[A Case of Retroperitoneal Liposarcoma].

A 52-year-old man visited a local hospital complaining of abdominal distension. Enhanced computed tomography scan revealed a giant retroperitoneal tumor surrounding the left internal iliac artery and left kidney. We performed en bloc tumor resection with left internal iliac artery resection. The tumor was 35 cm in size and weighed 6,860 g. The histological diagnosis was a dedifferentiated liposarcoma. After surgery, the patient experienced left lower limb paralysis. Clinical examination and neurological findings suggested a lumbosacral problem. After 6 months, the patient's lower limb paralysis had not improved. It is important to note that ischemic neuropathy may be related to internal iliac artery resection.

Relationship of endothelial area with VEGF-A, COX-2, maspin, c-KIT, and DOG-1 immunoreactivity in liposarcomas versus non-lipomatous soft tissue tumors.

Soft tissue tumors are rare tumors that show a heterogeneous structure; thus far, their molecular behavior has not been elucidated. The aim of our study was to define the relationship between microvessel density (MVD), evaluated with CD31, and other immunohistochemical markers, such as vascular endothelial growth factor (VEGF), cyclooxygenase-2 (COX-2), CD34, maspin, DOG-1, and c-KIT. Immunostains were done in 55 cases consisting of benign and malignant tumors, such as liposarcomas, dermatofibrosarcomas, and tumors with histiocytic differentiation. Renal tubes were used as external control for VEGF, maspin, and DOG-1. Although DOG-1 is considered a specific marker for gastrointestinal tumors (GISTs), its positivity, correlated with c-KIT and VEGF immunoexpression, was also shown by dermatofibrosarcomas and tumors with histiocytic and lipomatous differentiation, suggesting its possible pro-angiogenic role. Maspin expression was observed in adipose tissue tumors only. Regarding angiogenesis, 31 of the 55 cases were VEGF-positive, such positivity being directly correlated with COX-2 and CD34 positivity as evaluated in the tumor cells and also with MVD. Although no significant differences in angiogenic activity were found between benign and malignant non-lipomatous tumors, the MVD was directly correlated with the histological type/grade of liposarcomas. Based on these aspects, we conclude that VEGF/COX-2-induced angiogenesis is specific for non-lipomatous tumors, whereas liposarcomas are dependent on the VEGF/maspin angiogenic pathway. The DOG-1/c-KIT/VEGF target may be used for further personalized therapy of soft tissue sarcomas. No data about DOG-1 and maspin positivity in liposarcomas have been published to date.

Contrast-enhanced color Doppler ultrasonography increases diagnostic accuracy for soft tissue tumors.

Resolution of ultrasonography (US) has undergone marked development. Additionally, a new-generation contrast medium (Sonazoid) used for US is newly available. Contrast-enhanced US has been widely used for evaluating several types of cancer. In the present study, we evaluated the ability of color Doppler US (CDUS) and Sonazoid to differentiate between benign and malignant soft tissue tumors. A total of 180 patients (87 male, 93 female) were enrolled in the present study. The patient ages ranged from 1 to 91 years (mean 58.1±20.0 years). The maximum size, depth, tumor margins, shape, echogenicity and textural pattern were measured on gray-scale images. CDUS was used to evaluate the intratumoral blood flow with and without Sonazoid. Peak systolic flow velocity (Vp), mean flow velocity (Vm), resistivity index (RI) and pulsatility index (PI) of each detected intratumoral artery were automatically calculated with power Doppler US (PDUS). The present study included 118 benign and 62 malignant tumors. Statistical significances were found in size, depth, tumor margin and textural pattern but not in shape or echogenicity on gray-scale images. Before Sonazoid injection, CDUS findings showed 55% sensitivity, 77% specificity and 69% accuracy, whereas contrast-enhanced CDUS showed 87% sensitivity, 68% specificity and 74% accuracy. There were no statistically significant differences between malignant and benign tumors regarding the mean Vp, Vm, RI and PI values determined on PDUS. In conclusion, contrast-enhanced CDUS proved to be a reliable diagnostic tool for detecting malignant potential in soft tissue tumors.

Spontaneous reversion of the angiogenic phenotype to a nonangiogenic and dormant state in human tumors.

