Metastatic Neuroendocrine Carcinoma Research Articles

Very Long Survival of a Patient With a Metastatic Upper Jejunal Well-Differentiated Neuroendocrine Carcinoma

La Rosa, Stefano MD1,2; Finzi, Giovanna PhD1,2; Capella, Carlo MD1,2 Author Information

Fine‐needle aspiration of metastatic prostatic neuroendocrine carcinomas: Cytomorphologic and immunophenotypic features

Metastatic prostatic carcinoma may, in rare occasions, present as a neuroendocrine tumor. Its recognition is crucial to avert a wrongful exclusion of prostate as a primary site. We report five cases of metastatic prostatic neuroendocrine carcinoma diagnosed by image-guided fine-needle aspiration biopsy. The aspirate smears showed loosely cohesive or dyscohesive clusters of tumor cells with scanty (three cases) to moderate amount (two cases) of cytoplasm, speckled or coarse chromatin and inconspicuous nucleoli. Nuclear molding and necrosis were focally present in two cases. Immunohistochemically, the tumor cells were positive for synaptophysin or/and chromogranin, but negative for prostatic specific antigen and prostatic specific acid phosphatase. Review of prior prostate biopsies/resections revealed adenocarcinoma with focal neuroendocrine differentiation in all cases, with two cases being newly recognized on retrospective review. Confirming neuroendocrine differentiation in the prior biopsy/resection may help to establish a link between metastasis and prostate primary.

Metastatic neuroendocrine malignancy presenting as Sister Mary Joseph’s nodule

Sister Mary Joseph’s nodule (SMJN) is often the first sign of intra-abdominal and/or pelvic malignancy. We present an interesting case of SMJN in an 84-year-old woman referred by a rheumatologist to a gynaecological oncology team with mass in her umbilicus. Histology identified it as a metastatic neuroendocrine carcinoma origin, which was not clear from biopsy.

Array-based Comparative Genomic Hybridization (aCGH) Analysis is a Useful Tool for Distinguishing Primary Pulmonary From Metastatic Neuroendocrine Carcinoma to the Lung

Distinguishing primary from metastatic disease is vital for patient prognosis and care. This becomes a difficult task for both clinicians and pathologists when the clinical data, morphology, and immunohistochemistry (IHC) are not congruent. Array-based comparative genomic hybridization (aCGH) is a fairly recent technique that enables the analysis of whole tumor genome for discreet genetic abnormalities. As it is applicable to paraffin-embedded tissue, it could be suited for surgical pathology settings. We report a case of a 71-year-old woman diagnosed with uterine carcinosarcoma associated with high-grade neuroendocrine carcinoma (NEC). Six months later, the patient presented with pulmonary nodules. A wedge resection of one the nodules was performed and the histology and IHC were consistent with NEC. However, the diagnostic dilemma was whether the pulmonary lesions were primary of the lung or metastatic from the NEC component of the endometrium. Clinical, morphologic, and IHC analysis were not helpful to answer the above question. However, by revealing different genetic profiles of each of the 2 tumors, aCGH was suggestive of the existence of 2 independent primary tumors one endometrial and second pulmonary. In conclusion, aCGH is a powerful tool that is capable of revealing tumor gene fingerprinting and it can be used in routine surgical pathology especially in those cases where the other conventional techniques are not helpful.

Cytology of metastatic thymic well‐differentiated neuroendocrine carcinoma (thymic carcinoid) in pleural fluid: Report of a case

Thymic carcinoid tumors (well-differentiated neuroendocrine carcinomas) are uncommon anterior mediastinal neoplasms. These tumors are frequently accompanied by other endocrinopathies as part of a multiple endocrine neoplasia type I syndrome (MEN type I) and by paraneoplastic Cushing's syndrome and have a poor prognosis. We present the case of a 24-year-old man who presented for follow-up of thymic carcinoid with extensive bony metastases. He had recently completed radiotherapy to lesions involving his skull and mandible. An ultrasound-guided left-sided diagnostic and therapeutic thoracentesis was performed yielding 1 l of cloudy yellow fluid. The cytologic fluid preparations consisted of large "cannonballs" and atypical cell groups with salt and pepper nuclear chromatin. A panel of immunohistochemical stains were performed on the cell block material, and the atypical cells were positive for cytokeratin, synaptophysin, and chromogranin, but not for TTF1. These findings were consistent with metastatic well-differentiated neuroendocrine carcinoma (carcinoid tumor). This is the first reported case of a carcinoid tumor manifesting as large, spherical, smoothly contoured cell aggregates ("cannonballs") in a pleural fluid. Despite its rarity, a metastatic carcinoid tumor should be considered when "cannonballs" are found in effusions.

