Constitutive Activation of mTORC1 in Endothelial Cells Leads to the Development and Progression of Lymphangiosarcoma through VEGF Autocrine Signaling.

Angiosarcoma/lymphangiosarcoma is a rare malignancy with poor prognosis. We generated a mouse model with inducible endothelial-cell-specific deletion of Tsc1 to examine mTORC1 signaling in lymphangiosarcoma. Tsc1 loss increased retinal angiogenesis in neonates and led to endothelial proliferative lesions from vascular malformations to vascular tumors in adult mice. Sustained mTORC1 signaling was required for lymphangiosarcoma development and maintenance. Increased VEGF expression in tumor cells was seen, and blocking autocrine VEGF signaling abolished vascular tumor development and growth. We also found significant correlations between mTORC1 activation and VEGF, HIF1α, and c-Myc expression in human angiosarcoma samples. These studies demonstrated critical mechanisms of aberrant mTORC1 activation in lymphangiosarcoma and validate the mice as a valuable model for further study.

Establishment and characterization of a novel lymphangiosarcoma cell line (MO-LAS) compared with the hemangiosarcoma cell line (ISO-HAS).

The concept of "lymphangiosarcoma" remains obscure. Therefore, we reported a patient with lymphangiosarcoma, resistant to immunotherapy. The patient presented with impressive and discriminative features: clinically an ill-defined edematous lesion with lymphorrhea and pathologically atypical vascular channel formation without extravasation of blood, clearly distinguished from common angiosarcoma with hemorrhage. From this case, a lymphangiosarcoma cell line, MO-LAS, was established and its characteristics were compared with the hemangiosarcoma cell line, ISO-HAS. Flow cytometric analysis revealed that MO-LAS was negative for factor VIII-related antigen, but positive for CD31, D2-40, NZ-1, and vascular endothelial growth factor receptor-3 (VEGFR-3), similar to ISO-HAS. However, MO-LAS expressed a much higher level of homeobox gene PROX1, indicating a lymphatic phenotype, compared with ISO-HAS. Furthermore, MO-LAS showed a much lesser expression of oncogenes and much lower sensitivity against lymphokine-activated killer (LAK) cells. Lymphangiosarcoma may be difficult to recognize by the immune system. Conclusively, the establishment of MO-LAS, a novel angiosarcoma cell line bearing lymphatic characters, strongly suggests the entity of lymphangiosarcoma.

Lymphangiosarcoma in a cat.

This report describes a 5-year-old female cat with lymphangiosarcoma arising within the dermis and subcutis of the caudal mammary region. The mass presented as a large, poorly demarcated and fluctuant swelling with bruising of the overlying skin. Histopathologically, the dermis and subcutis in the affected region were diffusely oedematous, haemorrhagic, and infiltrated by plump spindle cells that formed irregular vascular clefts and cavernous channels. Neoplastic cells were aligned in one or more layers along oedematous collagenous trabeculae. The vascular clefts and channels contained only a few or no erythrocytes. The neoplastic cells had moderate to marked nuclear pleomorphism and prominent nucleoli. Lymphocytes and plasma cells were scattered throughout the neoplasm and the adjacent soft tissues. Immunohistochemical labelling revealed the neoplastic cells to express vimentin, factor VIII-related antigen and the lymphatic endothelial cell marker PROX-1, but the cells did not express cytokeratin. The nuclei of many neoplastic cells expressed the proliferation marker Ki67. These histopathological and immunohistochemical findings confirmed the diagnosis of lymphangiosarcoma. This is the first report describing the usefulness of expression of PROX-1 for differentiating between angiosarcoma of lymphatic and vascular origin in cats.

Platelet-derived growth factor receptor-beta in Gorham's disease.

BACKGROUND: A 17-year-old male presented with pain in his lower-left chest. He had no significant medical history and was previously in good health. He had a fractured ninth left anterior rib and the tenth, eleventh and twelfth ribs were absent, which was thought to be a congenital anomaly. Several months later, he presented again with back pain, an enlarging mass in the lower-left chest wall, erosion of the lateral pedicles of the lower thoracic vertebrae and pleural effusion. INVESTIGATIONS: Physical examination, chest X-ray, MRI of the spine, incisional biopsy, serial CT imaging of the hemithorax, immunohistochemistry, flow cytometry, and enzyme-linked immunosorbent assays. DIAGNOSIS: Gorham's lymphangiomatosis with expression of platelet-derived growth factor receptor-beta and elevated circulating platelet-derived growth factor-BB. MANAGEMENT: Spine stabilization, thalidomide, celecoxib, interferon-alpha2b, pamidronate, zoledronate, thoracotomy, pleurectomy, talc pleurodesis, and imatinib mesylate.