UNLABELLED: The angiogenic switch, a rate-limiting step in tumor progression, has already occurred by the time most human tumors are detectable. However, despite significant study of the mechanisms controlling this switch, the kinetics and reversibility of the process have not been explored. The stability of the angiogenic phenotype was examined using an established human liposarcoma xenograft model. Nonangiogenic cells inoculated into immunocompromised mice formed microscopic tumors that remained dormant for approximately 125 days (vs. <40 days for angiogenic cells) whereupon the vast majority (>95%) initiated angiogenic growth with second-order kinetics. These original, clonally derived angiogenic tumor cells were passaged through four in vivo cycles. At each cycle, a new set of single-cell clones was established from the most angiogenic clone and characterized for in vivo for tumorigenic activity. A total of 132 single-cell clones were tested in the second, third, and fourth in vivo passage. Strikingly, at each passage, a portion of the single-cell clones formed microscopic, dormant tumors. Following dormancy, like the original cell line, these revertant tumors spontaneously switched to the angiogenic phenotype. Finally, revertant clones were transcriptionally profiled and their angiogenic output determined. Collectively, these data demonstrate that the angiogenic phenotype in tumors is malleable and can spontaneously revert to the nonangiogenic phenotype in a population of human tumor cells. IMPLICATIONS: Leveraging the rate of reversion to the nonangiogenic phenotype and tumor dormancy may be a novel anticancer strategy.

Follicle-stimulating hormone receptor expression in soft tissue sarcomas.

AIMS: In adult humans, the follicle-stimulating hormone receptor (FSHR) is expressed only in the granulosa cells of the ovary and the Sertoli cells of the testis. Recently, it has been shown that FSHR is expressed selectively on the surface of blood vessels in a wide range of tumours. So far, the expression of FSHR in mesenchymal tumours has not been studied. METHODS AND RESULTS: We performed a semiquantitative evaluation of FSHR protein expression in a large cohort of soft tissue sarcomas (STS; n = 335), including 11 subtypes. FSHR-positive vessels were detected in all sarcoma subtypes analysed. Among liposarcomas, significantly more cases of dedifferentiated liposarcomas (28 of 44) showed FSHR expression compared to well-differentiated liposarcomas (WDLS; four of 21; P < 0.001). Vessels in lipomas (n = 9) and non-neoplastic fat were FSHR-negative. FSHR expression was also detected in tumour cells of all sarcoma subtypes examined, with the lowest incidence in WDLS (three of 21; 14.3%) and the highest frequency in undifferentiated high-grade pleomorphic sarcomas (41 of 60; 68.3%). CONCLUSIONS: These data supplement the previously reported results of FSHR expression in endothelial cells of various cancer types and form a solid basis for further studies of FSHR in mesenchymal neoplasms.

Carboxypeptidase M in apoptosis, adipogenesis and cancer.

This review covers carboxypeptidase M (CPM) research that appeared in the literature since 2009. The focus is on aspects that are new or interesting from a clinical perspective. Available research tools are discussed as well as their pitfalls and limitations. Evidence is provided to suggest the potential involvement of CPM in apoptosis, adipogenesis and cancer. This evidence derives from the expression pattern of CPM and its putative substrates in cells and tissues. In recent years CPM emerged as a potential cancer biomarker, in well differentiated liposarcoma where the CPM gene is co-amplified with the oncogene MDM2; and in lung adenocarcinoma where coexpression with EGFR correlates with poor prognosis. The available data call for extended investigation of the function of CPM in tumor cells, tumor-associated macrophages, stromal cells and tumor neovascularisation. Such experiments could be instrumental to validate CPM as a therapeutic target.

Dedifferentiated liposarcoma arising from the mesocolon ascendens: report of a case.

Dedifferentiated liposarcoma of the mesentery is an extremely rare tumor. A 71-year-old man with a 2-month history of abdominal distention was admitted to our department for evaluation and treatment of an abdominal mass. Computed tomography and magnetic resonance imaging revealed an 11 × 9 cm mass lesion with fat density in the upper right abdominal cavity, displacing the ascending and transverse colon ventrally. Abdominal angiography showed small feeding vessels of the tumor from the ileocolic artery and the middle colic artery. On basis of these findings, liposarcoma arising from the mesocolon ascendens was diagnosed, and complete removal of the tumor and central pancreatectomy (partial resection of the body of the pancreas) were performed. The histopathological diagnosis was dedifferentiated liposarcoma, and the patient is free from recurrence 6 months after surgery. The treatment strategy for abdominal dedifferentiated liposarcoma is surgical resection with a wide surgical margin.

