Small Cell Tumor Research Articles

Microencapsulation of small intestinal neuroendocrine neoplasm cells for tumor model studies

Basic cancer research is dependent on reliable in vitro and in vivo tumor models. The serotonin (5-HT) producing small intestinal neuroendocrine tumor cell line KRJ-1 has been used in in vitro proliferation and secretion studies, but its use in in vivo models has been hampered by problems related to the xeno-barrier and tumor formation. This may be overcome by the encapsulation of tumor cells into alginate microspheres, which can function as bioreactors and protect against the host immune system. We used alginate encapsulation of KRJ-1 cells to achieve long-term functionality, growth and survival. Different conditions, including capsule size, variations in M/G content, gelling ions (Ca(2+) /Ba(2+)) and microcapsule core properties, and variations in KRJ-1 cell condition (single cells/spheroids) were tested. Viability and cell growth was evaluated with MTT, and confocal laser scanner microscopy combined with LIVE/DEAD viability stains. 5-HT secretion was measured to determine functionality. Under all conditions, single cell encapsulation proved unfavorable due to gradual cell death, while encapsulation of aggregates/spheroids resulted in surviving, functional bioreactors. The most ideal spheroids for encapsulation were 200-350 μm. Long-term survival (>30 days) was seen with solid Ca(2+) /Ba(2+) microbeads and hollow microcapsules. Basal 5-HT secretion was increased (sixfold) after hollow microcapsule encapsulation, while Ca(2+) /Ba(2+) microbeads was associated with normal basal secretion and responsiveness to cAMP/PKA activation. In conclusion, encapsulation of KRJ-1 cells into hollow microcapsules produces a bioreactor with a high constitutively activate basal 5-HT secretion, while Ca(2+) /Ba(2+) microbeads provide a more stable bioreactor similar to non-encapsulated cells. Alginate microspheres technology can thus be used to tailor different functional bioreactors for both in vitro and in vivo studies.

Disseminated Neuroendocrine Carcinoma in a Pediatric Patient

A previously healthy 16-year-old female presented with 1-month history of fever, cough, extremity pain, left upper quadrant pain, and night sweats. Imaging studies revealed mediastinal lymphadenopathy, lung and liver masses, and bony lesions. Liver and bone marrow biopsies revealed small tumor cells with a high nuclear cytoplasmic ratio, stippled chromatin, and inconspicuous nucleoli surrounded by bands of collagen. Immunohistochemically, the tumor cells were positive for epithelial (epithelial membrane antigen and cytokeratin AE1/AE3) and neuroendocrine markers (chromogranin and synaptophysin), and negative for other antigens tested, including vimentin, desmin, CD99, and WT-1. The morphologic features and immunohistochemical profile was consistent with neuroendocrine carcinoma. Despite several chemotherapeutic regimens, the patient had progressive disease and enrolled in a phase 1 trial. Thorough histopathologic evaluation, including immunohistochemical stains is a crucial component for diagnosing this rare, aggressive tumor in children and adolescents.

Merkel cell carcinoma in a patient with noninvasive vulvar Paget's disease

We present the first case of inguinal Merkel cell carcinoma of unknown primary origin in a patient with vulvar Paget's disease. Correlation with immune suppression of both entities warrants further investigation. Additionally, this case highlights the value of ultrasound scanning in the detection of inguinal metastasis.

Ewing's sarcoma of the kidney: a case report and review of the literature

Objective To review the clinical features,management and prognosis of renal Ewing's sarcoma (ES) of a single case report. Methods A single case of renal ES was reported.A 33-year-old male presented with a mass in the left kidney found during a three day medical examination.B-ultrasound examination showed a lesion with rich blood flow signals and well defined margins in the inferior portion of the left kidney.The CT scan revealed a solid mass of 5.1 cm × 4.7 cm in the inferior portion of the kidney with un-even enhancement by contrast.A possible diagnosis of renal carcinoma was given prior to surgery.No metastasis was proven.A literature review of ES was then conducted. Results A left retroperitoneoscopic radical nephrectomy was successfully performed.Gross pathologic examination showed a solid tumor with necrosis,localized at the inferior pole of the left kidney.The histopathological examination revealed the tumor consisted of small round tumor cells,which were positive for CD99,vimentin and PAS,but negative for WT-1.A diagnosis of ES of the kidney was then determined.The patient received alternating short cycle ( CTX + VCR + THP) and long cycle ( IFO + VP-16) adjuvant chemotherapy for 6 cycles after the operation.There has been no evidence of recurrence at the 14-month follow up. Conclusions ES of the kidney is a rare disease with no specific clinical feature in most cases.Diagnosis of renal ES must be confirmed with histological features.Surgery combined with radiotherapy and chemotherapy is the main method of therapy for renal ES.The prognosis of renal ES is poor. Key words: Kidney neoplasms; Sarcoma, Ewing's; Pathology, clinical

