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Syndrome of inappropriate antidiuretic hormone secretion associated with head neck cancers: review of the literature.

In a minority of patients with malignant tumors, signs and symptoms develop that cannot be explained on the basis of the mass effect produced by the primary tumor or its metastases, or production of a hormone normally associated with the tissue type that has given rise to the malignant tumor; these peculiar symptom complexes are known as paraneoplastic syndromes, and may be divided into endocrinologic, dermatologic, hematologic, neurologic, and osteoarticular manifestations. In the head and neck region in particular, the syndrome of inappropriate antidiuretic hormone production (SIADH, or Schwartz-Bartter syndrome) is a well-recognized form of paraneoplastic syndrome that may accompany head and neck malignancies. Most of such tumors are squamous carcinomas, with lesser numbers of olfactory neuroblastomas, small cell neuroendocrine carcinomas, adenoid cystic carcinomas, and undifferentiated carcinomas; sarcoma was reported in only a single instance. The lesions associated with the development of SIADH have most often been located in the oral cavity, and less often in the larynx, nasopharynx, hypopharynx, nasal cavity, maxillary sinus, parapharyngeal space, salivary glands, and oropharynx. Key features of SIADH include serum hypo-osmolality; an unexpectedly high urinary specific gravity; an absence of edema or dehydration; normal adrenal, thyroid, and renal function; hyponatremia; and an elevation of plasma vasopressin.

Head and Neck Neoplasms↗

Five different anti-prostate-specific membrane antigen (PSMA) antibodies confirm PSMA expression in tumor-associated neovasculature.

Prostate-specific membrane antigen (PSMA) is a type II integral membrane glycoprotein that was initially characterized by the monoclonal antibody (mAb) 7E11. PSMA is highly expressed in prostate secretory-acinar epithelium and prostate cancer as well as in several extraprostatic tissues. Recent evidence suggests that PSMA is also expressed in tumor-associated neovasculature. We examined the immunohistochemical characteristics of 7E11 and those of four recently developed anti-PSMA mAbs (J591, J415, and Hybritech PEQ226.5 and PM2J004.5), each of which binds a distinct epitope of PSMA. Using the streptavidin-biotin method, we evaluated these mAbs in viable prostate cancer cell lines and various fresh-frozen benign and malignant tissue specimens. In the latter, we compared the localization of the anti-PSMA mAbs to that of the anti-endothelial cell mAb CD34. With rare exceptions, all five anti-PSMA mAbs reacted strongly with the neovasculature of a wide spectrum of malignant neoplasms: conventional (clear cell) renal carcinoma (11 of 11 cases), transitional cell carcinoma of the urinary bladder (6 of 6 cases), testicular embryonal carcinoma (1 of 1 case), colonic adenocarcinoma (5 of 5 cases), neuroendocrine carcinoma (5 of 5 cases), glioblastoma multiforme (1 of 1 cases), malignant melanoma (5 of 5 cases), pancreatic duct carcinoma (4 of 4 cases), non-small cell lung carcinoma (5 of 5 cases), soft tissue sarcoma (5 of 6 cases), breast carcinoma (5 of 6 cases), and prostatic adenocarcinoma (2 of 12 cases). Localization of the anti-PSMA mAbs to tumor-associated neovasculature was confirmed by CD34 immunohistochemistry in sequential tissue sections. Normal vascular endothelium in non-cancer-bearing tissue was consistently PSMA negative. The anti-PSMA mAbs reacted with the neoplastic cells of prostatic adenocarcinoma (12 of 12 cases) but not with the neoplastic cells of any other tumor type, including those of benign and malignant vascular tumors (0 of 3 hemangiomas, 0 of 1 hemangioendothelioma, and 0 of 1 angiosarcoma). The mAbs to the extracellular PSMA domain (J591, J415, and Hybritech PEQ226.5) bound viable prostate cancer cells (LNCaP and PC3-PIP), whereas the mAbs to the intracellular domain (7E11 and Hybritech PM2J004.5) did not. All five anti-PSMA mAbs reacted with fresh-frozen benign prostate secretory-acinar epithelium (28 of 28 cases), duodenal columnar (brush border) epithelium (11 of 11 cases), proximal renal tubular epithelium (5 of 5 cases), colonic ganglion cells (1 of 12 cases), and benign breast epithelium (8 of 8 cases). A subset of skeletal muscle cells was positive with 7E11 (7 of 7 cases) and negative with the other four anti-PSMA mAbs. PSMA was consistently expressed in the neovasculature of a wide variety of malignant neoplasms and may be an effective target for mAb-based antineovasculature therapy.

