Compromiso tumoral de vía aérea en pediatría / Pediatric airway compromise by tumors

Los tumores traqueo bronquiales son extremadamente infrecuentes en la edad pediátrica e incluyen lesiones benignas y malignas. Por la baja frecuencia en niños y sintomatología respiratoria inespecífica, la sospecha diagnostica es habitualmente tardía. El tratamiento de elección en la mayoría de ellos es la resección quirúrgica abierta, sin embargo, la remoción endoscopia podría estar indicada es casos muy seleccionados con histología benigna y de localización accesible.

Tracheobronchial tumors are extremely rare in children and include benign and malignant lesions. Due to the low frequency in children and nonspecific respiratory symptoms, diagnostic suspicion is usually late. The treatment of choice in most of them is open surgical resection, however, endoscopy removal could be indicated in highly selected cases with benign histology and accessible location.

Bronchial-pulmonary adenocarcinoma subtyping relates with different molecular pathways.

Lung cancer is one of the most common cancers in the world with a high mortality rate. We analyzed 45 surgical samples of the adenocarcinoma, 13 with lymph node metastasis. APC, BCL2, chromogranin A, CK 5/6/18 (LP34), CK20, CK7, cyclin D1, EGFR, ERCC1, HER2, Ki67, LRP, MRP, P53, RB and TTF1 expressions were evaluated by immunohistochemistry (IHC). Higher Ki67, APC, ERCC1 expressions and lower TTF1 expression were identified in advanced stages (IIA and IIIA) of adenocarcinomas, which reflect a more aggressive, less differentiated, possibly a non-TRU adenocarcinoma. Acinar, micropapillary and BA/lepidic adenocarcinoma patterns were the most similar patterns and papillary was the most different pattern followed by solid pattern, according to expression of these markers. Different adenocarcinoma patterns are engaged with different molecular pathways for carcinogenesis, based on the differences of expression. Acinar, BA/lepidic and micropapillary showed higher TTF1 expression (type TRU), and papillary and solid patterns revealed less TTF1 expression, exhibiting a non-TRU/bronchial phenotype. Solid pattern revealed lower HER2 and higher EGFR and ERCC1 (this compared to papillary) expression; papillary higher HER2 and lower ERCC1 expressions; micropapillary higher RB expression; and acinar lower ERCC1 and higher EGFR expressions. Ciclin D1 seems to have more importance in acinar and BA/lepidic patterns than in micropapillary. ERCC1 protein expression in micropapillary, solid and BA/lepidic patterns may indicate DNA repair activation. Inhibition of apoptosis could be explained by BCL2 overexpression, present in all adenocarcinoma patterns. MRP-1 and LRP were overexpressed in all patterns, which may have implications for drug resistance. Further studies are needed to interpret these data regarding to therapy response in advanced staged bronchial-pulmonary carcinomas.

Variability of Ki67 labeling index in multiple neuroendocrine tumors specimens over the course of the disease.

BACKGROUND: The Ki67-LI is a valid surrogate for biologic behavior of neuroendocrine tumors (NETs), with higher levels associated with aggressive behavior. The World Health Organization (WHO) classifies NETs according to Ki67-LI (G1: <3%; G2 : 3-20%; G3: >20%). Little is known about the evolution of NETs histologic characteristics over the disease course. We sought to evaluate variations in Ki67-LI throughout NETs disease course. METHODS: We retrospectively reviewed the Sunnybrook Odette Cancer Center NET database for patients with multiple pathology specimens. Primary outcome was the WHO NET class based on Ki67-LI for each specimen. We assessed change in WHO class between specimens. RESULTS: Forty-three patients were retrieved, of which 39 had specimens from the primary tumor and a metastatic focus, and 4 had specimens from multiple metastatic foci. Sixteen (37.0%) were identified with Ki67-LI falling in different WHO classes on distinct biopsies. For 12 (75.0%) of those 16 patients, Ki67-LI showed enough variability for WHO class to be upstaged: 5 (31%) from G1 to G2, 2 (13%) from G2 to G3, and 5 (31%) from G1 to G3. CONCLUSION: When multiple pathology specimens were available, Ki67-LI varied throughout NETs disease course, with a majority of cases upgraded to a higher WHO class. If confirmed, this finding may have implications in how neuroendocrine tumors are monitored and treated. Further research is warranted to confirm these findings, understand better the underlying mechanisms of Ki67 variability, and define its relationship to prognosis.

Endobronchial lipomatous tumors: clinicopathologic analysis of 12 cases with molecular cytogenetic evidence supporting classification as "lipoma".