High molecular mass radioimmunoconjugates are promising for intraperitoneal α-emitter immunotherapy due to prolonged retention in the peritoneum

Therapeutic efficacy of intraperitoneal radioimmunotherapy is dependent on the time of retention of the radioimmunoconjugates within the peritoneal cavity. Therefore, the aim of this study was to investigate intraperitoneal retention of Fab, IgG and IgM radioimmunoconjugates. Female Balb/c mice were injected with 213Bi- or 111In-labeled IgM, IgG and recombinant Fab conjugates intraperitoneally or intravenously. At different time points after injection, whole body distribution of radionuclides was imaged using a gamma camera. Distribution of radionuclides in selected organs was determined via γ-counting after sacrifice. Biological half-lives of the conjugates were calculated from whole body activities. After i.p. injection 213Bi-Fab rapidly accumulated in the kidneys indicative of glomerular filtration and reabsorption. Accumulation of 213Bi-IgG in the kidneys was significantly lower. 213Bi-IgM showed a striking accumulation in the liver 180 min after i.p. injection. 111In-IgG persisted in the circulation up to 72 h both after i.p. and i.v. injection. 111In-IgM showed a continuous accumulation in the liver. Moreover, 111In-IgM was significantly higher 24 h after i.v. injection than i.p. injection both in liver and spleen. These differences could be confirmed via scintigraphy. After injection of 111In-IgG differences in scintigraphic images between i.v. and i.p. were clearly visible only at 3 h. Biological half lives were 24 h, 45 h and 165 h for 111In-IgM, 111In-Fab and 111In-IgG, respectively. Retention of radioimmunoconjugates in the peritoneal cavity positively correlates with the molecular mass of the antibody. Therefore, IgM radioimmunoconjugates should be preferably used in radioimmunotherapy of free floating tumor cells and small tumor cell clusters in the ascites of the peritoneal cavity.

Therapies and outcomes of non-renal cell carcinoma (non-RCC) neoplasms of the kidney: A single-institution experience.

431 Background: Non-RCC neoplasms of the kidney include neuroendocrine tumors (small cell carcinoma and carcinoid) and Primitive Neuroectodermal Tumors (PNET). Small cell carcinoma and renal carcinoids are small blue cell tumors that rarely occur as primary renal neoplasms. PNET, known as extraskeletal Ewing sarcoma, is characterized by t(11;22), the gold standard for diagnosis. It is a small round cell tumor derived from the neural crest and treated with chemotherapy; the role of nephrectomy is unclear. Methods: We reviewed records of patients seen at MDACC between 01/01/2001 and 01/01/2011 for PNET, small cell carcinomas, and carcinoid tumors of the kidney. Overall survival (OS) was determined from diagnosis to death. Results: 21 pts met inclusion criteria. Disease-specific data is shown in the table. Common treatments included: carboplatin/etoposide for small cell carcinomas; vincristine/doxorubicin/ifosfamide, vincristine/doxorubicin/cyclophosphamide, and doxorubicin/ifosfamide alternating with cisplatin/etoposide for PNET. Irinotecan was a common salvage agent in PNET. Most carcinoid tumors were treated with surgery alone. Two patients with small cell received whole brain radiation for brain metastases. Conclusions: Carcinoid tumors of the kidney had better outcomes compared to renal small cell carcinomas or PNET. Local carcinoid tumors of the kidney were generally managed with surgery alone. Renal small cell carcinomas and PNET were treated with systemic therapies. [Table: see text]

Orbital Embryonal Rhabdomyosarcoma with Metastasis in a Young Dog

A 2-year-old male Welsh corgi dog was brought to an animal hospital because of left upper eyelid enlargement with lachrymal gland protrusion. The lachrymal and orbital cavity mass was removed surgically. Microscopically, the orbital mass consisted of a mixture of large rhabdomyoblastic and small round tumour cells. Immunohistochemically, the rhabdomyoblastic cells expressed desmin and myoglobin and the small round cells expressed desmin, myogenin and MyoD1. A diagnosis of embryonal rhabdomyosarcoma (ERS) was made. One month later, multiple masses throughout the body were identified, in particular around the cervical region. One of these lesions was sampled and diagnosed as metastatic ERS. The dog died 84 days after the time of first admission.

