Neuroendocrine tumors of the lung

Abstract

Neuroendocrine tumors may develop throughout the human body with the majority being found in the gastrointestinal tract and bronchopulmonary system. Neuroendocrine tumors are classified according to the grade of biological aggressiveness (G1-G3) and the extent of differentiation (well-differentiated/poorly-differentiated). The well-differentiated neoplasms comprise typical (G1) and atypical (G2) carcinoids. Large cell neuroendocrine carcinomas as well as small cell carcinomas (G3) are poorly-differentiated. The identification and differentiation of atypical from typical carcinoids or large cell neuroendocrine carcinomas and small cell carcinomas is essential for treatment options and prognosis. Pulmonary neuroendocrine tumors are characterized according to the proportion of necrosis, the mitotic activity, palisading, rosette-like structure, trabecular pattern and organoid nesting. The given information about the histopathological assessment, classification, prognosis, genetic aberration as well as treatment options of pulmonary neuroendocrine tumors are based on own experiences and reviewing the current literature available. Most disagreements among the classification of neuroendocrine tumor entities exist in the identification of typical versus atypical carcinoids, atypical versus large cell neuroendocrine carcinomas and large cell neuroendocrine carcinomas versus small cell carcinomas. Additionally, the classification is restricted in terms of limited specificity of immunohistochemical markers and possible artifacts in small biopsies which can be compressed in cytological specimens. Until now, pulmonary neuroendocrine tumors have been increasing in incidence. 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.

Figure 1

Precursor lesions.

Figure 2

(A) Cross section of lung specimen with peribronchiolar fibrosis inducing bronchial enlargement. Tumorlet (t) adjacent to bronchus (b) and vascular (v) tissue; (B) High power magnification of tumorlets with neuroendocrine growth pattern, cells are uniform, round with stippled chromatin (yellow arrow); (C) NEH with epithelial proliferation and tumorlets immunopositive for synaptophysin.

Figure 3

(A,B) Diffuse idiopathic neuroendocrine cell hyperplasia presented as small nodule aggregates within fibrotic tissue. Small cells with elongated or round nuclei without mitoses or nuclear atypia; (C) Synaptophysin stained small nodules of neuroendocrine cell clusters in the epithelium of bronchioli.

Figure 4

Well- and poorly-differentiated neuroendocrine tumors.

Figure 5

(A) Corresponding chest radiograph and (B) thorax CT scan (parenchymal window) of a patient with a tissue density/mass (left lower lobe compression) induced by an intrabronchial localized carcinoid tumor demonstrated in the lobe resection tissue (C). The tumor is seen as white to yellow tan intrabronchial tissue mass.

Figure 6

(A) Typical carcinoid with organoid growth pattern and (B) trabecular pattern with delicate intervening vascular stroma; (C) Neuroendocrine differentiation demonstratedby chromogranin positivity; (D) Absence of proliferation activity (MIB-1 ≤ 1%), no mitoses.

Figure 7

Atypical carcinoid tumor with vascularized stroma, focal necrosis and more than 2 mitosis/2 mm².

Figure 8

Immunohistochemical staining of atypical carcinoid tumor with (A) punctual positive KL1 reaction and (B) chromogranin positivity.

Figure 9

(A) Large cell neuroendocrine carcinoma with organoid nesting, trabecular growth, perilobular palisading patterns; (B) Tumor cells are large, nucleoli are frequent, high mitotic count (yellow arrow); (C) Positive staining of large cell neuroendocrine carcinoma with chromogranin.

Figure 10

(A,B) Microscopic feature of small cell lung cancer infiltrate in a bioptical obtained specimen with high mitotic rate. (C,D) Small cell lung cancer in higher magnification with malignant small cells with scant cytoplasm and defined cell borders, fine granular nuclear chromatin, absent or inconspicuous nucleoli, focal or extensive necrosis.

Figure 11

(A) Centrally located combined SCLC with histological features of a large cell carcinoma; (B) Presence of typical necrosis and (D) partly oval, spindle shaped and partly round small cells with mitotic figures. Immunopositive for (C) CD56, (F) synaptophysin and (E) CK7.