Differential diagnostic patterns of lung neuroendocrine tumours. A clinico-pathological and immunohistochemical study of 122 cases (original) (raw)
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Differential diagnostic patterns of lung neuroendocrine tumours
Virchows Archiv A Pathological Anatomy and Histopathology, 1992
A series of 3 tumourlets (TLs), 8l typical carcinoids (TCs), 14 atypical carcinoids (ACs) (well-differentiated neuroendocrine carcinomas, WDNCs) and 24 small cell-intermediate cell carcinomas (SCC-ICCs) of the lung were studied. HIstopatological features were correlated with amine and peptide hormone immunoreactivity and with clinical data. All types of tumours expressed general neuroendocrine (NE) markers: Grimelius positivity and chromogranins were detected more frequently in well-differentiated (TLs, TCs) than in less well differentiated tumours [ACs (WDNCs) and SCC-ICCs] whereas neuron specific enolase (NSE) was prominent in the latter tumours. TLs and peripheral TCs were benign, often showing a paraganglioid pattern and frequently expressing gastrin-releasing peptide (GRP), which is present in the peripheral airways of normal lung. Central TCs were associated with lymph node metastases in 8.5% of the cases, frequently had a trabecular architecture, often associated with human milk fat globule 2 (HMFG2)-positive acinar and rosette-like structures, and were mainly immunostained for the OE-subunit of human chorionic gonadotrophin (OE-hCG) and serotonin. ACs (WDNCs) were associated with intrathoracic and/or extrathoracic metastases in 57.1% of the cases with a mortality rate of 35.7%. Their histological and cytological features were intermediate between those of TCs and SCC-ICCs. ACs (WDNCs) expressed serotonin and OE-hCG less frequently than TCs. All SCC-ICCs were surgically treated and displayed a mortality rate of 91.6% with a mean survival of 10.2 months after operation. These tumours were characterized by high expression of HMFG2 and NSE, while the expression of both orthotopic (serotonin, GRP) and ectopic (ACTH) specific NE substances was very low. Since all TCs (either central or peripheral) had a favourable outcome, while about 36% of ACs (WDNCs) were fatal, the latter seem more appropriately designated "well-differentiated NE carcinomas". The differential diagnosis between different NE tumours of the lung is important and is mainly Offprint requests to : C. Capella based on morphology. Both panendocrine and specific immunohistochemical markers are helpful in distinguishing the less aggressive, mostly benign varieties from the more malignant varieties.
IJ Publication , 2021
The majority of neuroendocrine tumeurs in the gastrointestinal tractor and bronchopulmonary system may mature in the human body. The tumours of neuroendocrine are categorised according to the degree of biological aggression (G1–G3) and the degree of differentiation. Typical (G1) and atypical (G2) carcinoids are the well differentiated neoplasms. Largely distinguished neuroendocrine carcinomas in large cells and small cell carcinomas (G3). Identification and distinction of atypical carcinoids or large-cell neuroendocrine carcinomas and small-cell carcinomas in care choices and pronostics is important. The neuroendocrinal pulmonary tumours are distinguished by proportion of necrosis and mitotic activity, palisading, rosetary, trabecular pattern and organic nesting. The information provided on the histopathological evaluation, characterization, prognoses, genetic aberration and treatment options of neuroendocrine pulmonary tumours is based on their own experiences and on an examination of the present literature. In the identity of typical versus atypical carcinoids atypical versus regular, cell neuropheneous, and big neuroendocrine, large cell carcinomas versus small cell carcinomas, there is a majority of differences between classification of neuroendenocrine tumour entities. Of addition, the classification in small biopsies that can be packed into cytological specimens is constrained by the specimen specificity of the immunohistochemical markers and potential objects. To this day, the prevalence of neuroendocrine pulmonary tumours has increased. As compared to NSCLCs, only little research has been done with respect to new molecular targets as well as improving the classification and differential diagnosis of neuroendocrine tumors of the lung.
