Neuroendocrine tumors of the lung This lecture will follow a format - - PDF document

Neuroendocrine tumors of the lung This lecture will follow a format that includes precursor lesions, carcinoids, atypical carcinoids and then we'll examine the higher grade tumors, ending with a discussion of mimickers of these high- grade tumors. In that discussion we will cover problems with the use of CD56. Neuroendocrine tumors have a precursor lesion which is known as neuroendocrine cell

• hyperplasia. This type of hyperplasia can be seen in a variety of chronic lung diseases including

bronchiectasis, COPD and granulomatous inflammation. It remains controversial as to whether this progresses to carcinoid. Carcinoid tumorlets are nodules of the neuroendocrine cells that fail to reach the minimum requirement of 5 mm for the diagnosis of carcinoid tumor. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia is a term that was adopted for a multifocal process of neuroendocrine cell hyperplasia that may or may not be associated with obstructive lung disease in individual patients. The definition of DIPNECH remains imprecise. Some authors have chosen to distinguish symptomatic versus asymptomatic cases, or to quantify the WHO definition of "generalized”. Carcinoid tumorlets are aggregations of these neuroendocrine cells that have invaded into the wall of the airway while neuroendocrine cell hyperplasia is intraepithelial process of increased numbers of neuroendocrine

• cells. Whether the obstructive lung disease is a result of scarring in the airway wall alone or a

combination of luminal obstruction and secretion of substances that cause bronchus constriction, some patients have severe obstructive lung disease that can be unremitting and can require transplantation as treatment. Carcinoid tumors are divided into typical and atypical. Typical or classical carcinoid tumors are seen in younger patients than non-small cell carcinomas and small cell carcinoma, are not clearly smoking associated, and occur about equally in men and women. Carcinoid of the lung are uncommon relative to NSCLC and small cell, and are as about 3% of lung tumors overall. Carcinoids can be central or peripheral are more often central. They can be endobronchial. They are relatively circumscribed and there cut surface is tan without central umbilication. Histologic patterns of carcinoid are quite varied and this variation can be seen within one tumor or between

• tumors. These patterns can be paraganglioma-like, trabecular, rosette formation, oncocytic, or spindle
• cell. What all these tumors having common is a uniformity of cellularity with smoothly contoured

nuclei, fairly abundant cytoplasm, and a salt-and-pepper chromatin. Because such uniformity and nuclear changes can be seen other tumor types, the differential diagnosis includes plasma cell tumors, paragangliomas, tumors of salivary gland type such as mucoepidermoid carcinoma, metastatic breast carcinoma with solid growth pattern, the case of spindle cell carcinoids, smooth muscle tumors. Overall either changes in the cytoplasm such as a Golgi Zone clearing in a plasma cell neoplasm or differences in nuclear morphology are clues that the tumor is not a carcinoid. The growth pattern is well can be a clue, such as the fascicular arrangement of cells and a smooth muscle tumor. However immunohistochemistry should be able to resolve most of these differential diagnoses. Carcinoid tumor should be cytokeratin positive and should lack S100-positive sustentacular cells. While cytokeratin AE1 AE3 can be negative at up to 20% of carcinoids, low molecular weight keratin such as CAM 5.2 should be positive in most cases. Neuro endocrine markers are commonly used to confirm this diagnosis including synaptophysin chromogranin and CD56. TTF1 is often positive in pulmonary carcinoid tumors.

