Roman Kodet

Rhabdoid tumors of soft tissues: A clinicopathologic study of 26 cases enrolled on the intergroup rhabdomyosarcoma study

Twenty-six cases of malignant soft tissue tumors with features similar to renal rhabdoid tumors were identified among approximately 3,000 childhood sarcomas entered on Intergroup Rhabdomyosarcoma Studies I-III. The tumors consisted of polygonal cells with vesicular nuclei and prominent nucleoli and cytoplasmic intermediate filament inclusions as identified by electron microscopy and immunohistochemistry. The growth pattern was predominantly solid or solid-trabecular. Immunohistochemistry showed vimentin, wide spectrum keratin, and epithelial membrane antigen to be the most consistent antigenic phenotypes. Eleven patients were infants less than 1 year of age. The tumors affected predominantly soft tissues of proximal extremities, trunk, and retroperitoneum/pelvis/abdomen. Nineteen patients died within 1 to 82 months (median, 6 months) from the start of treatment. Five patients have survived the disease for 2 to 13 years. When compared with the survival analysis of 991 Intergroup Rhabdomyosarcoma Study II patients, it was obvious that this group of tumors fares very poorly (P less than .001). The tumor belongs to the group of soft tissue neoplasms showing mesenchymal and subtle epithelial differentiation, similar to epithelioid sarcoma. Because of its identifiable histology, site and age distribution, and poor outcome, it warrants a status as an independent entity.

Value of thyroid transcription factor-1 and surfactant apoprotein A in the differential diagnosis of pulmonary carcinomas: a study of 109 cases

Abstract Thyroid transcription factor-1 (TTF-1) and surfactant apoprotein A (SP-A) belong to tissue-specific markers expressed in the normal respiratory epithelium. Both proteins are expressed in some lung carcinomas, and they have potential diagnostic use. We performed an immunohistochemical study on 109 tumors to determine the usefulness of monoclonal SP-A (PE-10) and TTF-1 (8G7G3/1) antibodies in distinguishing primary and metastatic lung carcinomas (n=54) from a broad spectrum of nonpulmonary tumors (n=55). An immunoperoxidase method using a streptavidin—biotin kit was applied on paraffin sections. We found positive results for TTF-1 and SP-A in 75% and 46% of pulmonary adenocarcinomas and in 50% and 25% of pulmonary non-neuroendocrine large cell carcinomas (LCCs), respectively. Small cell lung carcinomas were TTF-1 positive in 89% of cases and completely negative for SP-A. Squamous cell carcinomas and carcinoid tumors were negative for both proteins. In the group of nonpulmonary tumors, TTF-1 was detected in 8 of 11 thyroid carcinomas and SP-A in 1 of 6 colorectal carcinomas. Other tumors, including seven cases of pleural mesothelioma, were negative for both TTF-1 and SP-A. The expression of both antibodies was independent of primary and metastatic sites of the tumor. We observed a significant decrease of SP-A immunoreactivity in poorly differentiated lung adenocarcinomas. The combination of anti-TTF-1 with anti-SP-A does not increase the diagnostic usefulness of TTF-1 alone. Because of its diagnostic utility TTF-1 should be added to a panel of antibodies used for assessing tumors of unknown origin.

Ki-67 as a prognostic marker in mantle cell lymphoma—consensus guidelines of the pathology panel of the European MCL Network

Mantle cell lymphoma (MCL) has a heterogeneous clinical course and is mainly an aggressive B cell non-Hodgkin lymphoma; however, there are some indolent cases The Ki-67 index, defined by the percentage of Ki-67-positive lymphoma cells on histopathological slides, has been shown to be a very powerful prognostic biomarker. The pathology panel of the European MCL Network evaluated methods to assess the Ki-67 index including stringent counting, digital image analysis, and estimation by eyeballing. Counting of 2 × 500 lymphoma cells is the gold standard to assess the Ki-67 index since this value has been shown to predict survival in prospective randomized trials of the European MCL Network. Estimation by eyeballing and digital image analysis showed a poor concordance with the gold standard (concordance correlation coefficients [CCC] between 0.29 and 0.61 for eyeballing and CCC of 0.24 and 0.37 for two methods of digital image analysis, respectively). Counting a reduced number of lymphoma cells (2 × 100 cells) showed high interobserver agreement (CCC = 0.74). Pitfalls of the Ki-67 index are discussed and guidelines and recommendations for assessing the Ki-67 index in MCL are given.