Pathology - Research and Practice, 1988
Formalin fixed, paraffin embedded sections of52 cases of pulmonary large cell undifferentiated carcinoma (LCUC) as defined in the current WHO classification were studied immunohistochemically to assess features ofexocrine and neuroendocrine (NE) differentiation. Monoclonal antibody 44-3A6 was applied to detect a membrane association protein related to exocrine differentiation. A panel of ten neuroendocrine markers including antibodies to synaptophysin, chromogranin A, serotonin, and seven neuropeptides was used to assess NE differentiation. The broad spectrum anticytokeratin antibody PKK1 was used to confirm the epithelial differentiation of these tumors. Exocrine differentiation was detected in 40/52 (77%) of surgically resected LCUC, despite the absence of recognizable glands by light microscopy. Eighteen of 52 (35%) LCUC exhibited NE differentiation; synaptophysin was the most frequently detected NE marker. Cytokeratin immunostaining with PKK1 was demonstrated in 41/52 (79%) cases. Subsets of LCUC were defined based on their expression of exocrine or NE phenotypic markers. Accordingly, 28/52 (54%) LCUC displayed an exocrine phenotype, 6/52 (12%) a NE phenotype, 12/52 (23%) had combined exocrine and NE phenotypes, and 6/52 (12%) exhibited neither phenotype. In this surgical series, there were no significant differences in stage at presentation for the four subsets. Interestingly, two year survival appeared decreased in patients with tumors displaying the "pure" NE phenotype.
Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, 2012
Pulmonary neuroendocrine tumors (NETs) are traditionally described as comprising a spectrum of neoplasms, ranging from low grade typical carcinoids (TCs) via the intermediate grade atypical carcinoids (ACs) to the highly malignant small cell lung cancers (SCLCs) and large cell neuroendocrine carcinomas (LCNECs). Recent data, however, suggests that two categories can be distinguished on basis of molecular and clinical data, i.e. the high grade neuroendocrine (NE) carcinomas and the carcinoid tumors. Bronchial carcinoids and SCLCs may originate from the same pulmonary NE precursor cells, but a precursor lesion has only been observed in association with carcinoids, termed diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. The occurrence of mixed tumors exclusively comprising high grade NE carcinomas also supports a different carcinogenesis for these two groups. Histopathologically, high grade NE lung tumors are characterized by high mitotic and proliferative indices, while carcinoids are defined by maximally 10 mitoses per 2 mm 2 (10 high-power fields) and rarely have Ki67-proliferative indices over 10%. High grade NE carcinomas are chemosensitive tumors, although they usually relapse. Surgery is often not an option due to extensive disease at presentation and early metastasis, especially in SCLC. Conversely, carcinoids are often insensitive to chemoand radiation therapy, but cure can usually be achieved by surgery. A meta-analysis of comparative genomic hybridization studies performed for this review, as well as gene expression profiling data indicates separate clustering of carcinoids and carcinomas. Chromosomal aberrations are much more frequent in carcinomas, except for deletion of 11q, which is involved in the whole spectrum of NE lung tumors. Deletions of chromosome 3p are rare in carcinoids but are a hallmark of the high grade pulmonary NE carcinomas. On the contrary, mutations of the multiple endocrine neoplasia type 1 (MEN1) gene are restricted to carcinoid tumors. Many of the differences between carcinoids and high grade lung NETs can be ascribed to tobacco consumption, which is strongly linked to the occurrence of high grade NE carcinomas. Smoking causes p53 mutations, very frequently present in SCLCs and LCNECs, but rarely in carcinoids. It further results in other early genetic events in SCLCs and LCNECs, such as 3p and 17p deletions. Smoking induces downregulation of E-cadherin and associated epithelial to mesenchymal transition. Also, high grade lung NETs display higher frequencies of aberrations of the Rb pathway, and of the intrinsic and extrinsic apoptotic routes. Carcinoid biology on the other hand is not depending on cigarette smoke intake but rather characterized by aberrations of other specific genetic events, probably including Menin or its targets and interaction partners. This results in a gradual evolution, most likely from proliferating pulmonary NE cells via hyperplasia and tumorlets towards classical carcinoid tumors. We conclude that carcinoids and high grade NE lung carcinomas are separate biological entities and do not comprise one spectrum of pulmonary NETs. This implies the need to reconsider both diagnostic as well as therapeutic approaches for these different groups of malignancies.
TURKISH JOURNAL OF MEDICAL SCIENCES, 2019
Introduction It is not always easy to diagnose pulmonary neuroendocrine tumors (PNET).The aim of the present study is to make a differential diagnosis by studying the same markers in patients with non-small-cell lung carcinoma (NSCLC), patients with benign lung disease (chronic obstructive pulmonary disease and pneumonia) and healthy volunteers to determine the roles of these markers in pulmonary neuroendocrine tumors (PNET) diagnosis and to identify their power. Methods A total of 100 participants including 23 PNET patients and 28 NSCLC patients who were pathologically diagnosed but not yet treated, 25 participants with benign disease and 24 healthy volunteers were included in this cross-sectional study. Results No significant difference was found between the chromogranin A (CgA)and squamous cell carcinoma antigen 1 (SCCA1) values among the groups (PNET - NSCLC - Benign - Healthy volunteers)but the difference in progesterone-releasing peptide (Pro-GRP), neuron-specific enolase (NSE...
