Pulmonary Neuroendocrine Tumor Presenting as a Left Pleural Effusion

Ki-67 LI in samples has the highest specificity and sensitivity for low-tointermediate- grade vs high-grade tumors. It is being used for guiding clinical and treatment decisions. ⁶ In SCLC, the Ki-67 LI is not necessary for diagnosis but will be about 80%. ¹¹ The tumor cells will show epithelial characteristics with positive cytokeratin AE1/AE3 and monoclonal antibody CAM5. ² and neuroendocrine markers, including NCAM/CD56, chromogranin A, and synaptophysin. ¹¹

Thyroid transcription factor-1 (TTF- 1) is positive in most cases. In LCNEC, the Ki-67 LI is between 40% and 80%. NCAM/ CD56, chromogranin A, and synaptophysin are present in 92 to 100%, 80 to 85%, and 50 to 60%, respectively. ¹¹ TTF-1 is identified in half of the tumors. All these tumors express pancytokeratin (AE1/AE3), cytokeratin 7 or low-molecular-weight cytokeratin. Likewise, the carcinoids will show markers, such as chromogranin A, synaptophysin, CD56, and epithelial markers like pancytokeratin. ¹¹ However, the high-molecular-weight cytokeratin and TTF-1 are negative. Furthermore, NSE is considered a good tumor marker in the diagnosis and prognosis of SCLC. NSE also has been reported in NSCLC. The level of NSE correlates with tumor burden, number of metastatic sites, and response to treatment. ¹² A potentially useful marker is the insulinoma-associated protein 1, which is a nuclear determinant of NE differentiation that stains all types of pulmonary NETs irrespective of the histology but does not stain adenocarcinoma or squamous cell carcinoma (SCC). ⁶

Recently, genomic studies have identified gene alterations that have become standard of care for diagnosis and targeted therapies. ⁸ For example, epidermal growth factor receptor (EGFR) and echinoderm microtubule- associated proteinlike 4, and anaplastic lymphoma kinase (EML4-ALK) mutations have been found in about 25% of lung adenocarcinomas. ⁸ Other abnormalities in LKB1/STK11, NF1, CDKN2A, SMARCA4 and KEAP1, KRAS, MET, ROS1, and RET have also been identified.8 On the other hand, SCC rarely have derangements in EGFR and EML4-ALK, but do show changes in RTKs, DDR2M, FGGRs, among others.8 In TC and AC, observed molecular alterations include MEN1 mutations, mTOR, and SSTRs pathway activation, and GC/ CEACAM1 and CD44/OTP expression. ¹³ LCNEC and SCLC have shown TP53 and RB1 mutations and CDX2/VIL1/BAI3 expression. DLL3 expression and MET mutations may be present in SCLC.13 Last, chromatin remodeling gene mutations have been identified in all these lung NET types. ¹³

Furthermore, neuropeptides and neuroamines may be measured in the blood and urine. ¹⁴ Pulmonary NETs may be functional and secrete these substances, leading to systemic symptoms based on the released molecules. ¹⁵ However, pulmonary NETs produce less serotonin than gastrointestinal NETs; therefore, carcinoid syndrome is less frequent in pulmonary NETs. ¹⁶ Liver metastasis is often present when it occurs. ⁵ Other possible clinical features include Cushing syndrome and acromegaly depending on the secreted hormones. ⁵

In a recent metanalysis, serum LDH has been found to have a prognostic role in Ewing sarcoma, urologic cancers, malignant mesothelioma, among others. ¹⁷ It demonstrated that a higher LDH concentration is associated with worse survival in patients with lung cancer. ¹⁷ Serum LDH is an enzyme that catalyzes the reaction between lactic acid and pyruvic acid that typically takes place in anaerobic conditions. ¹⁷ LDH levels are elevated in malignancies because tumors have an anaerobic environment. Elevated LDH levels correlate with the anaerobic metabolism in the tumor. Other studies also have noted that patients with high metastatic score have higher LDH levels. ¹⁷ Therefore, LDH may reflect tumor extension.