Breast Carcinoma with Neuroendocrine Differentiation and Myocardial Metastases

A 63-year-old Japanese woman was diagnosed with metastatic well-differentiated neuroendocrine carcinoma presenting as a perianal mass without an obvious primary site. Two years later, she presented with a breast mass determined on histologic examination to be the primary neuroendocrine carcinoma. The tumor was weakly positive for estrogen receptor and clearly originated in multifocal ductal carcinoma in situ. At the same time, she was found to have multiple metastases in bone and liver and, later, heart. Most studies report a relatively poor prognosis and limited treatment responsiveness for neuroendocrine breast carcinoma. Better understanding of the cellular origin and molecular pathogenesis of this relatively enigmatic rare disease is required.

Marked response to a cisplatin/docetaxel/temozolomide combination in a heavily pretreated patient with metastatic large cell neuroendocrine lung carcinoma

At present, there is no clear consensus on the most appropriate treatment approach for large cell neuroendocrine carcinoma of the lung. Large cell neuroendocrine carcinoma lesions differ from other nonsmall cell lung carcinomas in that they have a particularly aggressive clinical behaviour and extremely poor prognosis. We report a 52-year-old woman large cell neuroendocrine carcinoma patient with progressive stage IV disease in the chest, liver, adrenal glands and, particularly, the brain, who achieved a marked response to a fourth-line combination of docetaxel, cisplatin and temozolomide. This regimen significantly improved her quality of life and survival. The good response obtained in this heavily pretreated patient adds to the evidence regarding the use of temozolomide in patients with lung cancer with brain metastases.

Phase II study of thalidomide in patients with metastatic carcinoid and islet cell tumors

Carcinoid and islet cell tumors are known to be highly vascular. There is no effective systemic therapy currently available for metastatic disease. We conducted a phase II trial to evaluate the efficacy of the anti-antiangiogenic agent thalidomide in metastatic neuroendocrine tumors. Eighteen patients with measurable, histologically proven metastatic carcinoid neuroendocrine carcinomas (well-differentiated, n = 13; moderately-differentiated, n = 5) were enrolled on this study. The majority of the patients had gastrointestinal primaries (small bowel, 8; pancreas, 5; colon, 1). All but one patient had hepatic metastases, and 12 patients (67%) had carcinoid syndrome. All patients had Eastern Cooperative Oncology Group performance status of zero or one. Eight patients (44%) had received previous hepatic artery chemoembolization and 11 (61%) had undergone surgical resection. Patients were started on oral thalidomide at a daily dose of 200 mg that was escalated to the target dose of 400 mg daily after 2 weeks. Tumor response was assessed at 12-week intervals using RECIST criteria. Planned treatment duration was 24 weeks unless unacceptable toxicity or disease progression was observed. No patient achieved a partial remission or a complete remission. Best response was stable disease (SD) in 11 of 16 response-evaluable patients (69%). Serum pancreastatin results did not correlate with clinical response. Grade 3 toxicities included dizziness with orthostatic hypotension (n = 5), sensory neuropathy (n = 2), fatigue (n = 2), hemorrhagic cystitis (n = 1), and deep venous thrombosis (n = 1). Frequent Grade 1-2 toxicities were: fatigue (n = 13), constipation (n = 13), dry mouth (n = 12), somnolence (n = 12), dizziness/syncope (n = 10), weight gain (n = 5), and peripheral neuropathy (n = 5). Thalidomide was fairly well tolerated in patients with metastatic carcinoid/islet cell tumors, but failed to reveal any objective responses. The single stage design of the trial makes it difficult to determine whether observed SD in a subset of patients was attributable to the indolent nature of these tumors, or to beneficial effect of thalidomide.

