Immunohistochemical Staining for CDX-2, PDX-1, NESP-55, and TTF-1 Can Help Distinguish Gastrointestinal Carcinoid Tumors From Pancreatic Endocrine and Pulmonary Carcinoid Tumors

Dartmouth Medical School, Dartmouth-Hitchcock Medical Center Lebanon, NH, USA.
The American journal of surgical pathology (Impact Factor: 5.15). 04/2009; 33(4):626-32. DOI: 10.1097/PAS.0b013e31818d7d8b
Source: PubMed


Well-differentiated neuroendocrine tumors (WDNET) of the gastrointestinal tract, pancreas, and lung are histologically similar. Thus, predicting the site of origin of a metastasis is not possible on morphologic grounds. Prior immunohistochemical studies of WDNET have yielded conflicting results, and pancreatic and duodenal homeobox factor-1 (PDX-1) has not previously been evaluated in this context. We therefore analyzed the expression of CDX-2, PDX-1, TTF-1, and neuroendocrine secretory protein-55 (NESP-55), a recently described member of the chromogranin family, in primary and metastatic WDNET. In total, 64 gastrointestinal carcinoids (5 stomach; 5 duodenum; 31 ileum; 11 appendix; and 12 rectum); 39 pancreatic endocrine tumors (PET); and 20 pulmonary carcinoid tumors were studied. PET were positive for NESP-55 (16/39) and PDX-1 (11/39); 3/31 also showed heterogeneous positivity for CDX-2. Ileal carcinoids were exclusively positive for CDX-2 (30/31) and negative for all other markers. Appendiceal carcinoids were uniformly positive for CDX-2 (11/11). All rectal carcinoids were negative for CDX-2 and TTF-1; 2/12 were positive for PDX-1, and 1/12 for NESP-55. The gastric and duodenal carcinoids were only positive for PDX-1 (7/10). TTF-1 positivity was confined to pulmonary carcinoids (7/20); 1/20 was positive for NESP-55; and all were negative for CDX-2 and PDX-1. NESP-55 and PDX-1 positivity, in the presence of negative CDX-2 and TTF-1, was 97% specific for PET. The sensitivity and specificity of CDX-2 positivity for predicting an ileal primary, when PDX-1, NESP-55, and TTF-1 were negative, was 97% and 91%, respectively. TTF-1 positivity was confined to pulmonary carcinoids in our study but was present in only about a third of cases. A panel of these 4 markers may be useful in predicting the primary site of metastatic WDNET.