Antibodies, Monoclonal↗

[Cytogenesis and histogenesis of malignant and semimalignant bone tumors].

Our present knowledge about bone tumors is still in need of a convincing cytohistogenetic concept that would support the adequate differentiation and classification of different tumor types. The modern therapeutic approach must rely on subtle diagnostis using preferably cyto- and histomorphologic criteria. The present study depends on a considerable number of malignant and semimalignant bone tumors which were analysed by several modern investigative methods. Based on these results, we intend to find the answers to some problems of cytogenesis and histogenesis of bone tumors. Comparison and correlation of our findings with the results of other authors is attempted with the objective to propose an overall histogenetic concept of bone tumors in consideration of the known data and hypotheses. Our material comprises 85 malignant and semimalignant bone tumors. The following tumor types are discussed on the basis of cases from our collection (numbers in brackets): "Conventional" highly malignant osteosarcoma (32), parosteal and periosteal osteosarcoma (2), telangiectatic osteosarcoma (2), small cell osteosarcoma (1), small cell sclerosing osteosarcoma (2), histiocytic osteosarcoma (1), Ewing's sarcoma (15), "conventional" chondrosarcoma (7), dedifferentiated chondrosarcoma (2), mesenchymal chondrosarcoma (1), giant cell tumor (12), malignant fibrous histiocytoma of bone (5), fibrosarcoma of bone (3), The results of conventional light and electron microscopy, but also of enzyme histochemistry and autoradiography were included in the definitive classification by both histologic and cytologic criteria. In addition, different collagen types present in the ground substance of these tumors were studied by immunofluorescence microscopy; in anaplastic tumors of high malignancy the intermediate filaments of the cytoskeleton were further subjected to immunohistochemical analysis. The concept resulting from these studies may be briefly summarized as follows: The stem cell of conventional, highly malignant osteosarcoma is a stromal cell of the skeletal system, which is undergoing neoplastic transformation. At first this cell fails to show any sign of collagen synthesis, the activity of alkaline phosphatase is not increased. Of a primarily anaplastic nature, this tumor cell may differentiate in several directions: in osteoblastic differentiation, the cell will produce predominantly collagen type I, and alkaline phosphatase activity will increase. During fibroblastic differentiation we observe an increased synthesis of collagen type III, but alkaline phosphatase activity is not raised.(ABSTRACT TRUNCATED AT 400 WORDS)

Autoradiography↗

Concomitant administration of vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide for high-risk sarcomas: the St. Jude Children's Research Hospital experience.

BACKGROUND: Intensified chemotherapy may improve the outcome of patients with high-risk pediatric sarcomas. Vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide are highly effective against pediatric sarcomas. The authors investigated the feasibility of administering these agents concomitantly within a defined period. METHODS: In the prospective high-risk sarcoma (HIRISA) Phase II trial HIRISA1, pediatric patients with high-risk sarcomas received 3 cycles of intensive vincristine, ifosfamide, etoposide, cyclophosphamide, and doxorubicin (VACIE) before radiotherapy and/or surgery began at Week 9 with concurrent vincristine, cyclophosphamide, and doxorubicin (Week 9) and vincristine and ifosfamide (Week 12). Three additional cycles of VACIE were then given. After delayed hematologic recovery in the first 11 patients, the protocol was modified (HIRISA2) to delay local control therapy until after 5 cycles of VACIE (to be completed within 18 weeks). Patients who responded to the protocols were eligible for myeloablative consolidation with autologous stem cell support. RESULTS: Eleven of 24 patients (median age, 14.9 years) had Ewing sarcoma family of tumors, 9 patients had rhabdomyosarcoma, and 4 patients had unresectable desmoplastic small round cell tumors. Seven of 13 patients on HIRISA2, but none of 11 patients on HIRISA1, completed therapy within the specified time. Reversible Grade 4 myelosuppression was the most common toxicity. Major nonhematologic toxic effects were mucositis, nutritional impairment, hypotension, and peripheral neuropathy. Three patients died of toxicity. The 5-year survival and 5-year event-free survival estimates both were 45.8% +/- 11.2%. CONCLUSIONS: The feasibility of administering intensive chemotherapy regimens like VACIE was dependent in part on the timing of local control therapy. This regimen was associated with significant toxicity.

