sst receptor expression using specific antireceptor antibodies represents an ideal approach for characterizing sst subtype expression in medullary carcinoma of the thyroid for optimizing receptor targeted diagnosis and therapy with somatostatin analogs.

Somatostatin type 2A (sstr2A) and estrogen receptor (ER) are interrelated regulatory receptors present in normal breast epithelium and in a population of breast carcinomas. ER mediates growth stimulatory effects of estrogens whereas sstr2A mediates growth inhibitory actions of somatostatin. However, much work has been devoted to elucidate the biological role of ER, little is known about sstr2A in breast cancer. In the present study we examined immunoreactivity of sstr2A and ER in 64 breast carcinomas in correlation with tumor size and histological grade (HG), presence of lymph node metastasis (LNM), Nottingham prognostic index (NPI), and the patients' age. ER and sstr2A immunoreactivity were present in 78% and 63% of the breast carcinomas, respectively. Ninety percent of tumors immunoreactive for sstr2A were simultaneously immunoreactive for ER. ER immunoreactivity correlated significantly with lower HG (p = 0.03) and better NPI (p = 0.02). sstr2A immunoreactivity correlated significantly with lower HG (p = 0.012) but not with NPI (p = 0.26). There was no correlation of sstr2A immunoreactivity and tumor size, patients' chronological age or LNM. The results confirm prognostic value of ER immunohistochemistry in breast carcinoma. However sstr2A cannot substitute ER for prognostic evaluation, sstr2A immunoreactivity being significantly associated with lower HG seems to represent an independent prognostic factor in breast carcinoma.