Classification of pulmonary neuroendocrine tumors: new insights
Translational lung cancer research, 2017
Neuroendocrine tumors of the lung (Lu-NETs) embrace a heterogeneous family of neoplasms classified into four histological variants, namely typical carcinoid (TC), atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC) and small cell lung carcinoma (SCLC). Defining criteria on resection specimens include mitotic count in 2 mm and the presence or absence of necrosis, alongside a constellation of cytological and histological traits including cell size and shape, nuclear features and overall architecture. Clinically, TC are low-grade malignant tumors, AC intermediate-grade malignant tumors and SCLC/LCNEC high-grade malignant full-blown carcinomas with no significant differences in survival between them. Homologous tumors arise in the thymus that occasionally have some difficulties in differentiating from the lung counterparts when presented with large unresectable or metastatic lesions. Immunohistochemistry (IHC) helps refine NE diagnosis at various anatomical sites, parti...
Case Reports in Oncology, 2010
Bronchopulmonary neuroendocrine tumors are an uncommon group of neoplasms, accounting for about 20% of all lung carcinomas, arising from stem cells of the bronchial epithelium known as Kulchitsky cells. In the past, these tumors were grouped among benign or less aggressive malignant pulmonary tumors. Currently, according to the 2004 World Health Organization categorization, these tumors are separated into 4 subtypes characterized by increasing biologic aggressiveness: low-grade (typical carcinoid; TC), intermediate-grade (atypical carcinoid; AC) and high-grade (large-cell neuroendocrine carcinoma, LCNEC, and small-cell lung carcinoma, SCLC). They differ by morphologic, immunohistochemical and structural features. At histopathologic analysis, these tumors share progressive increase in a number of mitotic figures per 10 high-power fields and in the extent of necrosis, with TC having the lowest values and SCLC having the highest. TCs and ACs make up approximately 1-2% of all primary lung tumors. Differentiating ACs from TCs or LCNEC and SCLC is clinically important because the treatment modalities and prognoses for these types of tumors are different. We report a case of misdiagnosis of bronchopulmonary neuroendocrine tumor in a young woman which has heavily influenced her clinical history. Fig. 3. Second surgery. Left lung segment stained for MIB1/Ki67: TC with rare cells present nuclear staining (arrow).
Morphologic and molecular classification of lung neuroendocrine neoplasms
Virchows Archiv, 2021
Neuroendocrine neoplasms (NENs) of the lung encompass neuroendocrine tumors (NETs) composed of typical (TC) and atypical (AC) carcinoids and full-fledged carcinomas (NECs) inclusive of large cell neuroendocrine carcinoma (LCNEC) and small cell carcinoma (SCLC). NETs and NECs are thought to represent distinct and separate lesions with neither molecular overlap nor common developmental continuum. Two perspectives were addressed regarding the morphologic and molecular classification of lung NENs: (i) a supervised approach by browsing the traditional classification, the relevant gene alterations, and their clinical implications; and (ii) an unsupervised approach, by reappraising neoplasms according to risk factors and natural history of disease to construct an interpretation model relied on biological data. We herein emphasize lights and shadows of the current classification of lung NENs and provide an alternative outlook on these tumors focused on what we currently know about the biolo...
Oncology Research and Treatment, 2014
Neuroendocrine tumors (NETs; syn. carcinoid tumors) are highly or moderately differentiated neoplasms. They comprise a large variety of rare and heterogeneous tumors with an estimated incidence of 3-5/100,000/year. They can arise in virtually every internal organ, but mainly occur in the gastroenteropancreatic and bronchopulmonary systems. Around 25% of the NETs are localized in the bronchopulmonary system. Approximately 2% of all lung tumors are NETs. According to the World Health Organization (WHO) classification of lung tumors, bronchopulmonary NETs are subdivided into typical carcinoids (TCs) and atypical carcinoids (ACs). The parameter with the highest impact on NET behavior and prognosis is the histological classification and staging according to the tumor/node/metastasis (TNM) system. The diagnosis of NETs is established by histological examination and the immunohistochemical detection of general neuroendocrine markers, such as chromogranin A (CgA) and synaptophysin. Serum ma...