Lipomatous lesions rarely involve the bronchial tree, and detailed morphologic and molecular cytogenetic analysis of these tumors is lacking. The clinicopathologic features of 12 endobronchial lipomatous neoplasms were studied, with ancillary fluorescence in situ hybridization performed in subsets of cases for CPM, which is amplified in atypical lipomatous tumors/well-differentiated liposarcomas (ALT/WDL), and HMGA1 and HMGA2, which are often rearranged in lipomas. The cases occurred predominately in older men (91%) (age range 44 to 80 y, mean 65 y). Most patients (80%) had a former or current history of heavy smoking (20 to 100 pack-years). Three patients had concurrent pulmonary squamous cell carcinoma, and 1 had a history of multiple lung cancers. Most lesions were small (<2.5 cm) and discovered incidentally. A subset of tumors showed atypical morphologic features that would be suggestive of ALT/WDL in soft tissue sites, including regions of fibrosis and scattered hyperchromatic stromal cells. However, all cases with atypia were CPM negative and behaved in a clinically benign manner. Seven cases were tested for HMGA1 and HMGA2 rearrangement; 4 showed HMGA2 rearrangement, and 1 showed HMGA1 rearrangement, consistent with lipomas. Two cases were negative for HMGA1/2 rearrangements. We conclude that endobronchial lipomatous neoplasms represent lipomas, even in the presence of morphologic features suggestive of ALT/WDL. Ancillary fluorescence in situ hybridization testing may be very valuable in the analysis of these rare tumors, as true ALT/WDL seem to be very rare or nonexistent at this anatomic site.

Reclassifying bronchial-pulmonary carcinoma: differentiating histological type in biopsies by immunohistochemistry.

The current state of molecular knowledge on lung cancer demands a histological classification which goes beyond small-cell and non-small-cell carcinoma to provide support for tailored therapy in aiding in understanding of the drugs currently available. As diagnosis and follow-up in the vast majority of lung cancer cases is based on biopsies and cytology samples, Immunohistochemical Bronchial Pulmonary Carcinoma Classification (IBPCC) is necessary to reveal the raft of characteristics available. This provides morphological support for the WHO's 1999/2004 classification, in addition to an understanding of carcinogenesis. The immunohistochemical panel clarifies the main morphology and cytology characteristics to maintain the leading histological types as squamous cell carcinoma (high weight molecular cytokeratins/HWMC), adenosquamous carcinoma (CK7, TTF1, HWMA), neuroendocrine carcinoma (Chrg, Syn, CD56, TTF1, Ki67), adenocarcinoma (CK7, CK20, TTF1) and bring the polymorphic and pleomorphic carcinomas under a single banner of pleomorphic carcinoma (Ck7, TTF1, HWMC, VMT, Desmin, Actin) which shelters large cell carcinomas and sarcomatoid carcinomas. Lung cancer chemotherapy will still be based on platinum and gemcitabine for the near future and the IBPCC is a simple and efficient tool for streamlining the registration of lung cancer histological characteristics in biopsies and other reduced samples to support clinical evidence and trials.

Reclassification of neuroendocrine tumors improves the separation of carcinoids and the prediction of survival.

INTRODUCTION: The classification of neuroendocrine lung tumors has changed over the last decades. Reliable diagnoses are crucial for the quality of clinical databases. The purpose of this study is to determine to which extent the use of different diagnostic criteria of neuroendocrine lung tumors has influenced the classification of these tumors. The prognostic information of tumor, node, metastasis descriptors was also evaluated. METHODS: We retrieved 110 tumors from the period 1989 to 2007. All tumors were reclassified according to the World Health Organization classification of 2004. Tumor, node, metastasis descriptors were evaluated. RESULTS: By reclassification, the diagnoses on 48 tumors (44%) were changed. More diagnoses were changed in the older part of the material. A significantly different survival was shown for all patients in relation to tumor size (p < 0.0001). An endobronchial component was seen in 54%, 31%, and 11% of typical carcinoid, atypical carcinoid, and large cell neuroendocrine carcinoma, respectively with no impact on survival (p = 0.90). For all included patients the survival was significantly worse for patients having metastasis to N1 nodes as compared with N0 (p = 0.03). However, the number of removed lymph nodes were insufficient for definitive determination of the prognostic impact of node metastases. Regarding the revised diagnoses, a significant difference in survival between typical carcinoid, atypical carcinoid, large cell neuroendocrine carcinoma and small cell carcinoma was noted (p < 0.005). CONCLUSION: Tumors must be rediagnosed before entering a central database. Tumor and node seem to be useful predictors of survival.