The prognostic role of WHO classification, urinary 5-hydroxyindoleacetic acid and liver function tests in metastatic neuroendocrine carcinomas of the gastroenteropancreatic tract.

The World Health Organisation (WHO) classification (2000) is widely used to classify neuroendocrine carcinomas (NECs), yet its prognostic value needs to be confirmed. In this study, patients with metastatic NECs (n=119) were classified according to WHO guidelines into well differentiated and poorly differentiated (WDNECs and PDNECs). Histological differentiation based on WHO criteria had the highest impact on overall survival (OS) (PDNECs : WDNECs hazard ratio (HR)=4.02, P=0.02); however, PDNECs represented only a small percentage of patients (8%). In a WDNEC-restricted analysis, abnormal liver function tests (LFTs) and elevated urinary 5-hydroxyindoleacetic acid (u5HIAA) were independent prognostic factors for survival (HR=2.65, P=0.006 and HR=2.51, P=0.003, respectively) and were used to create a WDNEC-specific prognostic model (low risk=both normal, intermediate risk=one of them abnormal, high risk=both abnormal). Low-risk WDNECs had the most favourable prognosis (median OS, mOS 8.1 years), which was significantly better compared to both intermediate-risk and high-risk WDNECs (mOS 3.2 and 1.4 years, with P=0.01 and P<0.001, respectively). High-risk WDNECs displayed the shortest OS (1.3 years), which was similar to that of PDNECs (P=0.572). This analysis supports the prognostic value of WHO classification for metastatic NECs arising from the gastroenteropancreatic tract; however, risk stratification using readily available u5HIAA and LFTs may be necessary for the heterogeneous group of WDNECs.

Skin Metastasis of Neuroendocrine Carcinoma Arising in the Rectum

Neuroendocrine carcinoma is known to have features of neuroendocrine and epithelial differentiation through immunohistochemical and biochemical investigation. Cutaneous metastatic neuroendocrine carcinoma must be differentiated from Merkel cell carcinoma, a primary cutaneous neuroendocrine carcinoma and metastatic carcinoma from other visceral disease. Cutaneous metastases from neuroendocrine carcinomas of a variety of sites including the uterus, vulva, gall bladder and fallopian tubes have been reported. We report a 58-year-old Korean man with a metastatic skin tumor on his scalp from rectal neuroendocrine carcinoma. (Ann Dermatol (Seoul) 19(4) 163～165, 2007)

Evaluating the activity of temsirolimus in neuroendocrine cancer

Sir, Duran et al (10 October 2006) reported the results of a phase II trial of temsirolimus in 37 patients with advanced neuroendocrine carcinomas (NEC). The authors cite an intent-to-treat response rate of 5.6% (two out of 36 patients who received temsiroliums achieved a partial response by RECIST criteria), and conclude therefore that ‘temsirolimus appears to have little activity and does not warrant further single-agent evaluation in advanced NEC'. Yet, Duran et al found that tumour control (partial response plus stable disease), measured as the percent tumour change from baseline, was achieved in 23 out of the 36 patients (63.9%) on temsirolimus. When it is considered that all patients in this trial had to have documented, progressive disease within 6 months of the study entry, the significant percentage of patients experiencing disease stabilisation on temsirolimus and the 1-year progression-free rate of 40.1% suggest drug activity beyond the natural course of the disease. Temsirolimus also compares favourably with other agents previously studied in NEC (Oberg, 2002). As a comparison, Faiss et al (2003) prospectively studied the use of interferon-alpha and the somatostatin analogue lanreotide in treatment-naive NEC patients and found tumour control rates of 32% (lanreotide), 30% (interferon-alpha), and 25% (combination) at 1 year. Another study of 15 patients with metastatic NEC refractory to lanreotide examined the use of slow-release octreotide, and a partial response was seen in 7% of patients, stable disease in 40%, and progressive disease in 53% (Ricci et al, 2000). Duran et al also cite other recent reports of the use of sunitinib and, separately, gefitinib in NEC and acknowledge that the response rate and median time to progression with temsirolimus ‘compares favourably with other targeted therapies tested in this tumour population'. This trial exemplifies the difficulty of interpreting the results of single-arm trials using the RECIST criteria (Michaelis and Ratain, 2006). This is especially true for noncytotoxic agents being studied in indolent diseases for which one would expect a high rate of stable disease in the absence of treatment. In fact, the response rate for temsirolimus in NEC compares favourably to that observed with sorafenib in advanced renal cell cancer, where the RECIST response rate is less than 5% (Ratain et al, 2006). Furthermore, if one compares the figures demonstrating ‘tumour size change from baseline' for sorafenib in renal cell cancer to that of temsirolimus in NEC, the response distributions are nearly identical. However, the use of a randomised discontinuation design for the phase II trial of sorafenib demonstrated convincing evidence of activity and its subsequent widespread approval for the treatment of this disease. Rather than abandoning further evaluation of temsirolimus as a single-agent therapy for NEC, one should abandon the concept of single-arm studies of novel agents in neuroendocrine carcinomas.