Childhood rhabdomyosarcoma with anaplastic (pleomorphic) features. A report of the Intergroup Rhabdomyosarcoma Study.

The plemorphic subtype of rhabdomyosarcoma (RMS) is now rearely diagnosed in both children and adults. Most cases previously called pleomorphic RMS are probably diagnosed as something else, most often embryonal RMS in children and malignant fibrous histicytoma in adults. To analyze the concept of plemorphic RMS in children, we reviewed the tumors of patients enterd on the Intergroup Rhabdomyosarcoma Study (IRS I, II, and III). The presence of cells with lobated, hyperchromatic nuclei at least three times larger than the common tumor cell population (anaplastic cells) was selected as the main criterion. Of about 3,000 cases, 110 showed these types of cells, had sufficient histologic material, and had available follow-up data. These tumors were divided into two subgroups: Subgroup I tumors contained only scattered anaplastic cells, and tumors with foci or large sheets of anaplastic cells were classified as subgroup II. Besides the anaplastic-pelmorphic areas, most of these tumors had distinctive features of embryonal RMS (105 cases) and rarely had-characteristies of alvelar RMS (five cases). The age distribution of these patients did not differ significantly from those whose tumors did not show the anaplastic features. the average being 6 years and the median 4 years. Lower extermity, retroperitoneum, and the head and neck region were the most common primary tumor sites. The 5-year surival rate was 60% for subgroup I tumors and 45% for subgrup II tumors compared with the survial rate of 68% for 482 IRS II embryonal RMS cases with no anaplastic-pleomorphic features. The lower survival rate for patients in subgroup II was statistically significnt (p = 0.004) and similar to the unfavorable survival of patients with alveolar RMS and undifferntiated sarcoma. Because anaplastic cells are seen in many soft tissue sarcomas and in both embryonal and alveolar RMS in children, this feature is not sufficiently untisual to separate a pleomorphic subtype of RMS. The presence of anaplastic cells in aggregates of diffuse sheets throughout the tumor, however, portends a poor survival for these patints.

Allele loss in Wilms tumors of chromosome arms 11q, 16q, and 22q correlates with clinicopathological parameters

An extended analysis for loss of heterozygosity (LOH) on eight chromosomes was conducted in a series of 82 Wilms tumors. Observed rates of allele loss were: 9.5% (1p), 5% (4q), 6% (6p), 3% (7p), 9.8% (11q), 28% (11p15), 13.4% (16q), 8.8% (18p), and 13.8% (22q). Known regions of frequent allele loss on chromosome arms 1p, 11p15, and 16q were analyzed with a series of markers, but their size could not be narrowed down to smaller intervals, making any positional cloning effort difficult. In contrast to most previous studies, several tumors exhibited allele loss for multiple chromosomes, suggesting an important role for genome instability in a subset of tumors. Comparison with clinical data revealed a possible prognostic significance, especially for LOH on chromosome arms 11q and 22q with high frequencies of anaplastic tumors, tumor recurrence, and fatal outcome. Similarly, LOH 16q was associated with anaplastic and recurrent tumors. These markers may be helpful in the future for selecting high‐risk tumors for modified therapeutic regimens. Genes Chromosomes Cancer 22:287–294, 1998.