[Proposed terms for endobronchial lesions in patients suspected of having a bronchial neoplasm]. / Propuesta de terminología de las lesiones endobronquiales en pacientes con sospecha de neoplasia bronquial.

Endoscopists describe lung cancer lesions using varying terminology. This study aimed to assess the probability of neoplastic disease in terms of endoscopic findings expressed in an original classification system. The endoscopic lesions were classified as infiltrations (superficial lesions without a clear border with normal mucosa) or masses (exophytic lesions easily distinguished from the bronchial wall). Each lesion was categorized according to 3 grades reflecting probability of malignancy. A grade I infiltration was a lesion presenting 1 of the following characteristics: loss of luster, increased thickness, or redness, with a smooth surface. A grade II infiltration presented 2 of the aforementioned characteristics, with a rough surface. A grade III infiltration presented 3 of those characteristics. A grade I mass was an exophytic lesion with a smooth surface, uniformly colored. A grade II mass presented a smooth surface of a distinct color, and a grade III mass had a rough surface and irregular coloring. We assessed 377 patients with suspicion of neoplasm. Twenty-three percent of the infiltrations were grade I carcinomas, 74% were grade II, and 95% were grade III. Twenty-three percent of masses were grade I, 77% were grade II, and 97% were grade III. The probability of malignancy increased significantly with grade (P< .001) for both types of lesion. In summary, there is a positive correlation between the terms used and the probability of carcinoma. Most grade III lesions were carcinomas, but apparently innocuous grade I lesions could be carcinomas in a significant number of cases.

Bronchial typical carcinoid tumors.

The current WHO classification of lung tumors recognizes bronchial typical carcinoid as low-grade neuroendocrine tumors. These tumors grow slowly but can metastasize to regional nodes (4 to 20%) and more rarely to extrathoracic sites. Symptoms are usually related to local compression and obstruction of the bronchial tree. Paraneoplastic syndrome can be present (carcinoid syndrome, Cushing's syndrome, acromegaly). Preoperative diagnosis is usually obtained with bronchoscopic biopsy. Computed tomography and somatostatin receptor scintigraphy are useful in the preoperative staging. Only selected cases can be treated endoscopically with laser resection. The complete surgical resection remains the only therapy with curative intent in the majority of patients. Parenchyma-sparing resections are indicated whenever possible. Overall survival after surgery is excellent (5-year rate, 87 to 100%) with low recurrence rate (2 to 11%). N-status and type of resection seem not to affect prognosis. Local relapse can be treated successfully with surgery, whereas distant metastases have a poor prognosis even after chemotherapy.

Well-differentiated neuroendocrine carcinomas: the spectrum of histologic subtypes and various clinical behaviors.

The term "well-differentiated neuroendocrine carcinoma" was coined to describe a variety of demonstrably neuroendocrine tumors which were more aggressive (both with respect to their histologic appearance and their clinical course) than (typical) bronchial carcinoids but were also clearly distinguishable from small cell neuroendocrine carcinomas. This umbrella term encompasses a variety of tumors previously described by a variety of terms including "atypical" carcinoids, "malignant tumorlets," peripheral stage I small-cell carcinoma, as well as neoplasms described simply as "undifferentiated carcinoma" (prior to the recognition of their neuroendocrine properties). As such, this term is a broad term and is not simply synonymous with "atypical carcinoid." Over time, at least 3 subtypes have been identified based upon their histologic appearance and mitotic index, with correspondingly aggressive clinical courses.

Estudo da correlação entre a incidência de metástases em tumores carcinóides típicos broncopulmonares e biomarcadores teciduais, variáveis clínicas e índice de risco / Study of the correlation between metastasis incidence in typical bronchopulmonary carcinoid tumors and clinical features, tissue biomarkers and index risk

Tumores carcinóides broncopulmonares são proliferações celulares com baixo grau de malignidade. Porém, reltatos de metástases são cada vez mais comuns. Estudo de características clínicas e de biomarcadores teciduais tumorais nos casos referentes a 55 pacientes operados determinou fatores prognósticos para o desenvolvimento de metástases, e permitiu o estabelecimento de um Índice de Risco numérico relacionado com o fenômeno. Gênero masculino, idade acima de 40 anos, margem cirúrgica comprometida, hiperexpressão imunohistoquímica de p53, Ki67 e microvasos, hipodensidade de fibras estromais no tumor e o índice de risco estão correlacionados com maior incidência de metástases/Bronchopulmonary carcinoid tumors are low grade malignancy proliferations, although reports of metastatic behavior has been became more common. The study of clinical and tumoral histologic profiles in the group of 55 pacients underwent to surgical treatment stablished prognostic factors for the metastatic behavior, and a numeric risk index. Male gender, age above 40 years, residual tumor in surgical margin, imunohistochemical hiperexpression for p53, Ki67 and microvessels, hipodensity of estromal fibers in tumoral tissue, and risk index are correlated with increased incidence of metastasis...