Baseline demographics of patients with neuroendocrine tumors presenting to seven National Comprehensive Cancer Network (NCCN) institutions: Development of a multi-institutional outcomes database.

187 Background: Diagnostic strategies, management paradigms, and clinical outcomes of patients with neuroendocrine tumors (NETs) are diverse and poorly characterized. The National Comprehensive Cancer Network (NCCN) created a comprehensive longitudinal database to characterize patients treated for NETs at seven participating institutions. Preliminary results from the database are reported. Methods: Member IRB approval was obtained to identify patients at least 18 years of age presenting to each of seven NCCN institutions between 2004 and 2007 with pathologically confirmed newly or previously diagnosed NETs via hospital medical records. Eligible patients included those with carcinoid (any site); goblet cell or adenocarcinoid; composite carcinoid; poorly differentiated gastrointestinal small cell tumor; pancreatic NET; NET of unknown primary site; pheochromocytoma; and paraganglioma. Baseline demographic characteristics were summarized for this analysis. Results: Among the 2,542 patients identified with a NET diagnosis, patients most frequently presented with carcinoid tumor (51%), pancreatic NET (27%) and NET of unknown primary site (8%). Median age at diagnosis was 55 (SD=13) and median age at first presentation to the NCCN was 57 (SD=13). Fifty-three percent of patients were female. Most (88%) were Caucasian and 8% were African American. Forty percent of patients were diagnosed with NET before presenting to the NCCN. Among these, the median time between initial NET diagnosis and presentation to the NCCN was 2 years (SD=6). Significant differences in provider specialty referral patterns were observed between institutions. Conclusions: The baseline demographic characteristics of NET patients in this new database are consistent with those previously reported in population-based registries. The NCCN database will provide a valuable resource for further exploration of patterns of diagnosis, treatment, consistency with established guidelines, as well as clinical outcomes in patients with this condition. Existing differences among institutions in referral patterns will be further explored.

Intratumoral heterogeneity in anaplastic large cell lymphoma of non-common subtype

ALK-positive anaplastic large cell lymphoma (ALCL) with identical primary genetic aberration present with variable morphology. The eponymous anaplastic large cell morphology can be detected in the majority cases which are described as being of common type morphology. However, morphological variants displaying small tumor cells that are barely distinguishable from reactive lymphocytes occur often in combination with classical large tumor cells and characterize so-called non-common type ALCL. This subgroup has recently been shown to be associated with a weak immune response to the ALK1 protein and a poorer outcome in children. Expression of T cell markers like CD3 is often reduced or absent in these lymphomas, probably as a direct effect of the ALK1 protein. In non-common type ALCL, the expression of ALK is restricted to the nucleus, suggesting reduced activity of the enzyme. The goal of the present study was to gain insight into the intratumoral heterogeneity of these lymphomas and to understand how T cell marker expression is distributed among tumor cells. We analyzed the immunophenotype of ALK1-positive ALCL in 41 pediatric patients by fluorescence multi-staining and subsequent digital image analysis. The small tumor cells in non-common type ALCL expressed larger amounts of T cell surface markers such as CD3, CD5, and CD8 but less CD30 compared to the large tumor cells. Expression of ALK1 and phosphorylated STAT3 as well as cell proliferation measured by positivity for Ki67 was reduced in the small cells of non-common type ALCL. These data demonstrate heterogeneity of the immunophenotype of tumor cells within non-common type ALCL suggestive for differentiation of small tumor cells, thereby providing a possible first explanation for the reduced immunogenicity of non-common type ALCL.

