“Large cell neuroendocrine carcinoma” was once considered a type of “large cell carcinoma,” a term that is in decline, as subsets of that designation are currently being redefined by immunohistochemical profiles (see Chapter 82). For example, basaloid carcinoma, a previous subset of “large cell carcinoma,” is now considered a form of squamous carcinoma, provided that squamous markers are confirmed immunohistochemically. The current term “large cell neuroendocrine carcinoma” encompasses tumors that demonstrate neuroendocrine histologic features and immunohistochemical confirmation of diffuse endocrine differentiation.

The overall incidence of large cell neuroendocrine carcinoma is increasing, probably due to better awareness. It now accounts for 1% to 3% of lung cancers.^1,2

In contrast to small cell carcinoma, large cell neuroendocrine carcinoma is usually (80% of cases) peripheral.³ Dyspnea, chest pain, cough, hemoptysis, and symptoms related to postobstructive pneumonia are common symptoms.

Unlike small cell carcinoma, bulky enlargement of intrathoracic lymph nodes is uncommon.⁴ Pleural effusions and cavitation are not common.⁴ Central inhomogeneous enhancement occurs in larger tumors.⁵

Large cell neuroendocrine carcinomas are typically 3 to 4 cm^6,7,8,9 and are most frequent in the periphery (84%) and the upper lobes (63%).^5,10 Similar to small cell carcinoma, cavitation is rare, and the cut surface is usually homogenous and soft, because of the relative infrequency of fibrosis typical of adenocarcinomas.

By definition, large cell neuroendocrine carcinoma shows “neuroendocrine” morphology, in the form of nesting, trabecular growth, or rosettes (Figs. 80.1, 80.2, 80.3, 80.4). These are features that may also be seen in small cell carcinoma. Solid nests frequently form cribriform patterns with peripheral palisading (Figs. 80.2 and 80.4). In contrast to small cell carcinoma, cells are generally large, with moderate or abundant and, in areas, prominent nucleoli. Similar to small cell carcinomas, mitotic counts are >10 per 10 high-powered fields (by definition, in distinction from atypical carcinoid). The proliferation index is >50%, usually more than 75%.¹¹ Zonal or punctate necrosis is typical (Fig. 80.3B).

Unlike small cell carcinoma, the diagnosis of large cell neuroendocrine carcinoma requires immunohistochemical confirmation of diffuse staining (>10% of the tumor) with neuroendocrine markers.^11,12
Chromogranin A stains 80% to 85% of large cell neuroendocrine marker and is the most specific for endocrine differentiation (Fig. 80.5). The most sensitive (and least specific) marker is neural cell adhesion molecule (CD56), which stains 92% to 100% of tumors (Fig. 80.6). Synaptophysin is expressed in 50% to 60% of large cell neuroendocrine carcinoma (Fig. 80.7).^{6,10,12,13,14,15} Fewer large cell neuroendocrine carcinomas (about one-half) express TTF-1 than small cell carcinomas (Fig. 80.8). Therefore, this marker is of limited diagnostic use.^10,13,16 Ki-67 is helpful, especially in small biopsies, to distinguish large cell neuroendocrine carcinoma from atypical carcinoid (Fig. 80.9). Atypical carcinoid tumors generally have a proliferation rate of <30%, whereas large cell carcinomas have a proliferative index of more than 60%.¹¹ Napsin A has not been described in large cell neuroendocrine carcinoma.¹³