Epithelioid variant of a pleomorphic liposarcoma displaying arborizing vascular arrangements on cytology smears: a case report of an interesting cytomorphologic pattern in an uncommon tumor.

BACKGROUND: There is limited documentation on cytologic features of liposarcomas, especially pleomorphic liposarcomas (PLPSs), in view of their rarity. CASE: We present cytomorphologic features of an uncommon case of epithelioid variant of a PLPS appearing as a recurrent mass in a young adult man. Fine needle aspiration cytology smears displayed prominent arborizing vasculature with numerous lipoblasts with well-defined vacuolated cytoplasm, indenting the nuclei. In addition, mitoses were conspicuously noted. Biopsy from the scar recurrence and following wide excision showed a multinodular tumor with solid arrangement of tumor cells, separated by delicate vessels. Cells displayed well defined cytoplasmic borders, including several lipoblasts and focal areas of spindly sarcomatous differentiation. Typical and atypical mitoses were conspicuously seen and myxoid areas were absent. Immunohistochemistry showed diffuse positivity for vimentin and S-100; cytokeratin showed weak, focal cytoplasmic positivity. CD34 highlighted the delicate vasculature on tissue sections. Diagnosis of an epithelioid variant of a PLPS was finally offered. CONCLUSION: This rare case describes cytomorphologic features of an epithelioid variant of a PLPS, including prominent arborizing vasculature, a pattern that has invariably been described in a myxoid liposarcoma. Additionally, presence of numerous lipoblasts and mitoses led to the diagnosis of this rare variant.

Platelets actively sequester angiogenesis regulators.

Clinical trials with antiangiogenic agents have not been able to validate plasma or serum levels of angiogenesis regulators as reliable markers of cancer presence or therapeutic response. We recently reported that platelets contain numerous proteins that regulate angiogenesis. We now show that accumulation of angiogenesis regulators in platelets of animals bearing malignant tumors exceeds significantly their concentration in plasma or serum, as well as their levels in platelets from non-tumor-bearing animals. This process is selective, as platelets do not take up a proportional amount of other plasma proteins (eg, albumin), even though these may be present at higher concentrations. We also find that VEGF-enriched Matrigel pellets implanted subcutaneously into mice or the minute quantities of VEGF secreted by microscopic subcutaneous tumors (0.5-1 mm(3)) result in an elevation of VEGF levels in platelets, without any changes in its plasma levels. The profile of other angiogenesis regulatory proteins (eg, platelet-derived growth factor, basic fibroblast growth factor) sequestered by platelets also reflects the presence of tumors in vivo before they can be macroscopically evident. The ability of platelets to selectively take up angiogenesis regulators in cancer-bearing hosts may have implications for the diagnosis and management of many angiogenesis-related diseases and provide a guide for antiangiogenic therapies.

Revascularization after segmental resection of lower extremity soft tissue sarcomas.

BACKGROUND AND OBJECTIVES: Limb salvage surgery combined with vascular reconstruction has replaced amputation as the preferred treatment of soft tissue sarcomas involving major vascular structures of the extremities. We describe our experience with soft tissue sarcomas involving major vascular structures and examine outcomes according to the type of graft selected for arterial reconstruction. We also examine the effect of venous reconstruction on post-operative edema. METHODS: This retrospective review includes 14 patients with lower extremity soft-tissue sarcomas that encased major vessels, requiring combined limb-preserving tumor resection and revascularization with a synthetic or autogenous saphenous vein graft. Edema in patients with and without venous reconstruction was compared. The incidence of infection, wound dehiscence, and graft thrombosis were compared according to arterial graft type. RESULTS: There was no significant difference in edema in patients with venous reconstruction and those without. There was also no significant difference in infection and graft thrombosis in patients with synthetic grafts and those with autogenous saphenous vein grafts. Wound dehiscence occurred more often in patients with synthetic grafts (P = 0.029). CONCLUSIONS: Although this study was small, these results suggest that further studies are needed to determine the roles that vascular graft selection and venous reconstruction play in clinical outcome.