Malignant melanocytic matricoma: a case report and review of the literature

Aim To describe and review literatures for malignant melanocytic matricoma and, to discuss the differentials and potential diagnostic pitfalls. Method A skin excision from an 81-year-old man presenting with a skin lesion was processed routinely and examined, including several immunohistochemical studies, namely AE1/AE3, S-100, and MelanA. Result The tumour was characterised by an exophytic nodular growth with ulceration displaying biphasic features, and composed of both basaloid cells and larger pigmented melanocytic cells. Pigmentation was variable, with dendritic cells noted. Up to 20 mitoses/10 HPF were observed. The small basaloid tumour cells were positive for AE1/AE3, and the larger tumour cells were positive for S-100 and MelanA. Discussion This entity is a malignant neoplasm with hair matrix and hair differentiation. The histological criteria in favour of malignancy include infiltrative growth, numerous mitotic figures, abnormal mitoses, nuclear atypia, loss of ghost cells at the advancing edge, lymphatic and blood vessel invasion, perineural invasion, local recurrence and lymph node or visceral metastases.

Ewing Sarcoma of the Thoracic Wall in a 54-Year-Old Man

Ewing tumor is the second most common bone tumor in children. Its variant, malignant small cell tumor of the thoracopulmonary region, is infrequent in children and extremely rare in adults. A multimodal treatment approach is preferred for this tumor. We describe a rare case of primitive neuroectodermal tumor/Ewing sarcoma arising from the thoracic wall in a 54-year-old man. He underwent extensive resection of the tumor followed by adjuvant chemotherapy and radiotherapy.

Role of intra- and peritumoral budding in the interdisciplinary management of rectal cancer patients.

The presence of tumor budding (TuB) at the invasive front of rectal cancers is a valuable indicator of tumor aggressiveness. Tumor buds, typically identified as single cells or small tumor cell clusters detached from the main tumor body, are characterized by loss of cell adhesion, increased migratory, and invasion potential and have been referred to as malignant stem cells. The adverse clinical outcome of patients with a high-grade TuB phenotype has consistently been demonstrated. TuB is a category IIB prognostic factor; it has yet to be investigated in the prospective setting. The value of TuB in oncological and pathological practice goes beyond its use as a simple histomorphological marker of tumor aggressiveness. In this paper, we outline three situations in which the assessment of TuB may have direct implications on treatment within the multidisciplinary management of patients with rectal cancer: (a) patients with TNM stage II (i.e., T3/T4, N0) disease potentially benefitting from adjuvant therapy, (b) patients with early submucosally invasive (T1, sm1-sm3) carcinomas at a high risk of nodal positivity and (c) the role of intratumoral budding assessed in preoperative biopsies as a marker for lymph node and distant metastasis thus potentially aiding the identification of patients suitable for neoadjuvant therapy.

Management of Neuroendocrine Tumors of Unknown Origin

Neuroendocrine tumors (NETs) of unknown origin account for more than 10% of all NETs. Most of these tumors are poorly differentiated and, thus, very aggressive. Establishing the location of the primary tumor can be challenging. Workup of these NETs of unknown origin includes a thorough family history, immunohistochemistry, imaging, and OctreoScan. If the location of the primary malignancy is not determined, treatment is often initiated based on the grade and level of differentiation of the tumor, with well- and moderately differentiated tumors treated as carcinoid tumors, whereas poorly differentiated tumors are treated similarly to small cell tumors. Therapy is chosen based on symptoms and with the goal of debulking tumor when feasible and safe.

Abstract C13: Human Eag1 potassium channel expression in lung cancer biopsies.

