Morphologic and molecular classification of lung neuroendocrine neoplasms

Abstract

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 biological determinants and the natural history of disease.

Keywords: Atypical; Carcinoid; Carcinoma; Classification; Differentiation; Gene; Large cell; Lung; Molecular; Neuroendocrine; Progression; Signature; Small cell; Stem cell; Typical.

Fig. 1

Composition of lung neuroendocrine neoplasms. A binary subdivision into neuroendocrine tumors (NETs) and neuroendocrine carcinoma (NECs) is preliminary to the identification of typical carcinoid (TC) as G1 tumor, atypical carcinoid (AC) as G2 tumor, and NEC with small cells (namely small cell lung carcinoma, SCLC) and large cells (namely large cell neuroendocrine carcinoma, LCNEC), both of them making tautologically G3—high-grade neoplasms

Fig. 2

Histomorphologic and immunohistochemical features of lung carcinoids. Typical carcinoid shows a variety of histological patterns, including organoid to trabecular (a), lobular (b), or spindle cells (c), but always with < 2 mitoses per 2 mm² and absent necrosis. Immunohistochemistry for neuroendocrine markers documents diffuse and intense positivity for chromogranin A (d) and synaptophysin (d, inset). This atypical carcinoid featuring a trabecular architecture exhibits at least two mitoses (e, dotted white circle), which are also easily recognizable in another similarly patterned case (f, dotted white circle). Atypical carcinoid may exhibit punctate necrosis, in this case against a background of a solid-appearing tumor (g, dotted white circle). Immunohistochemistry for neuroendocrine markers in atypical carcinoid documents reactivity for synaptophysin (h), chromogranin A (h, inset) and INSM1 (i), all consistent with neuroendocrine morphology. Of note, INSM1 is also expressed in normal and hyperplastic neuroendocrine cells, as well as in tumorlets (not shown in the picture) (j)

Fig. 3

Histomorphologic and immunohistochemical features of lung neuroendocrine carcinomas. LCNEC features organoid aggregates with peripheral palisading and plentiful mitoses (a), but even SCLC-like appearance (b). LCNEC is usually positive for INSM1 (c), while retinoblastoma nuclear decoration is often missing (d). SCLC is composed of small-sized tumor cells with prominent nuclear molding, inconspicuous nucleoli, and abundant necrosis (e), but spindling of neoplastic cells may be on record (f). Synaptophysin is largely retained in this case (g), along with INSM1 labeling (h), while chromogranin A is usually reduced to negative (g, inset), just like does retinoblastoma that is consistently unreactive (h, inset). Differential diagnosis between carcinoids (i) and SCLC (j) may be demanding upon morphology in cytology samples, but Ki-67 staining helps to operate such a separation confidently showing low expression in carcinoid (i, inset) and high expression in SCLC (j inset). Note that distinction of typical and atypical carcinoids rests on mitotic count and/or punctate necrosis, while neuroendocrine carcinomas are especially distinguished according to cell size appreciation.

Fig. 4.

Development model of lung neuroendocrine neoplasms. Mechanisms of horizontal or de novo/basal-like propagation from cancer stem cells early blocked-in differentiation give rise to primary early-aggressive high-grade tumors (PEA-HGNETs/NECs). They are characterized by undifferentiated cells resembling typical SCLC featuring diffuse pattern of growth. Mechanisms of vertical- or luminal-like propagation from progenitor cells with an intermediate block of differentiation cause more differentiated lesions to develop from pre-existing neuroendocrine tumors or non-small cell carcinoma (NET-like DS-HGNET/NEC and NSCC-like DS-HGNET/NEC, respectively). They are characterized by better differentiated cells featuring a variety of histologic appearances along with organoid patterns of growth. Lastly, there are indolent NETs (I-NETs) composed of fully differentiated cells (in red and green on the right of picture), which usually do not progress further over time but can contribute to DS-HGNETs/NECs by re/deprogramming events. PEA-HGNET/NEC, primary early-aggressive high-grade neuroendocrine tumor/carcinoma; DS-HGNET/NEC, differentiating secondary high-grade neuroendocrine tumor/carcinoma; I-NET, indolent NET