Demographic and risk factors in patients with head and neck tumors

The association between human papillomavirus (HPV) infection and the development of head and neck cancer has been documented recently. In this study on 86 head and neck cancer patients and 124 controls, data regarding demographics, behavioral risk factors, and risks related to HPV exposure were collected. HPV detection was carried out using polymerase chain reaction in the tumors and in oral exfoliated cells, and HPV typing by a reverse line blot assay specific for 37 HPV types. Sera were tested by an enzyme‐linked immunosorbent assay specific for HPV proteins. Head and neck cancer cases report significantly more oral‐anal contact (P = 0.02) and tobacco and alcohol use than controls (P = 0.001; P = 0.02, respectively). High‐risk HPV DNA was detected in 43% of oral washings of cases and 4% of controls (P < 0.0001). The association between the presence of high‐risk HPV DNA in oral exfoliated cells and in tumor tissues was statistically significant (adjusted P < 0.0001). The prevalence of HPV‐specific antibodies was significantly higher in cases than in controls (adjusted P < 0.0001). These results provide epidemiological and immunological evidence for HR HPV as a strong risk factor (OR = 44.3, P < 0.0001) for head and neck cancer, even after controlling for age, tobacco and alcohol use. The detection of high‐risk HPV DNA in oral exfoliated cells and HPV‐specific antibodies in serum can be considered as clinically relevant surrogate markers for the presence of a HPV‐associated head and neck cancer, with a high sensitivity (83%) and specificity (88%). J. Med. Virol. 81:878–887, 2009.

Pediatric Intracranial Ependymomas: Prognostic Relevance of Histological, Immunohistochemical, and Flow Cytometric Factors

The correlation between the histological features and clinical outcome remains poor in pediatric intracranial ependymomas. We performed a retrospective study of a group of 31 patients (diagnosed from 1985 to 1995) to assess prognostic implications of the current grading system, of histological and immunohistochemical features, and of ploidy status estimated by flow cytometry. Immunoexpression of a broad spectrum of antigens was evaluated, including MIB-1, topoisomerase-IIα, cyclin D1, glial and epithelial proteins (GFAP, EMA, cytokeratins), molecules involved in controlling apoptosis (bcl-2, caspase-3/CPP32), and p53 oncoprotein. Univariate and multivariate statistical analyses were performed to evaluate the influence of each variable on both the progression free survival (PFS) and the overall survival (OS) with at least 7-year follow up. Although we showed a significant correlation between histological grade and prognosis, the current grading system failed in predicting outcome in nearly one third of individual cases. Problems with interpathologist reproducibility were also demonstrated. The extent of surgical resection was the only clinical factor that was associated with survival. Both the PFS and the OS were significantly decreased for the following pathological variables: increased cellularity (>300 nuclei per HPF), mitotic activity of >7 per 10 HPF, increased MIB-1 labeling index (LI), topoisomerase-IIα LI, S-phase fraction, and p53 and bcl-2 positivity. Increased cyclin D1 LI was demonstrated to have only a marginally significant impact on PFS. A flow chart modeling was further performed to formulate a scheme for discriminating of prognostic subgroups. Based on that, p53 immunopositivity and/or MIB-1 LI of >5% (after subtotal resection) or MIB-1 LI of >15% (after complete resection) were the strongest indicators of the tumors aggressive behavior and of a poor prognosis of the disease. Foci of hypercellularity should be specifically looked for in ependymomas for assessing the immunohistochemical studies.

Comparison of 18F-FDG-PET and standard procedures for the pretreatment staging of children and adolescents with Hodgkin’s disease

PurposeThe aim of this study was to perform a prospective, blinded comparison of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) and conventional staging methods (CSMs) for initial staging of children and adolescents with Hodgkin’s disease (HD).MethodsOver a period of 4 years, 55 children and adolescents with HD (mean age 15.5 years, range 3.9–18.9 years) were prospectively recruited into the study. They underwent 61 FDG-PET studies using a dedicated whole-body PET scanner as a part of their initial staging work-up. PET findings were correlated with the results of CSMs, including computed tomography (CT), ultrasound, bone scanning and bone marrow examination. Discordant findings were resolved by magnetic resonance imaging or clinical follow-up (range 2–47 months).ResultsPET correctly changed the staging in 15% of patients (seven upstagings, two downstagings). Only two out of 61 patients (3%) were not accurately staged by PET; in these children, PET missed small lymphoma nodules detected on lung CT. The sensitivity of PET and CSMs for pretreatment staging was 96.5% and 87.5%, respectively; specificity was 100% and 60%, and accuracy, 96.7% and 85.2%, respectively. Upon combination of FDG-PET and lung CT, the diagnostic accuracy reached 100% in our series.ConclusionOur study showed that whole-body FDG-PET is an efficient and useful method for the initial staging of children with HD. FDG-PET in combination with lung CT should be recommended as a screening method prior to other conventional imaging modalities to plan a rational staging protocol. Large multicentre prospective studies are necessary to verify this conclusion.