Abstract Introduction. Lung cancer is the most common malignancy in the world including Mexico [1, 2]. Smoking is the main risk factor for the development of different types of lung cancer, about 70–80% of lung cancer cases are associated with smoking and approximately 50% of new cancer cases are diagnosed in ex-smokers. Current therapies rarely cure the disease, and the high relapse rate with the delay in diagnosis results in a poor prognosis and overall survival rates of 10% [1]. Several ion channels are over-expressed in cancer including Kv1.3, K2p9.1, Kv10.1 (Eag1) and Kv11.1 (HERG) channels. These channels are expressed in different cell types and tumor tissues and have been shown to increase cell proliferation. Eag1 is expressed aberrantly with a high frequency (75%) in tumor cells of different histological origins including sarcomas, carcinomas of the breast, colon, and cervix. Eag1 inhibition by either astemizole, imipramine, or Eag1 specific monoclonal antibodies reduces tumor cell proliferation in vitro and in vivo [3, 4, 5]. Eag1 channels are over-expressed in lung cancer [6]. However, a detailed study of Eag1 expression in the different types of lung cancer is missing. Materials and Methods: Lung biopsies: 44 Lung biopsies were obtained from patients attending the Instituto Nacional de Enfermedades Respiratorias (National Institute for Respiratory Diseases) in Mexico City following local ethical considerations. Patients had no prior treatment (chemotherapy or radiotherapy). 37 biopsies were classified as lung cancer samples and included adenocarcinoma, epidermoid, small cell, adenosquamous and neuroendocrine tumors. 5 samples were diagnosed as inflammatory disease and 2 were form patients with thyroid carcinoma. RNA extraction was performed with TRIzol (Life Technologies, Invitrogene) according to the manufacturer's recommendation. cDNA was synthesized by reverse transcription under the manufacturer's recommendations (New England BioLabs). Eag1 gene expression was assessed by real-time PCR under the manufacturer's recommendations (Fermentas SYBR Green/ROX qPCR Master Mix). Eag1 expression in lung biopsies was compared to Eag1 basal expression in fibroblasts from normal lung (WI-38) which was given the value of 1. Results: Eag1 expression was found in 81% of the cancer biopsies while 8% of the samples did not showed changes and in 10% of the biopsies Eag1 was found to be under-expressed. Interestingly, Eag1 was over-expressed in 80% of the samples from chronic inflammation while no changes were observed in the samples from thyroid carcinoma. Conclusions: Our results suggest Eag1 as a tumor marker for different types of lung cancer and as a potential early marker of the disease.

P63 Immunohistochemical Staining Is Limited in Soft Tissue Tumors

p63 is a p53 homolog that is expressed in various normal epithelial tissues and epithelial malignancies. Its expression in mesenchymal lesions has not been examined in depth; therefore, we studied p63 expression by immunohistochemical analysis in 650 soft tissue tumors. We found that p63 expression is limited in soft tissue tumors. The majority of tumors studied were p63-, including all cases of angiosarcoma, lipomatous neoplasms, dermatofibrosarcoma protuberans, solitary fibrous tumor, schwannoma, neurofibroma, gastrointestinal stromal tumor, and leiomyosarcoma. Nuclear p63 reactivity was found in a subset of soft tissue myoepithelioma and myoepithelial carcinoma of soft tissue, cellular neurothekeoma, soft tissue perineurioma, Ewing sarcoma/peripheral neuroectodermal tumor, diffuse-type giant cell tumor, and giant cell tumor of soft parts. Infrequent, weak, or focal p63-staining patterns were observed in low-grade fibromyxoid sarcoma, malignant peripheral nerve sheath tumor, extraskeletal myxoid chondrosarcoma, myxofibrosarcoma, proximal-type epithelioid sarcoma, synovial sarcoma, embryonal rhabdomyosarcoma, desmoplastic small round cell tumor, atypical fibroxanthoma, and spindle cell melanoma. Absent p63 expression is typical for most soft tissue tumors, including most (but not all) that would be in the differential diagnosis of spindle cell squamous carcinoma.

Targeting of nanoparticles in cancer

Anticancer agents continue to be a preferred therapeutic option for several malignancies. Despite their effectiveness, oncologists are continually looking for tumor-specific anticancer agents to prevent adverse effects in patients. Targeting of imaging agents to cancerous tissue is another area that is enthusiastically explored to circumvent some of the drawbacks that current imaging agents possess, including the inability to target small tumor cells, inadequate imaging period, and the risk of renal damage. Formulation scientists have explored nanotechnology-based delivery systems for targeting anticancer agents and tumor-imaging agents to cancer tissue. Targeting with nanotechnology-based delivery systems has been investigated by both passive and active mechanisms with significant clinical success. This review presents a discussion on targeting strategies used for the delivery of nanoparticles by passive and active mechanisms, focusing more specifically on active targeting of nanoparticles using albumin, folic acid, transferrin, and aptamers as targeting ligands.