Adolescent↗

Phase II study of pegylated liposomal doxorubicin: inactive in recurrent small-cell lung cancer. A Hellenic Cooperative Oncology Group Study.

PURPOSE: Although clinical experience with liposomal doxorubicin is still limited in solid tumours, single agent Caelyx (pegylated liposomal doxorubicin) treatment has shown promising results in AIDS-related Kaposi's sarcoma, metastatic breast and ovarian cancer and anecdotally in other solid tumours. This is the first report of its use in small-cell lung cancer (SCLC). The objective of this multicenter phase II study was to evaluate the safety, tolerance and anti-tumour activity of Caelyx as monotherapy in patients with recurrent SCLC. PATIENTS AND METHODS: A total of 14 patients with recurrent SCLC who had not received prior treatment with doxorubicin, were accrued into this phase II study. All patients had progressed or relapsed after first-line chemotherapy. All but one had achieved objective responses to first-line treatment with median duration of five months (range 2-18 months) but half of them had experienced 'refractory' relapses (within 3-4 months). Study treatment consisted of Caelyx 50 mg/m2 (1-hour i.v infusion every 4 weeks for 6 cycles). RESULTS: No responses were seen but in three patients disease was stabilised for a median of three months. The median number of cycles was 2 per patient, with 11 of 14 patients not completing 6 cycles of Caelyx treatment. From those, five patients were removed from the study after only one cycle due to rapid disease progression, and one was withdrawn after three cycles due to prolonged toxicity. Overall, treatment was well tolerated with no episodes of grade 4 toxicity and only two episodes of grade 3 toxicities: one of thrombocytopenia and one of prolonged palmar-plantar erythrodysesthesia (PPE). CONCLUSIONS: These results demonstrate limited activity of Caelyx in this patient population, which may be related to the poor prognostic features of such patients. Our findings are in agreement with previous observations that doxorubicin-containing combinations are rarely active in platinum/etoposide failures. However, as in other studies the favourable toxicity profile of Caelyx is confirmed.

Aged↗

Synovial sarcoma: an immunohistochemical study.

The immunohistochemical staining pattern of 18 cases of synovial sarcoma with two epithelial-specific monoclonal antibodies is described. This is compared with normal synovium, cases of giant cell tumour of tendon sheath (benign synovioma) and a variety of spindle celled sarcomas. Sixteen cases of synovial sarcoma showed staining of the epithelial component with at least one antibody. No staining was seen in normal synovium or in giant cell tumours of tendon sheath. A small number of malignant schwannomas contained groups of cells which stained positively whilst other spindle cell sarcomas either did not stain or showed 'cross-reaction' type staining only. These results add weight to the proposition that synovial sarcomas do not arise from normal synovium, despite their morphological similarities, but from mesenchymal connective tissue. It is also shown that immunohistochemical staining with anti-epithelial antibodies will emphasize the biphasic pattern of synovial sarcomas allowing their distinction from other sarcomas.

Antibodies, Monoclonal↗

Detection of ganglioside GD2 in tumor tissues and sera of neuroblastoma patients.