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    • "CDX-2 and Nkx2-1 (Lin et al., 2007; Strickland-Marmol et al., 2007) were characterized as highly specific for identifying the original site of intestinal and lung tumors from metastatic neuroendocrine neoplasms. An immunohistochemical staining panel for distinguishing the primary site of metastatic well-differentiated neuroendocrine tumors (WDNETs) from the gastrointestinal tract, pancreas and lung included CDX-2, pancreatic duodenal homeobox-1 (PDX-1), neuroendocrine secretory protein-55 (NESP-55) and Nkx2-1 (Srivastava and Hornick, 2009). Nkx2-1, Nkx2-8 (Nkx homeobox-8 gene), and PAX9 (paired box gene 9), the three transcription factors known to mediate lung development and maturation, were recently characterized as cooperating oncogenes located together on chromosome 14q13 (Hsu et al., 2009). "
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    ABSTRACT: Nkx2-1 (Nkx homeobox-1 gene), also known as TTF-1 (thyroid transcription factor-1), is a tissue-specific transcription factor of the thyroid, lung, and ventral forebrain. While it has been shown to play a critical role in lung development and lung cancer differentiation and morphogenesis, molecular mechanisms mediating Nkx2-1 cell- and tissue-specific expression in normal and cancerous lungs have yet to be fully elucidated. The recent identification of prognostic biomarkers in lung cancer, particularly in lung adenocarcinoma (ADC), and the different reactivity of patients to chemotherapeutic drugs have opened new avenues for evaluating patient survival and the development of novel effective therapeutic strategies. The function of Nkx2-1 as a proto-oncogene was recently characterized and the gene is implicated as a contributory factor in lung cancer development. In this review, we summarize the role of this transcription factor in the development, diagnosis, and prognosis of lung cancer in the hope of providing insights into the utility of Nkx2-1 as a novel biomarker of lung cancer.
    Journal of Zhejiang University SCIENCE B 11/2012; 13(11):855-66. DOI:10.1631/jzus.B1100382 · 1.28 Impact Factor
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    • "In patients with multiple endocrine neoplasia type 1, specific markers such as gastrin, insulin, and pancreatic polypeptide (PP) should be determined. For patients with unknown primary tumors, TTF1 (bronchial/lung), CDX2 (intestinal serotonin-midgut), and PP/Islet-1/Glucagon (pancreatic) can be used to guide the search for the primary tumor (14),(15). "
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    ABSTRACT: Neuroendocrine tumors are a heterogeneous group of malignancies that present a diagnostic challenge. The majority of patients (more than 60%) present with metastatic disease at diagnosis. The diagnosis is based on histopathology, imaging, and circulating biomarkers. The histopathology should contain specific neuroendocrine markers such as chromogranin A, synaptophysin, and neuron-specific enolase and also an estimate of the proliferation by Ki-67 (MIB1). Standard imaging procedures consist of computed tomography or magnetic resonance imaging together with somatostatin receptor scintigraphy. 68Ga-DOTA-octreotate scans will in the future replace somatostatin receptor scintigraphy because they have higher specificity and sensitivity. Other positron imaging tomographic scanning tracers that will come into clinical use are 18F-DOPA and 11C-5HTP. Neuroendocrine tumors secrete many different peptides and amines that can be used as circulating biomarkers. The most useful general marker is chromogranin A, which is both a diagnostic and prognostic marker in most neuroendocrine tumors. However, there is still a need for improved biomarkers for early detection and follow-up of patients during treatment. In addition, molecular imaging can be further developed for both detection and evaluation of treatment.
    Clinics (São Paulo, Brazil) 04/2012; 67 Suppl 1(S1):109-12. DOI:10.6061/clinics/2012(Sup01)18 · 1.19 Impact Factor
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    • "They also demonstrated that extrapulmonary neuroendocrine tumors are negative for TTF1, rating it to be 100% specific but not very sensitive for bronchopulmonary carcinoids and possibly also LCNECs [39]. The predominance of TTF1 in carcinoids of bronchopulmonary origin was confirmed by other studies [40-42]. In contrast to these and other publications, Cai et al. gave an account of positive TTF1-expression in 69% of their studied carcinoid cases, all tumors except one were TCs [40]. "
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    ABSTRACT: Overdiagnosis of bronchopulmonary carcinoid tumors together with overtreatment can cause serious postoperative consequences for the patient. We report of a patient with a typical bronchopulmonary carcinoid tumor, which was initially misdiagnosed and treated as an adenocarcinoma of the lung. GnrH receptors and the associated Raf-1/MEK/ERK-1/2-pathway are potential targets for analogs in cancer treatment. We suspected a correlation between the lack of tumor growth, application of leuprolide and the Raf-1/MEK/ERK-1/2-pathway. Therefore, we examined GnrH receptor status in the examined specimen. In 2010 a 77 year-old male patient was shown to have a tumor mass of about 1.7 cm diameter in the inferior lobe of the left lung. Since 2005, this tumor had hitherto been known and showed no progression in size. The patient suffered from prostate cancer 4 years ago and was treated with TUR-P, radiation therapy and the application of leuprolide. We conducted an explorative thoracotomy with atypical segment resection. The first histological diagnosis was a metastasis of prostate cancer with lymphangiosis carcinomatosa. After several immunohistochemical stainings, the diagnosis was changed to adenocarcinoma of the lung. We conducted a re-thoracotomy with lobectomy and systematic lymphadenectomy 12 days later. The tumor stage was pT1 N0 MX G2 L1 V0 R0. Further immunohistochemical studies were performed. We received the results 15 days after the last operation. The diagnosis was ultimately changed to typical carcinoid tumor without any signs of lymphatic vessel invasion. The patient recovered well from surgery, but still suffers from dyspnea and lack of physical performance. Lung function testing revealed no evidence of impairment. The use of several immunohistochemical markers, careful evaluation of hematoxylin-eosin sections and the Ki-67 labelling index are important tools in discriminating between carcinoids and other bronchopulmonary carcinomas. Although we could not detect GnrH-receptors in the examined specimen, there may be individual differences in expression. GnrH receptor profiles in typical and atypical carcinoids should be scrutinized. This could lead to new therapeutical options, since the GnrH receptor has already been described on atypical carcinoids. Clinically tested drugs such as leuprolide could come to use.
    World Journal of Surgical Oncology 01/2012; 10(1):19. DOI:10.1186/1477-7819-10-19 · 1.41 Impact Factor
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