Cytopathologic findings and differential diagnostic considerations of primary clear cell carcinoma of the lung

Primary clear cell carcinoma (CLCC) of the lung is an extremely rare disease and is a subtype of large cell carcinoma, according to the World Health Organization (WHO) classification. A case is presented here in which intraoperative squash smears in a 53-year-old man revealed sheet and small clusters or tumor cells with prominent nucleoli and fine granular chromatin. Abundant translucent cytoplasm with occasional cytoplasmic vacuoles and intracytoplasmic eosinophilic inclusions was also identified. A cytopathologic diagnosis of a CLCC was suggested. Further evaluation and immunohistochemical studies were conducted on formalin-fixed, paraffin-embedded material. Nests of slightly acidophilic clear tumor cells with a prominent cellular membrane and an alveolar growth pattern were identified on H&E sections. Immunohistochemically, the tumor cells showed diffuse and strong membranous staining for CK(AE1/AE3), CK7, and CA19-9 but were negative for Napsin A, CK20, CDX2, TTF-1, alpha-fetoprotein, chromogranin A, synaptophysin, CD10, and CD56. The diagnosis of primary CLCC of the lung was confirmed based on cytopathologic, histopathologic, immunohistochemical results, and a detailed systemic examination to exclude a possible extrapulmonary origin. We report here the cytopathological features of CLCC of the lung with an emphasis on differential diagnostic considerations.

A water soluble tri-cationic porphyrin–EDTA conjugate induces apoptosis in human neuroendocrine tumor cell lines

In this study, a completely water soluble tri-cationic porphyrin–EDTA conjugate was synthesized. We present data demonstrating the tumoristatic effects of the novel fully water soluble cationic porphyrin TMPy3PhenEDTA-P-Cl4 in the dark, in the medullary thyroid carcinoma cell lines MTC-SK and SHER-I and weaker effects in the small intestinal neuroendocrine tumor cell line KRJ-I. In addition, cytotoxic effects were also studied in normal human fibroblasts that represent normal tissue and the results are compared to the tumor cell lines.

Prognostic significance of tumor budding in gastrointestinal tumors

Tumor budding describes the presence of single tumor cells or small tumor cell clusters at the invasion front of carcinomas. It is currently thought to be the result of epithelial–mesenchymal transformation. Tumor budding can be appreciated histologically during routine evaluation of malignant polyps or surgical specimens of malignant tumors. Many studies have been published assessing cancers in all locations from the esophagus to the rectum, almost always reporting similar results. This seems especially remarkable as a generally accepted definition of how budding must be evaluated is still lacking. Regardless of the location, tumor budding generally is associated with nodal metastases and aggressive behavior, and it is mostly independent from other adverse factors. While the prognostic value of tumor budding is evident, especially in stage II colorectal cancers, it still has no therapeutic implications. This is owing to the heterogeneity of the performed studies and the lack of oncological studies, which are urgently needed.

Prognostic impact of isolated tumor cells in breast cancer axillary nodes: single tumor cell(s) versus tumor cell cluster(s) and microanatomic location

In breast cancer, it has been shown that pN0(i+) and pN1mi have a comparable negative impact on disease-free survival, compared with pN0. However, pN0(i+) is considered to be a heterogeneous group. We determined the effect of metastatic size and microanatomic location within the pN0(i+) group on breast cancer recurrence. We included all Dutch breast cancer patients diagnosed in 1998-2005 with favorable primary tumor characteristics and a final nodal status of pN0(i+). For this analysis, only patients without adjuvant systemic therapy were eligible (n = 513). Presence of single tumor cells versus cell clusters, metastatic size and microanatomic location were recorded. Primary endpoint was disease-free survival. Analyses were adjusted for age at diagnosis, tumor size, tumor grade, axillary treatment and hormone receptor status. The 5-year disease-free survival of patients with single tumor cell(s) (n = 93) was 78.6% and with tumor cell cluster(s) (n = 404) 77.1%. The hazard ratio for disease events was 1.05 (95% CI 0.63-1.76) for cell cluster(s) compared with single cell(s). In a Cox regression model, doubling of metastatic tumor size corresponded to a hazard ratio of 1.21 (95% CI 1.02-1.43). The adjusted hazard ratio was 0.90 (95% CI 0.54-1.50) for parenchymal (n = 112) versus sinusoidal location (n = 395). Single tumor cells bear similar prognostic information as small tumor cell clusters, even though results do suggest that within the pN0(i+) group, increasing size of nodal involvement is associated with reduced survival. Microanatomic location does not seem to have prognostic relevance.