Epithelial and soft tissue tumors of the tracheobronchial tree.

This article provides a broad overview of tumors that can involve the tracheobronchial tree. For the most part, the clinical, radiographic, and endoscopic presentation of these rare tumors does not differ significantly from the more common tumors of the lung. Appropriate classification of many tracheobronchial tumors ultimately requires complete sampling and a thorough microscopic evaluation. The introduction of ancillary diagnostic techniques such as immunohistochemistry and molecular analysis will continue to refine tumor classification.

[Classification of broncho-pulmonary cancers (WHO 1999)]. / Classification des cancers broncho-pulmonaires (OMS 1999).

Tumour classification systems provide the foundation for tumour diagnosis and patient therapy and a critical basis for epidemiological and clinical studies. This updated classification was developed with the aim to adhere to the principles of reproducibility, clinical significance, and simplicity in order to minimize the number of unclassifiable lesions. Major changes in the revised classification as compared to the previous one (WHO 1981) include the addition of two pre-invasive lesions to squamous dysplasia and carcinoma in situ: atypical adenomatous hyperplasia (AAH) and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. Another change is the subclassification of adenocarcinoma: the definition of bronchioloalveolar carcinoma has been restricted to non-invasive tumours. There has been substantial evolution of concepts in neuroendocrine lung tumour classification. Large cell neuroendocrine carcinoma (LCNEC) is now recognized as a histologically high-grade non-small cell carcinoma showing histopathological features of neuroendocrine differentiation as well as immunohistochemical neuroendocrine markers. The large cell carcinoma class has been enriched with several variants, including the large cell neuroendocrine carcinoma and the basaloid carcinoma, both of which have a poor prognosis. Finally, a new class has been defined called carcinoma with pleomorphic, sarcomatoid, or sarcomatous elements, which gathers a number of proliferations characterized by a spectrum of epithelial to mesenchymal differentiation. Immunohistochemistry and electron microscopy are invaluable techniques for diagnosis and subclassification, but our intention was to render the classification simple and practical to every surgical laboratory so that most lung tumours can be classified by light microscopic criteria.

Neuroendocrine tumors of the bronchopulmonary tract: a reappraisal of their classification after 20 years.

This article is an overview of the classification of pulmonary neuroendocrine neoplasms, their presentation, their pathologic appearance, and their clinical management. In addition, the original classification, based on histologic features, is reassessed in the light of newer areas in study, including neurosecretory products, neuroendocrine markers, ultrastructural studies, ploidy analysis, cell adhesion markers, apoptosis, oncogene mutation analysis, and genetic alterations. The histologic classification proposed in 1983 remains the single most valuable factor in establishing the diagnosis and, together with the TNM status, the prognosis of this group of interesting neoplasms.

[Biological variables and stratification of patients with inoperable non-small-cell bronchial cancer: recommendations for future trials]. / Variables biologiques et stratification des patients atteints de cancer bronchique non à petites cellules non opérés: recommandations pour de futurs essais.

OBJECTIVE: To identify, through a review of the literature, the laboratory variables that would allow a more accurate stratification of unresected non small-cell lung cancer patients who participate in clinical trials. METHOD: Systematic review, without meta-analysis, following the recommendations of the International Federation of Clinical Chemistry and Laboratory Medicine, and taking into account the Consolidated Standards of Reporting Trials statement. RESULTS: Of 1106 publications retrieved, we were able to include only fourteen studies in our review. Available evidence would support the use of several laboratory variables as prognostic covariables to stratify non resected non small-cell lung cancer patients in clinical trials, but blood haemoglobin would be the only one that could be recommended on a routine basis, and only in patients treated with radiotherapy (three studies out of three). The possible consequences in terms of therapeutic decision of haemoglobin measurements remain however to be clarified. CONCLUSION: Until better designed studies are published, a number of arguments would support the pre-treatment measurements of the following variables in patients participating in clinical trials: blood haemoglobin, white blood cell count with differential, serum LDH, albumin, calcium, and NSE. Further studies would also be necessary to support the addition to this list, of other tumour markers (including Cyfra 21-1), and/or measurements during or after treatment.