Malignant lymphoepithelial lesions of the salivary gland.

OBJECTIVES: To describe a relatively large series of patients with uncommon malignant lymphoepithelial lesions (MLEL) in the salivary glands, to present treatment-outcome data to support therapeutic decision-making, and to evaluate the incidence of co-occurrence of MLEL and Epstein-Barr virus (EBV). STUDY DESIGN AND SETTING: Ten patients with MLEL were treated between 1987 and 2002. All lesions were surgically removed, with or without neck dissection, and the patients treated with radiotherapy or radiotherapy and chemotherapy. Histopathology and in situ hybridization studies for EBV-encoded RNA (EBER1) were performed. RESULTS: With aggressive treatment, outcomes were good, regardless of the presenting stage, except when distal metastases were present. All 10 patients tested positive for EBV. CONCLUSION AND SIGNIFICANCE: This and previous investigations support the use of aggressive surgical excision of the tumor and local metastases and radiotherapy or radiotherapy and chemotherapy, as optimal treatment for MLEL. The EBV finding may indicate a role for EBV in the pathogenesis of MLEL. EBM RATING: C-4.

Intra-arterial mitoxantrone and paclitaxel in a patient with Stewart-Treves syndrome: selection of chemotherapy by an ex vivo ATP-based chemosensitivity assay.

We report on a 72-year-old patient developing Stewart-Treves syndrome (STS) of the right arm 9 years after curative irradiation for ipsilateral stage III breast cancer. Facing the poor track record of both irradiation and chemotherapy in this highly malignant lymphangiosarcoma, amputation was recommended but refused by the patient. Therefore, limb conserving-therapy using three courses of intra-arterial mitoxantrone (MX) and paclitaxel (PTX) was attempted. This novel chemotherapy protocol was selected by pretherapeutic ex vivo ATP-based chemosensitivity testing of autologous tumor tissue. The patient experienced complete response, which was subsequent histologically confirmed by compartment resection. When developing recurrent STS outside of the perfused area 6 months after primary therapy, the patient was retested and reinduced with three other courses of intraarterial MX/PTX which again produced durable complete remission. This case demonstrates the benefit of indivdualized therapy in this prognostically desperate disease allowing both limb conservation and maintained quality of life.

Primary malignant lymphoma arising in postmastectomy lymphedema. Another facet of the Stewart-Treves syndrome.

In rare cases, primary malignant lymphomas may arise in the soft tissues. Only one previous case has arisen in the context of chronic lymphedema. Because of the clinical appearance of such lesions, which resemble violaceous nodular or plaquelike tumors, they may be confused clinically with lymphedema-associated angiosarcomas occurring after radical mastectomy (Stewart-Treves syndrome). Furthermore, the histologic appearance of some lymphomas and angiosarcomas may also be similar. We studied two women with primary postmastectomy lymphedema-related malignant lymphoma in the soft tissues of the upper arm. These tumors arose 11 and 30 years, respectively, after radical removal of ductal mammary carcinomas. Histologically, one neoplasm mimicked metastatic carcinoma or epithelioid angiosarcoma; whereas the other was initially confused with a variety of pathologic entities, including vasculitis, epithelioid hemangioma, and malignant fibrous histiocytoma. The lymphoid nature of both lesions was confirmed by immunoreactivity for leukocyte common antigen in addition to the B-lymphocyte marker, L26. Conversely, vascular and epithelial determinants were absent. One patient's disease pursued an indolent course; she died of unknown causes but with no evidence of lymphoma at last follow-up. The second patient is currently in remission on chemotherapy. Awareness of the existence of lymphedema-related malignant lymphoma and familiarity with methods used for its distinction from epithelioid vascular sarcomas should prevent unnecessary surgery.