The prognostic role of the WHO classification, urinary 5-hydroxyindoleacetic acid (u5HIAA) and liver function tests (LFTs) in metastatic neuroendocrine carcinomas (NECs) of the gastroenteropancreatic (GEP) tract

4092 Background: The aim of this study was to assess the prognostic value of the revised neuroendocrine tumour (NET) WHO classification (2000) and to identify additional prognostic factors. Methods: 119 pts with metastatic NET arising from the GEP tract treated at the RMH were eligible for this retrospective study. All were classified according to WHO guidelines into well-differentiated and poorly-differentiated neuroendocrine carcinomas (WDNEC and PDNEC). Demographic, clinical and biochemical data at diagnosis were recorded as potential prognostic factors. The hazard ratios (HRs) between subgroups of patients were estimated by Cox regression analysis; survival curves were generated by Kaplan-Meier method. Approval for the study was obtained from the local ethics committee. Results: 8% of pts had PDNECs, 92% had WDNECs. Histological differentiation had the most impact on overall survival (OS) (HR = 4.02, 95%CI 1.26–12.82, p = 0.02, using WDNECs as the reference). In a WDNEC-restricted multivariate analysis, significantly abnormal LFTs and elevated u5HIAA were independent prognostic factors for survival (HR = 2.65, 95% CI 1.33–5.30, p = 0.006 and HR = 2.51, 95% CI 1.35–4.63, p = 0.003, respectively). Radiological evidence of liver metastases was not predictive of survival. These variables were used to create a WDNEC-specific prognostic model (low-risk = both normal, intermediate-risk = one abnormal, high-risk = both abnormal) (see table ). Statistically distinct median OS (mOS) were identified for each of the 3 risk groups. High-risk WDNECs had similar poor survival to PDNECs. Conclusion: This analysis supports the prognostic value of the WHO classification for metastatic NETs arising from the GEP tract. Risk stratification using readily available u5HIAA and LFTs may give additional prognostic information for WDNECs, although these observations need to be confirmed in an independent dataset. [Table: see text] No significant financial relationships to disclose.

Metastatic thymic neuroendocrine carcinoma presenting as a pancreatic tumor

A 65-year-old man was admitted to hospital with obstructive jaundice. Three years previously he had been diagnosed with pulmonary tuberculosis. During his antituberculous treatment he was found to have a 10-cm cystic mass in the anterior mediastinum that was increasing in size. Computed tomography-guided biopsy showed this to be an epithelial neoplasm with neuroendocrine differentiation. This was surgically removed and pathological examination revealed a moderately differentiated neuroendocrine carcinoma of the thymus. There was focal involvement of the resection margin and lymphovascular spread. He was given postoperative adjuvant radiotherapy and remained well for 2 years.

The Role of Cytoreductive Hepatic Surgery as an Adjunct to the Management of Metastatic Neuroendocrine Carcinomas

Patients with metastatic neuroendocrine cancers to the liver often present with disabling endocrinopathies and pain associated with bulky disease. Quality of life for these patients is poor and can require long-term therapy with somatostatin analogs for control of their symptoms. Alternative therapies to decrease tumor burden and subsequent hormone release have been investigated. Of these, cytoreductive surgery was found to have the most consistent and profound impact on symptom regression and overall survival. Several cases are reported that illustrate an aggressive multimodality approach in the treatment of metastatic neuroendocrine cancers to the liver. The literature is reviewed and the role of cytoreductive surgery in the management of hepatic neuroendocrine metastases is discussed. Cytoreductive surgery can be performed safely with minimal morbidity and mortality. Regression of symptoms occurs in the majority of patients and survival is prolonged. Surgical intervention as part of an aggressive multimodality treatment plan results in improved outcomes for patients with advanced hepatic metastases of neuroendocrine origin. Future directions may include earlier surgical intervention with adjuvant therapies reserved for aggressive recurrent disease.