Prolonged dormancy of human liposarcoma is associated with impaired tumor angiogenesis.

The disease state of cancer appears late in tumor development. Before being diagnosed, a tumor can remain for prolonged periods of time in a dormant state. Dormant human cancer is commonly defined as a microscopic tumor that does not expand in size and remains asymptomatic. Dormant tumors represent an early stage in tumor development and may therefore be a potential target for nontoxic, antiangiogenic therapy that could prevent tumor recurrence. Here, we characterize an experimental model that recapitulates the clinical dormancy of human tumors in mice. We demonstrate that these microscopic dormant cancers switch to the angiogenic phenotype at a predictable time. We further show that while angiogenic liposarcomas expand rapidly after inoculation of tumor cells in mice, nonangiogenic dormant liposarcomas remain microscopic up to one-third of the normal severe combined immune deficiency (SCID) mouse life span, although they contain proliferating tumor cells. Nonangiogenic dormant tumors follow a similar growth pattern in subcutaneous (s.c.) and orthotopic environments. Throughout the dormancy period, development of intratumoral vessels is impaired. In nonangogenic dormant tumors, small clusters of endothelial cells without lumens are observed early after tumor cell inoculation, but the nonangiogenic tumor cannot sustain these vessels, and they disappear within weeks. There is a concomitant decrease in microvessel density, and the nonangiogenic dormant tumor remains harmless to the host. In contrast, microvessel density in tumors increases rapidly after the angiogenic switch and correlates with rapid expansion of tumor mass. Both tumor types cultured in vitro contain fully transformed cells, but only cells from the nonangiogenic human liposarcoma secrete relatively high levels of the angiogenesis inhibitors thrombospondin-1 and TIMP-1. This model suggests that as improved blood or urine molecular biomarkers are developed, the microscopic, nonangiogenic, dormant phase of human cancer may be vulnerable to antiangiogenic therapy years before symptoms, or before anatomical location of a tumor can be detected, by conventional methods.

Distinction between well-differentiated liposarcoma and intramuscular lipoma by power Doppler ultrasonography.

BACKGROUND: This study evaluates the feasibility of ultrasonography in the distinction between well-differentiated liposarcoma (WDLS) and intramuscular lipoma (IL). MATERIALS AND METHODS: Three WDLSs and 9 ILs were included. Gray scale images were assessed for echogenicity, textural pattern and margins. Power Doppler ultrasonography was used to assess the number of detectable flow velocity signals in a 3 x 3 cm area. Furthermore, the ratio of the area occupied by colour flow signals relative to the selected area was determined. RESULTS: Gray scale images showed no differences between WDLSs and ILs. However, power Doppler showed more than 2 flow velocity signals in all WDLSs, whereas only 11% of the ILs had 2 signals. In all WDLSs, colour flow signals occupied more than 30% of the selected area. In contrast, ILs were characterized by a low color-dot ratio. Histologically, increased vascularity was found close to malignant cell invasions. CONCLUSION: Power Doppler ultrasonography is feasible to evaluate increased vascularity and thus differentiate WDLSs from ILs.

Heterogeneity of angiogenic activity in a human liposarcoma: a proposed mechanism for "no take" of human tumors in mice.

