Primary Tumor Site In Patients Research Articles

Lack of NKX2.2 Expression in Bronchopulmonary Typical Carcinoid Tumors: Implications for Patients with Neuroendocrine Tumor Metastases and Unknown Primary Site

Patients with neuroendocrine tumors (NETs) may have metastatic disease and unknown primary site. NETs commonly arise from the bronchopulmonary (BP) and gastrointestinal (GI) tract. The largest subgroups of well-differentiated BP-NETs are typical carcinoids (TCs). The homeodomain transcription factor NKX2.2 regulates development of gut serotonin cells and is a marker of GI-NETs. Previous work on a limited number of samples suggested that BP-TCs do not express NKX2.2. We hypothesized that lack of NKX2.2 expression in BP-TCs might be useful to distinguish BP- from GI-NETs, and evaluated NKX2.2 expression in a larger number of BP-TCs. Archived formalin-fixed, paraffin-embedded tissues were obtained from 13 previously undescribed patients with BP-TCs. Expression of NKX2.2, serotonin, and the NE marker chromogranin A (CgA) were assessed by immunohistochemistry. CgA expression was robust in all 13 BP-TCs, confirming the NE phenotype. Serotonin expression was less frequent (9/13; 69%). Two patients with BP-TCs in which serotonin expression was absent exhibited Cushing's syndrome due to ectopic ACTH production. NKX2.2 expression was not observed in any of the 13 tumors. Bronchopulmonary TCs uniformly express CgA but not NKX2.2. Because most of these tumors express serotonin, our findings suggest that NKX2.2 may not be required for serotonin production by BP-TCs. We conclude that the presence or absence of NKX2.2 expression may assist in the determination of the primary tumor site in patients with NET metastases of unknown origin. NET metastases that are CgA-positive/NKX2.2-negative would suggest a BP primary, whereas those that are CgA-positive/NKX2.2-positive would suggest a GI primary.

Usefulness of Narrow-band Imaging for Detecting the Primary Tumor Site in Patients with Primary Unknown Cervical Lymph Node Metastasis

ObjectiveWe sometimes experienced patients with primary unknown cervical lymph node metastasis. In such cases, if computed tomography, magnetic resonance imaging, laryngoscopy and gastrointestinal endoscopy cannot detect a primary site, there is no other effective method to identify a possible primary tumor. We investigated whether narrow-band imaging can detect a possible primary tumor in such.MethodsForty-six patients with primary unknown cervical lymph node metastasis were surveyed about primary tumors, from January 2003 to December 2006. All cervical lymph nodes were histologically proved to be squamous cell carcinoma by fine-needle aspiration cytology. Narrow-band imaging combined with magnifying endoscopy was used to identify the primary site in the head and neck region and cervical esophagus. Histological analysis was performed for all suspicious lesions by a biopsy specimen.ResultsTwenty-six lesions were suspected to be cancerous lesions by narrow-band imaging in the head and neck region. Sixteen lesions in 16 (35%, 16/46) patients were squamous cell carcinoma. Ten lesions were located in the hypopharynx and the remaining six lesions were located in the oropharynx. White light endoscopy could not point out any lesion.ConclusionsNarrow-band imaging endoscopy can detect possible primary cancer in patients with primary unknown cervical lymph node metastasis.

Lack of NKX2.2 Transcription Factor Expression Distinguishes Bronchopulmonary Typical Carcinoids from Gastrointestinal Neuroendocrine Tumors

Introduction: Neuroendocrine tumors (NETs) most commonly arise from the bronchopulmonary (BP) tree and gastrointestinal (GI) tract. Typical carcinoids (TCs) are the largest subgroup (90%) of BP NETs. The homeodomain transcription factor NKX2.2 regulates NE differentiation and the development of serotonin-producing cells in normal gut. NKX2.2 is also a GI NET marker. In this study, we evaluated NKX2.2 expression in TCs. Methods: Archived formalin-fixed, paraffin-embedded tissues were obtained from 13 patients with BP NETs classified as TCs. Expression of NKX2.2, serotonin, and the general NE marker chromogranin A (CHGA) were assessed by immunohistochemistry. Results: We observed robust CHGA expression in every TC (13/13, 100%), confirming the NE phenotype. Less frequently, we detected serotonin expression in 9/13 (69%) TCs. Two patients, who had TCs in which serotonin expression was absent, exhibited Cushing's syndrome due to ectopic ACTH production. We did not observe NKX2.2 expression in any TC (0/13, 0%). Conclusions: We show that TCs uniformly express CHGA but not NKX2.2. Although most TCs express serotonin, we did not observe serotonin expression in patients with Cushing's syndrome. These results suggest that serotonin and ACTH expression by TCs may be mutually exclusive. Our data also suggests that NKX2.2 is dispensable for serotonin production by TCs. Thus, distinct pathways may modulate NE differentiation in BP and GI NETs. We conclude that the presence or absence of NKX2.2 expression may assist in the identification of the primary tumor site in patients with NET metastases of unknown origin. NET metastases that are CHGA-positive/NKX2.2-negative would suggest a BP NET primary, while those that are CHGA-positive/NKX2.2-positive would suggest a GI NET primary.