Prognostic Value of Ki-67 Index, Cytology, and Growth Pattern in Mantle-Cell Lymphoma: Results From Randomized Trials of the European Mantle Cell Lymphoma Network

PURPOSE Mantle-cell lymphoma (MCL) is a rather aggressive B-cell malignancy whose considerable variability of individual outcome is associated with clinical characteristics (Mantle Cell Lymphoma International Prognostic Index [MIPI]). The Ki-67 index is a strong independent prognostic factor; however, the biologic MIPI (MIPI-b) distinguishes only two groups, which does not appropriately depict the clinical heterogeneity. By using the cohort from the European MCL Younger and MCL Elderly trials, we aimed to evaluate the additional prognostic impact of cytology and growth pattern and to improve risk stratification with the Ki-67 index and MIPI. PATIENTS AND METHODS Diagnostic tumor biopsies were reviewed by the European Mantle Cell Lymphoma Pathology Panel to determine Ki-67 index by using published guidelines, cytology, and growth pattern. We evaluated prognostic effects for overall survival (OS) by Cox regression. For the cohort used for MIPI-b development (German Low-Grade Lymphoma Study Group [GLSG] 1996 and GLSG2000), we checked whether the equally weighted combination of Ki-67 index (dichotomized at the validated 30% cutoff) and MIPI risk groups was adequate and compared the prognostic power of this modified combination to MIPI and MIPI-b for the MCL Younger/MCL Elderly cohort. RESULTS The Ki-67 index was assessed in 508 of 832 patients (median age, 62 years). Blastoid cytology was associated with inferior OS independently of MIPI but not independently of the Ki-67 index. Growth pattern was not independently prognostic. The modified combination of the Ki-67 index and MIPI separated four groups with 5-year OS: 85%, 72%, 43%, and 17% (P < .001) and was more discriminative than MIPI and MIPI-b. CONCLUSION Using the Ki-67 index is superior to using cytology and growth pattern as prognostic factors in MCL. The modified combination of the Ki-67 index and MIPI showed a refined risk stratification, reflecting their strong complementary prognostic effects while integrating the most relevant prognostic factors available in clinical routine.

Rhabdomyosarcomas with Intermediate-Filament Inclusions and Features of Rhabdoid Tumors: Light Microscopic and Immunohistochemical Study

A group of 27 rhabdomyosarcomas (RMS) whose histology showed abundant cells containing cytoplasmic intermediate-filament globular inclusions resembling those seen in rhabdoid tumors has been identified among Inter-group Rhabdomyosarcoma Study (IRS) I-III patients (less than 1%). Their histologic subtype was embryonal RMS in 22 and alveolar RMS in 5. One-half of tumors occurred in deep muscles of the extremities, retroperitoneum, or in the pelvis. Immunohistochemical analysis of 12 cases showed the inclusions to be vimentin or desmin positive. Anti-muscle-specific actin antibodies were positive in the cytoplasm of 11 cases, but not in the site of the intermediate-filament inclusions. Seven poorly differentiated neoplasms closely resembled rhabdoid tumors and possessed large nucleoli in most cells along with cytoplasmic inclusions. In contrast to true rhabdoid tumors, their nuclear chromatin was usually coarse. Immunohisto-chemistry proved useful in distinguishing tumors with early myoblastic differentiation. A positive anti-desmin, when confined to the cytoplasmic inclusions only, should be complemented with other muscle-specific antibodies, especially anti-muscle actin to separate RMS from rhabdoid tumors. The statistical analysis was limited by the small number of cases, but there was no statistical difference in survival when this group of RMS was compared with 996 IRS-II patients as a whole. The distinction of RMS with abundant intermediate-filament inclusions from rhabdoid tumors is of clinical importance because patients with true rhabdoid tumors have a highly unfavorable prognosis.