Metástasis en la tráquea y en los bronquios / Tracheobronchial metastases

Antecedentes: Las metástasis tráqueo-bronquiales (MB) de tumores distintos del carcinoma broncogénico, son muy rara ocurrencia. Por el momento, casi la totalidad de las comunicaciones de la literatura se refieren sobre todo a tratamientos paliativos para desobstrucción de la vía aérea. Objetivo: Informar sobre la incidencia de MB observadas en un instituto oncológico en relación a las broncofibroscopías (BFC) realizadas a pacientes neoplásicos y al número de MP estudiadas para evaluar su posible tratamiento quirúrgico, así como los resultados de los diferentes procedimientos locales para desobstrucción o control de hemorragias, realizados en enfermos derivados con tal propósito a un centro de intervencionismo endoscópico. Lugar de aplicación: a) Departamento de cirugía torácica de un instituto de oncología universitario público, y b) centro de intervencionismo endoscópico de un hospital de comunidad. Diseño: Trabajo retrospectivo. Población: En total, 56 casos de MB. Esta serie está integrada por: a) 19 pacientes con MB halladas entre 1677 enfermos con neoplasias broncopulmonares sometidos a BFC (1,1 por ciento) y 669 pacientes con MP (2,8 por ciento) en plan de indicación quirúrgica, b) 37 pacientes tratados mediante procedimientos endoscópicos desobstructivos y/o hemostáticos. Método: Se analizaron manifestaciones clínicas, imágenes radiográficas, hallazgos endoscópicos, indicaciones terapéuticas, y procedimientos instrumentales aplicados para desobstruir o controlar sangrado en los casos que merecieron esa conducta. Resultados: En el centro oncológico público, durante el período 1986-2000, se observaron 19 MB, cuyos tumores primarios tenían las más diversas localizaciones y tipos histológicos. Once pacientes fueron asintomáticos. La Rx simple fue normal en 4. En tomografías se observaron atelectasias lobulares, o infiltrados. En 2 casos, el cuadro debido a MB precedió al descubrimiento del tumor primario luego de que la biopsia orientara investigaciones dirigidas. En 3 pacientes se hallaron focos bronquiales múltiples y en otro 2, MB sincrónicas traqueales y bronquiales. A 10 pacientes se les prescribió radioterapia, quimioterapia o ambas, en tanto a los otros 9 solamente recursos paliativos generales. En el centro de intervencionismo endoscópico, durante el período 1987-2000 se observaron 37 MB. El tratamiento endoscópico fue desobstructivo en 35 y hemostático en 2...(AU)

Reproducibility of the WHO/IASLC grading system for pre-invasive squamous lesions of the bronchus: a study of inter-observer and intra-observer variation.

AIMS: Although many workers have graded pre-invasive squamous lesions arising in the bronchus, there has been no consensus classification system until the latest edition of the WHO/IASLC histological classification of pulmonary and pleural tumours. Because the value of any such system is dependent on its reproducibility, we have circulated a series of such lesions to a panel of histopathologists to assess interobserver and intra-observer variation when the WHO/IASLC classification was applied. METHODS AND RESULTS: Colour transparencies of 28 pre-invasive squamous lesions were assessed by six histopathologists (two with a special interest in pulmonary pathology, two generalists and two trainees) on three separate occasions over a period of 3 months, using the criteria of the WHO/IASLC (mild, moderate and severe dysplasia, and in-situ carcinoma). An additional category of metaplasia was added for those cases that showed no dysplasia. Weighted kappa coefficents of agreement (K(w)) were used to evaluate paired observations with a standard quadratic weighting being employed, such that kappa coefficients corresponded to intra-class correlation coefficients. Wilcoxon's sign-ranked test was used to measure the statistical significance of group trends, when comparing kappa values for the three grading systems. Various 3-point systems were also assessed, through combination of the above groups. Intra-observer agreement was substantially better than interobserver variation (mean: 0.71 vs. 0.55). Between the various pathologist groups, inter-observer variation was relatively minor, although intra-observer variation was higher within the trainee pathologist group. Using weighted kappa values, there was no significant difference in either inter-observer or intra-observer agreement between the five point grading system and a 3-point system of metaplasia/mild, moderate and severe/in-situ grades. However, there was a significant increase in variation when a 3-point system of metaplasia/mild, moderate/severe and in-situ carcinoma was used. CONCLUSION: This study shows levels of interobserver and intra-observer variation similar to those found in other grading systems in histopathology, with no significant decrease in variability found by abridging the system. The WHO/IASLC system is therefore recommended for future use in both clinical and research fields.