Yu Zhongxin, M.D., M.S.¹, Nighat F. Mehdi, M.B., B.S.²,  Kar-Ming Fung, M.D., Ph.D.¹

¹ Department of Pathology, ² Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK

Clinical information: The patient was a 17 year-old boy who was in good health and was an active basket ball player. There was no history of asthma or other major illness. He developed chronic cough, wheezing and shortness of breath about 13 months before presentation.  The patient was initially treated in an outside facility under the clinical impression of asthma and his condition improved. Two months before presentation to our institution, he developed fever spikes with worsening of his cough and sputum production. There was also a weight loss of 10 pounds. His pulmonary function tests showed an obstructive pattern with both inspiratory and expiratory abnormal flow volume loops suggestive of variable intrathoracic airway obstruction. The PPD test was negative. A chest x-ray revealed mild atelectasis in the right upper lobe. A bronchoscopy was performed and a biopsy was taken. Based on the pathology results of the biopsy, a lobectomy of the right upper lobe was performed. The following photographs were taken from representative areas of the surgically resected specimen.

Pathology of the case:           

   

A	B	C	D	E	F
G	H	I	J	K. Synaptophysin

Gross patholgy: The tumor is a pedunculated dark purple nodule that protrude into the lumen of the bronchus (Panel A). The nodular surface is intact and is focally shinny (arrow in Panel A). These type of nodules tend to produce a ball-valve type of effects leading to atelectasis. These areas correspond to mucosal surface with squamous metaplasia (arrow in Panel B).

Histopathology: The surface of the tumor nodule is covered partly by epithelium with squamous metaplasia (arrow in Panel B), partly by respiratory type epithelium and partly denuded (Panel C). Even at this magnification, several dilated blood vessels can be seen. The tumor locally invades to the level of cartilage (Panel D). Some dilated blood containing space (Panel E) are present. On higher magnification, some areas arrange in nests (Panel F), cords and trabeculae (Panel G), cribiform (Panel H), and microcysts (Panel I). On high-magnification, the tumor cells appear monotonus, with round nuclei and "salt and pepper" like chromatin, and lacks nucleoli. The cells look epithelioid and have fine, granular, amphophilic cytoplasm. The delicate vascular network around the tumor cell nest is best appreciated at this magnification (Panel J). There are neither significant mitotic activity or necrosis. On immunohistochemistry, the tumor cells are strongly reactive for synaptophysin (Panel K). There are also immunoreactive for cytokeratin. 

Discussion: General Information    Pathology    Differential diagnosis

General Information    

    Literally, carcinoid means something similar to but not the same as carcinoma. This term was first used by Obendorfer in 1907 to separate a group of tumors in the small intestine that behave better than conventional carcinomas ¹. Argentaffin granules were demonstrated in carcinoid cells by Gosset and Masson and suggested that they arise from Kulchitsky cells ². The Kulchitsky cells is finally shown to be a subpopulation of the amine precursor uptake and decarboxylation (APUD) cells which forms the neuroendocrine system. Carcinoid tumors are neuroendocrine carcinoma of low-grade malignancy. These tumors are also known as low-grade neuoendocrine carcinoma to address their potential malignant behavior.

    Because of the diffuse distribution of neuroendocrine cells carcinoid (well-differentiated neuroendocrine carcinoma) can be found in many organs with the appendix and small intestine as the most common sites (73%). The bronchopulmonary system (25.1%) is the most common extragastrointestinal site ³. pulmonary carcinoid tumors comprises about 1-2% of all primary bronchopulmonary tumors ⁴. In children, the lung is the most commonly involved site followed by the liver ⁵. Although uncommon in children, carcinoid tumor is the most common primary endobronchial and pulmonary parenchymal tumor in children and comprises about one-third of all these tumors. There is no sex predilection. In contrast to adult bronchopulmonary carcinoids that may remain asymptomatic, bronchopulmonary carcinoids in children are typically symptomatic. Clinical manifestations include wheezing and atelectasis in addition to the characteristic adult triad of cough, hemoptysis, and pneumonitis. The less common manifestations include weight loss and hoarseness ^{6, 7, 8}. Diagnosis may be delayed due to its varied ways of clinical presentations. It is very important for clinician to aware its existence because early diagnosis and intervention will improve the outcome of the patient’s management.

