neuroendocrine lung tumors arise from a population of neuroendocrine cells normally present in the bronchoalveolar structures and are characterized by secretory activity and ability to take up and decarboxylate the amine precursors ( apud system cells ) .
these neuroendocrine phenotypical and morphological characteristics are present within a broad spectrum of histologies of lung neuroendocrine tumors ( nets ) , from relatively indolent typical carcinoids ( tcs ) to histologically high - grade , biologically aggressive tumors , as large - cell neuroendocrine carcinomas ( lcnec ) and small - cell lung cancers .
the spectrum of pulmonary nets , according to the 2004 world health organization ( who ) categorization , includes 4 subtypes characterized by increasing biologic aggressiveness : tcs and atypical carcinoids ( acs ) are categorized together as carcinoids , lcnec is considered a subgroup of large - cell carcinomas and small - cell lung carcinoma ( sclc ) as an independent category .
bronchopulmonary ( bp ) tcs and acs are uncommon , representing 1 - 2% of all pulmonary neoplasms ; these variants are associated with relatively slow growth , and generally show a favorable outcome .
the tc subtype is predominant ( 80 - 90% ) , and occurs most frequently in the 5th and 6th decades of life .
the most important difference between typical and atypical form is represented by the mitotic index .
tcs have < 2 mitoses per mm in 10 high - power fields ( hpf ) without signs of necrosis , while acs are characterized by 2 - 10 mitoses per mm/10 hpf and/or foci of necrosis .
the lcnec and sclc subtypes are the most malignant of neuroendocrine lung tumors with a 5-year survival that , up to date , remains very poor . in particular
, for the sclc form the necrosis is typically extensive and the mitotic rate is very high with > 10 mitoses/2 mm .
nevertheless , diagnosis of bp carcinoids can be difficult and they may be mistaken for sclc .
a review of pathologic material by an experienced pathologist is important prior to diagnosis and specific treatments in this type of tumors . in combination with the histologic appearance , the cell proliferation characterized by low labeling index ki67 ( mib1 ) < 20% seems to be the most useful marker to distinguish the low - grade from the high - grade malignancy subgroups within the bp nets . in particular ,
the immunoreactivity for nuclear markers ( especially ki67 ) is easily accessible and may be helpful in the differential diagnosis between tcs / acs and sclcs , high - grade nets being characterized by a proliferative cell fraction much higher than that of carcinoids ( mib1 > 50% ) .
several peptide and amine markers , including chromogranin a ( cga ) , neuron - specific enolase ( nse ) , serotonin , synaptophysin , and adrenocorticotropic hormone ( acth ) , can provide us with further tools in order to better establish a differential diagnosis .
molecular genetic changes may be useful as an adjunctive element to differentiate tcs from acs .
retinoblastoma gene ( 13q13 ) and p53 ( 17p13 ) mutations , multiple endocrine neoplasia ( men ) 1 gene activation ( 11q13 ) , and telomerase activity are particularly frequent in acs if compared with tcs .
we report a case of a young woman with misdiagnosis of bp net which has heavily influenced her clinical story .
a 41-year - old symptomatic female patient , nonsmoker , following the onset of cough and low - grade fever despite empirical antibiotic therapy , underwent chest radiogram , which revealed an uneven area in the right lung , near the hilum . because symptoms persisted after empirical antibiotic therapy
thorax ct scan documented a nodule in the right lung , near the hilum , 2 millimetric nodules in the left lung , in the lower lobe , and subcarinal lymphadenopathies .
cytological examination of fine - needle aspiration specimens showed atypical cells immunohistochemistry - positive for cytokeratin mnf116 , indicative of infiltration of small - cell lung cancer .
after 5 cycles of chemotherapy with cisplatin and etoposide and radiotherapy on mediastinum , the patient was referred to surgery ( sleeve bilobectomy , pericardial resection and mediastinal lymphadenectomy ) .
histological examination showed an ac tumor ( ki67 > 2% ) with pathological staging pt2 n2 . during the follow - up
, the patient was subjected to ct scan every 6 months and then every year , to inspect the 2 millimetric nodules in the controlateral lung .
after 8 years , ct scan documented an increase in the size of 1 of the 2 nodules in the lower lobe of the left lung , confirmed by pet ( suv5 ) .
histological examination documented tc ( ki67 < 2% ) , pt1 n1 as pathologic staging .
ct and pet were negative for cancer , but blood test showed hypercalcemia ( 14 mg / dl ) .
therefore , neck ultrasound and thyroid scintigraphy were performed , and both revealed an increase in size of the right parathyroid gland .
the presence of 3 distinct histological types of bp nets in the same subject is unusual .
sporadic lung carcinoids may occur as a component ( ~5% ) of the familial endocrine cancer syndrome multiple neuroendocrine neoplasia 1 ( men1 ) ; in contrast , in poorly differentiated lung nets ( sclc and lcnec ) , this condition was rarely identified . analyzing the patient 's family history
, we learned that her mother had zollinger - ellison syndrome , a cousin had pancreatic neuroendocrine carcinoma and parathyroid adenoma and an uncle underwent surgery for a parathyroid adenoma .
thus , the patient and her children will be subjected to genetic counseling and evaluation for men1 gene mutation .
consistent with our hypothesis , our histological review documented ac on the first cytological diagnosis , with immunohistochemical positivity for cga , synaptophysin and ki67 : 5.3% , while it confirmed the diagnosis of acs and tcs , after lung surgery , according to who classification ( fig . 1 , fig
this case report demonstrates that diagnosis by cytologic sampling can be confounding and it alone does not allow a correct and complete characterization of pulmonary tumors .
it is also important that the diagnostic iter must be followed , as far as possible , in a specialized center , especially when we are faced with rare neoplastic diseases , as in this case .
 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 12% 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 . 
Introduction
Case Report
Discussion
Conclusion