Immunzytochemische Abklärung des initialen CUP-Syndroms an Feinnadelpunktaten

Clinical investigations with imaging- and endoscopic techniques in order to identify the primary tumor sites in patients with CUP syndrome generally entail a significant diagnostic effort. If costs exceed <euro> 800.00, a financial loss ensues for German hospitals, as public health insurance companies do not reimburse above this amount. Combined cytological/immunocytochemical investigation of metastatic cancer cells represents a cost-effective, minimally invasive procedure to identify the probable primary cancer site that can be applied on an outpatient basis. We report on 85 fine needle aspiration biopsies of metastases to the liver, 30 to the lymph nodes and over 180 serous effusions and/or ascites with metastatic cancer cells in CUP. After conventional microscopic inspection, a routine panel of six monoclonal antibodies was applied (CK 5/6, CK 7, CK 20, Cdx 2, TTF 1 and CA 125). We were thus able to correctly identify the primary tumor sites in 90.3%, 92.0% and 85.1%, respectively, within three days. In total, 23 primary hepatocellular carcinomas could all be classified correctly, applying the antibodies HepPar 1, BerEp 4, AFP, CD 31, CD 68 and Ki 67. In addition, 141 malignant epithelial mesotheliomas were typed correctly in 97.1%, using the antibodies BerEp 4, Calretinin, Mesothelin, EMA and WT. Therefore, immunocytochemical investigation of metastatic cancer cells from fine needle aspiration biopsies or in serous effusions offers an efficient, cost-effective diagnostic alternative to imaging and endoscopic techniques in the workup of patients with CUP syndrome.

Prognostic factors and grading systems for overall survival in patients treated with radiosurgery for brain metastases: variation by primary site

The authors conducted a study to determine whether prognostic factors and the applicability of prognostic systems vary by primary tumor site in patients treated with radiosurgery for brain metastases. The authors evaluated data obtained in patients who underwent radiosurgery with or without whole-brain radiotherapy (WBRT) from 1991 to 2005 for newly diagnosed brain metastases. Four groups were analyzed: 1) all primary sites combined, 2) breast, 3) lung, and 4) melanoma primary sites. Kaplan-Meier, log-rank, Cox proportional hazard uni- and multivariate analysis, and recursive partitioning analysis (RPA) were used to assess prognostic factors and 4 prognostic systems: Radiation Therapy Oncology Group (RTOG) RPA, Graded Prognostic Assessment (GPA), basic score for brain metastases (BSBM), and the newly proposed Golden grading system (GGS). The GGS divides patients into 4 prognostic groups by age >or= 65 years, Karnofsky Performance Scale (KPS) score < 70, and known presence of extracranial metastases. Data acquired in 479 newly diagnosed patients with 1664 lesions were analyzed. The median survival time from diagnosis of brain metastases was 12.1 months; the median follow-up was 25.4 months in 73 patients who were censored. Survival and prognostic factors were equivalent for 369 patients treated with radiosurgery compared with 110 patients treated with radiosurgery and WBRT, so these subsets were combined. Multivariate analysis of all primary sites combined demonstrated age < 65 years, KPS score >or= 70, no known extracranial metastases, and <or= 3 brain metastases were associated with longer survival, and primary tumor control was not. In subgroup multivariate analysis of patients with breast, lung, or melanoma primaries, favorable factors included only primary tumor control in 87 patients with breast primary; age < 65 years, no known extracranial metastases, and <or= 3 brain metastases in 169 patients with lung primary; and KPS >or= 70 years, primary tumor control, and <or= 3 brain metastases in 137 patients with melanoma primary. The median survival for <or= 3 versus > 3 metastases was 15.6 and 16.9 months, respectively, for breast, 16.5 and 11.3 months for lung, and 9.0 and 5.7 months for melanoma. Analysis of the 4 prognostic systems (RTOG RPA, BSBM, GPA, and GGS) showed that each prognostic system's clinical applicability varied depending on primary tumor site. The RPA confirmed that GGS and primary tumor site are significant variables for prognosis. Favorable prognostic factors for patients with newly diagnosed brain metastases treated with radiosurgery vary by primary site. The 4 prognostic grading systems analyzed were applicable to different primary sites depending on which prognostic factors each individual system incorporated. Therefore, the authors recommend further development and use of primary-specific prognostic systems.

Neoadjuvant radiochemotherapy of oral cavity and oropharyngeal cancer: evaluation of tumor response by CT differs from histopathologic response assessment in a significant fraction of patients.

Our aim was to compare and assess the predictive value of CT and histopathologic grading of tumor regression at primary tumor sites in patients with squamous cell carcinoma of the oral cavity and oropharynx after neoadjuvant (preoperative) radiochemotherapy (RCT). We investigated 55 patients with carcinomas of the oral cavity and oropharynx who underwent RCT before curative surgery. Two blinded observers measured RCT-induced reduction of tumor volume in pretherapeutic and posttherapeutic CT scans. Volume changes were compared with histopathologic findings obtained at surgery. Histopathologic response evaluation revealed 31 complete remissions, 12 cases of partial response, and 12 nonresponders. We performed a logistic regression analysis to evaluate whether measured volume reduction could predict the likelihood of belonging to a certain response group. Taken together, we found 35 correct, 12 false-negative, and seven false-positive predictions. The extent of remission as assessed by CT scans 4 to 5 weeks after completion of neoadjuvant RCT leads to false predictions in a significant percentage of patients.