    Carcinoids occasionally occurs as part of multiple neuroendocrine neoplasm (MEN) syndrome. Carcinoid may also produce an excess amount of neuropeptides and amines (hormone-like substances, such as bradykinin, serotonin, histamine, and prostaglandins, which can cause the carcinoid syndrome (flushing, bluish skin, abdominal cramps, diarrhea, heart damage, and other symptoms). Although most carcinoids are amenable to resection, they carry a low metastatic potential. Prognosis is general good with a low rate of metastasis. In adult, the 5- and 10-year survival rates are 87% and 87%, separately. Prognosis is also good in pediatric cases hoarseness ⁷.  Currently, surgery is considered the only potentially curative therapy in this group of patient because most carcinoids are resistant to both radiation and chemotherapy.

Pathology    

    Grossly, the majority of these tumors arise as is polypoid, endobronchial mass that protrude into the bronchial lumen. The main to segmental bronchi are the most common sites probably because this area has the highest concentration of neuroendocrine cells in these regions. Entire peripheral tumors in lung parenchyma can be seen. Grossly, endobronchial tumor has a smooth surface and is pink to purple because of its rich vascularity. The tumor in the periphery of the lung presents in a solid and nodular pattern. Carcinoid tumors are well-circumscribed and contain infrequent areas of hemorrhage. Foci of calcification or ossification may be present. Necrosis is uncommon and, when detected, should raise the possibility of a higher grade tumor. 

    Histological features of typical carcinoid tumors are similar to those of carcinoid tumors found elsewhere in the body. Architecturally, the tumor cells form nests, cords, or broad sheets separated by highly vascular septa of connective tissue, or they may take a glandular or alveolar configuration. Individual cells are medium-sized polygonal with oval to spherical, rather uniform, finely granular nuclei and lightly eosinophilic granular to clear cytoplasm; rosettes and small acinar structure with or without mucin may be present. Pleomorphism is minimal and mitotic figures are rare. Spindle-shaped cells are an accepted variant, especially in peripherally located tumors. The stroma is vascular and scanty, and amyloid deposits with bone formation may be seen. Small foci of atypical hyperplastic bronchial epithelium may form tumorlets in adjacent bronchial epithelium location and may represent local metastatic disease. These lesions may suggest a more aggressive tumor and a poorer prognosis.

    Immunohistochemical findings in carcinoid tumors include the reactivity to chromogranin A, neuron-specific enolase (NSE), synaptophysin, serotonin, gastrin, MSH, vasopresin, bombesin, somatostatin.  Neural cell-adhesion molecule (N-CAM) reactivity was detected in all bronchial carcinoid tumors and S-100 protein is present in the sustentacular cells situated at the border of cell nest in approximately 40% of cases. They are also positive for epithelial markers such as cytokeratins. Ultrastructurally, membrane-bound electron-dense granules 100 nm to 400 nm in diameter (neurosecretory-type granules) are seen in the cytoplasm beneath the cell membrane, often at the base. Microvilli and junctional complexes are also present.

Differential diagnosis

    Typical carcinoid tumors have their unique macroscopic and microscopic characteristics and do not usually pose any diagnostic problem. Immunohistochemical stains and other special stains can be useful in confirming the neuroendocrine differentiation of suspected carcinoid tumors.  Attention may be attended to the followings:

    Atypical carcinoid (moderately differentiated neuroendocrine carcinoma) refers to carcinoid tumors with anaplastic feature and less favorable prognosis than typical carcinoid tumor. The 5- and 10 year survival rates are 56% and 35%. Aside from the typical neuroendocrine morphology of typical carcinoids, moderately differentiated neuroendocrine carcinoma have increased mitotic activity (>5 mitoses per 10 high-power fields), pronounced cytologic atypia and frequent necrosis ^{9, 10, 11, 12}. There is no significant difference in immunohistochemical ultrastructural characteristics between typical and well-differentiated neuroendocrine carcinoma (atypical carcinoid tumor).

    Large cell neuroendocrine carcinoma (LCNEC) and small cell lung carcinoma (SCLC) are other two major histological types of neuroendocrine tumors of the lung, along with typical and atypical carcinoids. They are highly malignant with an extremely low 5- and 10-year survival rate, 27% and 9% for LCNEC, 9% and 5% for SCLC, respectively (Shimosato).  LCNEC is a rare tumor that, with the exception of the size of the tumor cells, is very similar to SCLC in its prognosis and in its treatment.  These two types of tumors often possess certain cellular-chemical features with neruoendocrine tumors. With the highly anaplastic features of these tumors, differentiation from typical and atypical carcinoids are not difficult.

Reference: 

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2. Gosset A, Masson P. Tumerus endocrines de l’appendice. Pre med 1914 22:37-40

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