A murine monoclonal antibody (monoclonal antibody 126) produced against cultured human neuroblastoma cells (LAN-1) was found to be specifically directed to a disialoganglioside (GD2) antigen preferentially expressed on both cell lines and tissues derived from melanoma and neuroblastoma. In enzyme-linked immunosorbent assays, monoclonal antibody 126 failed to react with leukemic and lymphoblastoid cells as well as with a variety of carcinoma and sarcoma cell lines. Immunohistological analysis by the immunoperoxidase technique revealed strong reactivity of monoclonal antibody 126 with frozen and formaldehyde-fixed neuroblastoma and melanoma tissues. Tissues from patients with glioma or with small cell cancer of the lung showed faint staining, whereas those from individuals with sarcoma, lymphoma, and a variety of other neoplasms proved to be negative. Sera of neuroblastoma patients showed significantly elevated GD2 levels compared to normal children (p less than 0.001) and children with other tumors (p less than 0.001) as determined by a quantitative competitive enzyme-linked immunosorbent assay. Furthermore, the GD2 serum level of one neuroblastoma patient, when followed serially, was found to correlate with progression of disease, suggesting the potential usefulness of this assay for the diagnosis and monitoring of neuroblastoma.

Antibodies, Monoclonal↗

A small interfering RNA targeting vascular endothelial growth factor inhibits Ewing's sarcoma growth in a xenograft mouse model.

Angiogenesis plays an essential role in tumor growth and metastasis and is a promising therapeutic target for cancer. Vascular endothelial growth factor (VEGF) is a key regulator in vasculogenesis as well as in angiogenesis. TC71 human Ewing's sarcoma cells overexpress VEGF, with a shift in isoform production from membrane-bound VEGF189 to the more soluble VEGF165. Transfection of TC71 cells with a vector-based VEGF targeted small interfering RNA expression system (VEGFsi) inhibited VEGF165 expression by 80% and VEGF165 protein production by 98%, with no alteration in VEGF189 expression. Human microvascular endothelial cell proliferation and migration induced by conditioned medium from VEGFsi-transfected TC71 cells was significantly less than that induced by conditioned medium from TC71 cells and control vector-transfected TC71 cells. Furthermore, after s.c. injection into athymic nu/nu mice, the tumor growth of VEGFsi-expressing TC71 cells was significantly less than that of parental or control vector-transfected cells. Vessel density as assessed by CD31 immunohistochemical analysis and VEGF165 expression as assessed by Northern blotting were also decreased. Intratumor gene therapy with polyethylenimine/VEGFsi also resulted in tumor growth suppression. When inoculated into the tibias of nude mice, VEGFsi-expressing TC71 cells induced osteolytic bone lesions that were less severe than those induced by control groups. These data suggest that targeting VEGF165 may provide a therapeutic option for Ewing's sarcoma.

Animals↗

Immunity to a syngeneic sarcoma induced in rats by dendritic lymph cells exposed to the tumour either in vivo or in vitro.

Rats were prepared surgically so that peripheral intestinal lymph could be collected from them while a syngeneic tumour (the HSN sarcoma) was growing in each major Peyer's patch of the small intestine. Dendritic lymph cells were isolated from the lymph and injected i.p. into naive, syngeneic rats. Each of the 16 recipients received just under 10(6) such cells and was challenged 10 days later with a subcutaneous dose of 10(4) viable HSN cells. Six weeks after this challenge only 7 of the recipients had a tumour and these were small (mean weight 1.8 g), while 17 controls (which had each been treated with 10(6) thoracic duct lymphocytes from the same donors, and given the same challenge) all had large tumours (mean weight 8.8 g). The remaining 9 test rats were still free of tumours when they were killed and autopsied 4 months after challenge. Dendritic lymph cells from normal rats were 'sensitised' by incubating them overnight on a monolayer of HSN cells. They were then transferred to 5 naive recipients which received the usual challenge. Six weeks later they all had tumours (mean weight 1.3 g) but these were much smaller than those in the 5 controls (mean weight 9.3 g).

Animals↗

Undifferentiated carcinoma of the lung with osteoclast-like giant cells.

We treated a patient with undifferentiated carcinoma of the lung, with osteoclast-like giant cells resembling those of the giant cell tumor of bone. The clinical and morphologic characteristics of this case are documented, and the literature concerning this type of tumor is reviewed. The tumor differed histologically from the pleomorphic carcinoma, which occurs most commonly in the lung, and showed diverse pleomorphic manifestation with benign looking osteoclast-like multinucleated cells and bizarre giant cells. In addition, and undifferentiated carcinoma with a sarcoma-like appearance containing small areas of papillary adenocarcinoma was evident in the tumor.