BACKGROUND: Tumor cells are known to be heterogeneous with respect to their metastatic activity, proliferation rate, and activity of several enzymes. However, little is known about the heterogeneity of tumor angiogenic activity. We investigated whether heterogeneity of angiogenic activity could be responsible for the well-known observation of "no take" of human tumors transplanted into immunodeficient mice. METHODS: Severe combined immunodeficient (SCID) mice were xenotransplanted subcutaneously with tumor tissue (n = 55) or cell suspension of a human liposarcoma cell line (SW-872) or subclones (n = 28), with varying cell proliferation rates. Xenograft tumor growth was recorded for up to 6 months. Tumor tissues were then removed and analyzed for tumor cell apoptosis, microvessel density, and cell proliferation. All statistical tests were two-sided. RESULTS: Pieces of tumor derived from the parental cell line or its clones gave rise to three kinds of tumors: 1) highly angiogenic and fast-growing (aggressive) tumors, 2) weakly angiogenic and slow-growing tumors, and 3) nonangiogenic and stable tumors. Most tumors retained the original phenotype of their parental tumor. Tumor volume correlated positively with microvessel density (Spearman correlation coefficient [r] =.89; P< or =.0001) and inversely with tumor cell apoptosis (Spearman r = -.68; P =.002). Tumor volume was less strongly but still positively correlated with tumor cell proliferation in vivo (Spearman r =.55; P =.02). CONCLUSIONS: Human liposarcoma cells appear to be heterogeneous in their angiogenic activity. When tumor cells with little or no angiogenic activity are transplanted into SCID mice, a microscopic, dormant tumor results that may not grow further. Because such tiny tumors are neither grossly visible nor palpable, they have previously been called "no take." The finding that an angiogenic tumor can contain subpopulations of tumor cells with little or no angiogenic activity may provide a novel mechanism for dormant micrometastases, late recurrence, and changes in rate of tumor progression.

Expression of growth hormone receptor in human liposarcomas and lipomas.

Our immunohistochemical results clearly demonstrated the occurrence of growth hormone receptors (GH-R) in the tumour cells of lipomas and liposarcomas. In liposarcomas staining intensity in the cytoplasm of tumour cells varied between weak and distinct but could not be correlated to the histological grade of the malignant tumours. These findings were corroborated to some extent by the RT-PCR results. RT-PCR analysis of human lipomas and liposarcomas revealed the amplified cDNA fragment of GH-R in 8 out of 12 lipomas but only in 3 out of 10 liposarcomas. The reduced number of GH-R positive tumours found with PCR may be explained by the extraction method of RNA from paraffin sections. An interesting finding was the distinct immunoreactivity of the endothelium of blood vessels in liposarcomas, which was especially pronounced in the newly forming capillaries. This points to an important role of GH-R in tumour angiogenesis which could significantly contribute to tumour growth in liposarcomas and may open the possibility for therapeutic intervention using antiangiogenic substances.

Paradoxical cerebral embolism originating from thrombus in tumour veins as presenting manifestation of retroperitoneal liposarcoma.

The coincidence of pulmonary and systemic emboli suggests paradoxical embolism. We present the case of a young man in whom a blood clot travelled from the veins in a retroperitoneal liposarcoma via a patent foramen ovalis to the systemic arterial circulation. Young patients with embolic disease but no obvious source of thrombus may have underlying neoplastic disease. Venous thrombosis is a frequent complication of neoplastic disease. Arterial embolism associated with neoplasm is, however, not widely recognised.

Vena caval involvement with renal tumors: surgical considerations.

We reviewed the experience at the University of Virginia over the past 10 years with renal tumors involving the inferior vena cava. There were 107 patients with renal tumors, 41 with invasion of the renal vein and 18 with involvement of the inferior vena cava. The groups with and without vena caval tumors were compared, and the operative approach is described. Although the rate of complications was higher in operations on the vena cava, none were fatal and no patient required chronic dialysis. Life-table analysis revealed that patients with involvement of the inferior vena cava survived longer than those with incomplete resection. Because extraction of these tumors can be accomplished with acceptable morbidity and mortality, because complete resection confers a survival advantage, and because chemotherapy and radiation are ineffective, we recommend aggressive workup and resection of renal tumors involving the inferior vena cava.

Positron emission tomography in oncology--the Massachusetts General Hospital experience.

Positron tomography has been used to measure blood flow, oxygen utilization, and glucose metabolism in soft-tissue tumors in rabbits and in human tumors in extremities. Both blood flow and oxygen utilization were increased in tumor in contrast to normal muscle tissue. Oxygen extraction fraction was, however, decreased in tumor. The most sensitive indicator of tumor growth was the glucose metabolic rate. The effect of irradiation was observed by blood flow measurements in human tumors and by blood flow and oxygen utilization in tumors in rabbits. Blood flow increased both in tumor and normal muscle tissue during irradiation and decreased afterwards. Oxygen utilization decreased in tumor and increased in normal tissue during irradiation.