The carcinoid tumor is not a benign neoplasm however malignant potential is low. The current classification of neuroendocrine tumors which we will discuss in more detail divides low, intermediate, and high-grade tumors. For typical carcinoid, this means a high rate of survival at 10 years even in the setting of node metastasis. In fact N1 nodal disease which can occur in about 10% of cases does not appear to effect mortality. Because of the paucity of data this is less clear with N2 nodal disease. The term atypical carcinoid was originally coin by Arrigoni et al and was further clarify by Travis in 1998. His clarification solidified the use of necrosis and a mitotic rate of 2-9 in 10 HPF or 2 mm2, as the important criteria. Using his clarification, when compared to the Arrigoni critieria, an intermediate group is clearly identified. Mitotic count in this tumor has always been an area of some concern. The cut off of two in 10 HPF/2 mm2 has been further clarified the latest WHO. If the tumor is near the cutoff value, 3 sets a field should be counted and an average taken. This means, from a practical point of view, six mitoses must be found within three sets of fields the average two mitoses per set of 10 HPF/ 2mm2. This average approach is a change from the peak approach which was applied previously. While Ki-67 can be useful in the distinction from high and low grade tumors, precise cutoff have yet to be fully established in the lung. Therefore the utility of Ki-67 remains unclear in pulmonary neuroendocrine tumors outside of the distinction of low/intermediate from high grade disease. One can rarely, cross a tumor that is morphologically carcinoid like but has a mitotic activity that would place it outside of the range of atypical carcinoid. While this would be currently classified as a large neuroendocrine carcinoma, some of the molecular insights are interesting. Using these criteria, typical and atypical carcinoid need to be distinguish because they are behavior is quite different clinically. A high rate of significant nodal metastasis and a lower 5-10 year survival warrants the use of adjuvant therapy in the setting of atypical carcinoid. Larger atypical carcinoids are also a consideration for adjuvant therapy. The discussion of high-grade tumors will be divided into different problems. The 1st problem is small cell versus large cell type and carcinoma. The prominent often the result of small sample diagnosis as well as morphologic overlap between these two tumors. The other difficulty is that combined small cell often has a large cell neuroendocrine component. However reproducibility of small cell diagnosis remains high especially with the use of adjunct immunohistochemistry. There are some clinical features that help us to distinguish small cell from large cell neuroendocrine carcinoma. Small cell carcinoma generally presents with advanced disease while large cell type neuroendocrine carcinoma can present in early stage disease in as many as 50% of cases. Small cell carcinomas often are associated with paraneoplastic syndrome while this is not true of large cell neuroendocrine carcinoma. Both are seen in smokers and both are associated with a high SUV on PET. Histologically small cell carcinomas have the classic scant cytoplasm with nuclear molding and frequent crush artifact and the cells themselves are usually smaller than those of large cell neuroendocrine carcinoma. Large cell neuroendocrine carcinoma will have larger cells with visible cytoplasm, small nucleoli with a coarser chromatin than small cell carcinoma. Other features such as a apoptosis mitosis and necrosis are seen in both. The presence of frequent rosettes and palisading may be more common in large cell neuroendocrine carcinoma.

Immunohistochemistry does not usually distinguish these two tumors. However the use of pan- cytokeratin can be helpful in highlighting two cellular populations within the tumor. These considerations are important in difficult cases. For example, occasional small cell will be

• rgan localized and present as a peripheral nodule. In addition basaloid squamous carcinoma can be a

mimicker of large cell neuroendocrine carcinoma. And as previously mentioned, the frequent combination of small cell and large cell neuroendocrine within the same tumor is an important point as combined tumors are considered small cell carcinoma. The 2nd problem is the distinction of a solid adenocarcinoma with large cell neuroendocrine

• carcinoma. There is clearly overlap here. Part of the difficulty is that neuroendocrine markers can be

positive in adenocarcinomas, even those with acinar and papillary patterns. With this in mind, morphologic criteria become most important. Specifically the presence of a vesicular chromatin and nucleoli are against large cell neuroendocrine carcinoma and a more abundant cytoplasm is also against the diagnosis. Not surprisingly overlap cases occur. The molecular story highlights this overlap. The presence of frequent K-ras mutations in series that include Napsin positive and tumors with a lower mitotic rate show the problem. There is a proposal

• f there are three types of large cell neuroendocrine carcinoma - those that are small cell like, those that

are adenocarcinoma-like, and those of the carcinoid like. It is unclear what is the clinical significance of reclassifying a solid adenocarcinoma with K-ras mutation as a large cell neuroendocrine carcinoma with K-ras mutation. The 3rd problem is that of mimickers of high-grade endocrine carcinoma. These are generally rare tumors and occur in an epidemiology outside of small cell carcinoma. However, the consideration

• f the possibility of these tumors is the key to avoiding misdiagnosis. Morphologic and

immunohistochemical features of PNET tumors is discussed as an example of a mimicker of small cell carcinoma. The use of CD56 as a sole neuroendocrine marker is a practice that needs careful consideration. In situations in which age, location, distribution is unusual or nonsmoking history is obtained CD56 should not be used as the sole neuroendocrine marker. Its staining is too ubiquitous to be diagnostically

• reliable. It may be that markers such as INSM1 will become a viable replacement for CD56, with

comparable sensitivity and higher specificity. However until then, a panel approach is recommended. It is interesting however that the high rate of TTF1 immunoreactivity can be used to your advantage in that the other “small blue cell tumors” is in the differential of small cell carcinoma are negative for TTF1 wall small cell carcinomas frequently positive.