Adenocarcinoma, Papillary↗

A study of eleven cutaneous malignant melanomas in adults with small-cell morphology: emphasis on diagnostic difficulties and unusual features.

AIMS: To describe the clinicopathological and immunohistochemical features of cutaneous malignant melanomas with a pure or mixed small-cell pattern in 11 adult patients, and to discuss the diagnostic difficulties encountered. METHODS AND RESULTS: Haematoxylin and eosin-stained sections of each case of cutaneous small-cell malignant melanoma, together with locally recurrent skin lesions and, where available, metastatic deposits, were re-examined. Available immunohistochemical sections were evaluated. Clinical follow-up data were obtained in each case. One patient presented with metastatic disease, the others presented with cutaneous lesions. Suggested initial diagnoses included malignant melanoma, non-Hodgkin's lymphoma, Merkel cell carcinoma and sarcoma. All the tumours were in the vertical growth phase. Nine had a junctional component, often inconspicuous. The lesions showed either a pure small-cell pattern or a mixed pattern with more conventional areas. In one case, there was colonization of a basal cell carcinoma by invasive malignant melanoma. Variable retention of small-cell morphology in local recurrences and metastases was observed, although in some cases more typically pleomorphic cells were present. In the cases tested, there was strong immunostaining for S100 protein and NKI-C3, and variable immunostaining for HMB45 and Melan-A. Non-melanocytic markers were negative. CONCLUSIONS: The possibility of a small-cell malignant melanoma should be considered in the assessment of cutaneous and non-cutaneous small-cell neoplasms. The correct diagnosis requires careful evaluation for junctional activity, melanin production and the use of a panel of melanocytic markers.

Adult↗

Femoral mesenchymal chondrosarcoma with secondary aneurysmal bone cysts mimicking a small-cell osteosarcoma.

Mesenchymal chondrosarcoma is a rare but aggressive, high-grade malignancy of primitive cartilage-forming mesenchyme that arises most commonly from skeletal sites. Although there are radiological findings suggestive of the diagnosis, imaging features often overlap with those of other skeletal sarcomas. The definitive diagnosis relies on the histological finding of a typical bimorphic appearance, consisting of nests of small, round, poorly differentiated cells and more mature cartilaginous tissue. To highlight this, we present the case of a 21-year-old man who was referred to our institution with a history of right knee pain. Initial imaging and histological evaluation of a core biopsy of the lesion suggested osteosarcoma of the distal right femur; after review, however, the correct diagnosis of mesenchymal chondrosarcoma was made. Adequate tissue sampling and thorough histological evaluation of biopsy specimens is vital for the accurate diagnosis of primary bone malignancies, especially those of chondroid origin.

Adult↗

The role of high-dose therapy and autologous stem cell transplantation for pediatric bone and soft tissue sarcomas.

The prognosis for children with bone and soft tissue sarcomas has significantly improved since the advent of effective multiagent chemotherapy, aggressive surgery for local disease and more precise delivery of radiotherapy doses. However, in a small proportion of patients that present with high-risk disease, long-term outcome has not substantially increased, with disease-free survival rates still in the order of 20-30%. It is therefore clear that novel therapies are needed for children with these tumors. Based on the highly chemosensitive nature of the majority of pediatric sarcomas, several small studies have been conducted to investigate the potential role of high-dose chemotherapy followed by hematopoietic stem cell reconstitution. This review will provide an overview of the current literature concerning the use of high-dose therapy with stem cell transplantation for the three main pediatric sarcomas--Ewing sarcoma, rhabdomyosarcoma and osteosarcoma.

Bone Neoplasms↗

Etoposide: current status and future perspectives in the management of malignant neoplasms.