Metastatic neuroendocrine carcinoma with cytologic features suggestive of secretory activity: A study by fine‐needle aspiration and immunocytochemistry

Metastatic neuroendocrine carcinoma with cytologic features suggestive of secretory activity: A study by fine‐needle aspiration and immunocytochemistry

Small-cell tumors of the liver: A cytological study of 91 cases and a review of the literature

This study was designed to consider the cytomorphological spectrum, differential diagnosis, and the role of ancillary studies in small-cell tumors of the liver. Three independent pathologists reviewed cytological slides from 91 cases of small-cell tumors of the liver. The results were compared with the findings of three recently published studies (Cytopathology 11 (2000) 262-267; Diagn Cytopathol 19 (1998) 29-32; and Acta Cytol 40 (1996) 937-947). The role of immunohistochemistry in reaching timely and specific diagnoses was also examined. The diagnostic categories included 44 cases of metastatic small-cell undifferentiated carcinoma, 15 cases of metastatic neuroendocrine carcinoma, 10 cases of metastatic adenocarcinoma, 7 cases of malignant lymphoma, 4 cases of hepatocellular carcinoma with small-cell features, 2 cases of cholangiocarcinoma, 1 case of poorly differentiated carcinoma, and 8 cases of rare tumors including granulosa cell tumor (2 cases), sarcoma (4 cases), malignant melanoma with small-cell features (1 case), and meningioma with small-cell features (1 case). Metastatic granulosa cell-tumor, metastatic melanoma, and metastatic meningioma should be included in the differential diagnoses of small-cell malignancies found in the liver.

High-grade neuroendocrine carcinomas display unique cytogenetic aberrations

Neuroendocrine tumors represent a spectrum of tumor types with different biologic and clinical features. The morphologic types include the low-grade typical and atypical carcinoids and the high-grade small cell and large cell neuroendocrine carcinomas (NECs). Cytogenetic descriptions of high-grade NECs are rare. Complete karyotypic descriptions of 34 high-grade NECs are reviewed: 7 extrapulmonary small cell NECs, 3 metastatic NECs of unknown primary, and 24 small cell lung carcinomas (SCLCs). Chromosomal deletions are more frequent than gains and often involve the entire chromosome arm. Typical aberrations are deletions of chromosome 3p, 5q, 10q, and 17p and gains of 1q, 3q, and 5p occurring as isochromosomes. Non-small cell lung cancers (NSCLCs) have different cytogenetic aberrations, but those with a metastatic phenotype display the identical aberrations as SCLC, a tumor known for its metastatic phenotype at onset. A genetic classification of lung cancer that incorporates the pattern of recurrent chromosome aberrations may be a better predictor of clinical outcome than a morphologic classification.

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Mixed hepatocellular carcinoma-neuroendocrine carcinomas (HCC-NECs)1 are rare, and they usually carry a poor prognosis. We report a fascinating case of mixed HCC-NEC — the neuroendocrine component of the tumor was diagnosed retrospectively after discovery of the metastatic neuroendocrine carcinoma (NEC).2 A 50-year-old man with cirrhosis underwent resection of a 2.7 cm hepatocellular carcinoma (HCC)3 at the segment II of the liver. Thirteen months after the surgery he had local recurrence in the liver that was treated with radio-embolization. Eighteen months after the initial diagnosis, he was found to have metastatic NEC in the left shoulder. Later, re-evaluation of the previously resected liver tumor revealed a small focus of tumor cells with neuroendocrine morphology within the tumor, which were negative for HepPar1 and positive for synaptophysin, whereas the majority of the tumor cells were positive for HepPar1 and negative for synaptophysin that reclassified the liver tumor as a combined type of mixed HCC-NEC tumor. Upon discovery of the metastatic NEC, the patient was treated with eight cycles of cisplatin and etoposide with a partial response. Nonetheless, his disease progressed two months after finishing chemotherapy, and he was treated with nivolumab for two cycles. In addition, he received palliative radiation to different skeletal metastases. The patient died of sepsis thirty-three months after the initial diagnosis of liver tumor. In conclusion, mixed HCC-NECs are rare and aggressive— an accurate diagnosis may require a high degree of clinical suspicion and re-evaluation of the pathological specimen, especially when one of the components is scarce. Strategic use of multiple modalities of treatment may prolong the life of patients with this type of aggressive tumor.