Etoposide has demonstrated highly significant clinical activity against a wide variety of neoplasms, including germ-cell malignancies, small-cell lung cancer, non-Hodgkin's lymphomas, leukemias, Kaposi's sarcoma, neuroblastoma, and soft-tissue sarcomas. It is also one of the important agents in the preparatory regimens given prior to bone marrow and peripheral stem-cell rescue. Despite its high degree of efficacy in a number of malignancies, the optimal dose, schedule, and dosing form remain to be defined. It is possible that continuous or prolonged inhibition of the substrate, i. e., topoisomerase II, may be the key factor for the cytotoxic effects of etoposide. Clinical studies have shown the activity of etoposide to be schedule-dependent, with prolonged dosing, best accomplished by the oral dosing form, offering a therapeutic advantage. This benefit awaits validation by prospective randomized studies, some of which are in progress. Recent clinical investigations have focused on the use of etoposide in combination with (a) cytokines to ameliorate myelosuppression, the dose-limiting toxicity of etoposide; (b) agents such as cyclosporin A and verapamil to alter the p-glycoprotein (mdr1) function; and (c) topoisomerase I inhibitors to modulate the substrate upon which it acts. There is continued interest in the development of etoposide to its maximal clinical dimensions and in the examination of alternative biochemical and mechanistic approaches to further our understanding of this highly active agent.

Acquired Immunodeficiency Syndrome↗

Perforation of the terminal ileum with cytomegalovirus vasculitis and Kaposi's sarcoma in a patient with acquired immunodeficiency syndrome.

This case report documents a perforation of the terminal ileum in a 40-year-old white male homosexual with the acquired immunodeficiency syndrome. The perforation occurred at a site that had severe cytomegalovirus infection and was in close proximity to multiple nodules of Kaposi's sarcoma. The ileum showed multiple deep ulcers with large numbers of cytomegalovirus inclusions and vasculitis with infected endothelial cells, small-vessel thrombosis, focal disruption, and hemorrhage. We review the evidence that cytomegalovirus infection--and not Kaposi's sarcoma--was responsible for this perforation and, in light of the new medical therapy for such infections, should be regarded as an important cause of gastrointestinal perforation in patients with the acquired immunodeficiency syndrome.

Acquired Immunodeficiency Syndrome↗

Precursor B-Lymphoblastic lymphoma presenting as a solitary bone tumor and mimicking Ewing's sarcoma: a report of four cases and review of the literature.

Precursor B-lymphoblastic lymphoma (B-LBL) may present as a solitary bone tumor. Fewer than 10 cases with a proven precursor B-cell phenotype have been reported in the English literature. In this report, we describe four cases of B-lymphoblastic lymphoma presenting as a localized intraosseous mass, which clinically and histologically mimicked Ewing's sarcoma. Three tumors occurred in the tibia and one in the humerus. In all four cases, the initial diagnosis was either "Ewing's sarcoma" or "consistent with Ewing's sarcoma." All four patients were female. Three were children and one was an adult; mean age was 12.5 years (range, 4 to 31 years). All had extremity pain without significant constitutional symptoms. In three cases, the tumors were osteolytic on radiographic evaluation, and in one case, osteosclerotic. Immunohistochemical stains on paraffin-embedded tissue showed that the neoplastic cells expressed terminal deoxynucleotidyl transferase, CD43, vimentin, and CD99 (MIC2 gene product) in all cases. Three cases were negative for CD45. CD79a was positive in all four cases studied; however, CD20 (L26) was positive in only two of four cases. CD3 was negative in all cases. Two cases showed focal granular cytoplasmic staining for keratin. Two cases analyzed by polymerase chain reaction (PCR) revealed clonal rearrangement of the immunoglobulin heavy chain (IgH) gene. Follow-up revealed that the three pediatric patients, who received a high-dose multiagent chemotherapy regime for LBL, are disease free at follow-up intervals of more than 1, 11, and 12 years, respectively. The adult patient died two years after diagnosis with disseminated disease. Although rare, B-lymphoblastic lymphoma should be considered in the differential diagnosis of small round cell tumors of bone. A diagnosis of Ewing's sarcoma should be made only after complete immunophenotyping and, if necessary, molecular diagnostic tests to exclude lymphoblastic lymphoma. A limited panel of antibodies can lead to an erroneous diagnosis; B-lymphoblastic lymphoma may be negative for CD45 and CD20 but positive for CD99 and even for keratin, mimicking Ewing's sarcoma. Correct diagnosis is extremely important because LBL usually is curable in the pediatric age group with appropriate therapy.

Adult↗