Cdx2 as a Marker for Neuroendocrine Tumors of Unknown Primary Sites

The transcription factors CDX1 and CDX2 are homeobox genes that regulate development of the epithelium of the small and large intestine. A few studies have shown that Cdx2 protein expression is useful in the diagnosis of adenocarcinomas as well as neuroendocrine tumors of the small and large intestine. To examine the utility of Cdx2 in recognizing neuroendocrine tumors of unknown primary sites, we analyzed 224 primary and metastatic neuroendocrine tumors by immunohistochemistry. The specificity of the antibody reaction was confirmed by Western blotting. Cdx2 antibody stained all primary and most metastatic midgut carcinoid tumors. A few rectal and pulmonary carcinoids were positive, while gastric carcinoids were negative for Cdx2. One of five small cell carcinomas (20%) of the colon was positive for Cdx2, while all pulmonary small cell carcinomas were negative. Neuroendocrine tumors of the pituitary, parathyroid, medullary thyroid carcinomas, paragangliomas, pheochromocytomas and Merkel cell carcinomas were all negative for Cdx2. Western blot analysis of seven cases showed a 40 kDa band in both primary and metastatic midgut carcinoid tumors. These results indicate that Cdx2 can be very useful in recognizing metastatic neuroendocrine carcinomas of unknown primary sites, especially when they are derived from the small intestine.

Diagnostic and therapeutic management of cancer of an unknown primary

Metastatic Cancer of Unknown Primary Site (CUP) accounts for approximately 3% of all malignant neoplasms and is therefore one of the 10 most frequent cancer diagnoses in man. Patients with CUP present with metastatic disease for which the site of origin cannot be identified at the time of diagnosis. It is now accepted that CUP represents a heterogeneous group of malignancies that share a unique clinical behaviour and, presumably, unique biology. The following clinicopathological entities have been recognised: (i) metastatic CUP primarily to the liver or to multiple sites, (ii) metastatic CUP to lymph nodes including the sub-sets involving primarily the mediastinal–retroperitoneal, the axillary, the cervical or the inguinal nodes, (iii) metastatic CUP of peritoneal cavity including the peritoneal papillary serous carcinomatosis in females and the peritoneal non-papillary carcinomatosis in males or females, (iv) metastatic CUP to the lungs with parenchymal metastases or isolated malignant pleural effusion, (v) metastatic CUP to the bones, (vi) metastatic CUP to the brain, (vii) metastatic neuroendocrine carcinomas and (viii) metastatic melanoma of an unknown primary. Extensive work-up with specific pathology investigations (immunohistochemistry, electron microscopy, molecular diagnosis) and modern imaging technology (computed tomography (CT), mammography, Positron Emission Tomography (PET) scan) have resulted in some improvements in diagnosis; however, the primary site remains unknown in most patients, even on autopsy. The most frequently detected primaries are carcinomas hidden in the lung or pancreas. Several favourable sub-sets of CUP have been identified, which are responsive to systemic chemotherapy and/or locoregional treatment. Identification and treatment of these patients is of paramount importance. The considered responsive sub-sets to platinum-based chemotherapy are the poorly differentiated carcinomas involving the mediastinal-retroperitoneal nodes, the peritoneal papillary serous adenocarcinomatosis in females and the poorly differentiated neuroendocrine carcinomas. Other tumours successfully managed by locoregional treatment with surgery and/or irradiation are the metastatic adenocarcinoma of isolated axillary nodes, metastatic squamous cell carcinoma of cervical nodes, or any other single metastatic site. Empirical chemotherapy benefits some of the patients who do not fit into any favourable sub-set, and should be considered in patients with a good performance status.