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PubMed2006

Mismatch repair protein expression and microsatellite instability: a comparison of clear cell sarcoma of soft parts and metastatic melanoma.

Clear cell sarcoma of soft parts is a rare soft tissue malignancy that shows phenotypic overlap with cutaneous melanoma but can be distinguished by the presence of a t(12;22) translocation. Microsatellite instability (MSI), a variation in the lengths of short repeat DNA segments in the genome, has been implicated in melanoma tumorigenesis, but is rare or absent in clear cell sarcoma. Defects in the mismatch repair (MMR) enzyme complex correlate with MSI in some tumor types, allowing the use of immunohistochemistry for the MMR proteins hMLH1 and hMSH2 to predict the presence of MSI. To determine if the association between MMR defects and MSI extends to clear cell sarcoma, we compared a group of nine clear cell sarcomas to 11 metastatic melanomas on the basis of MSI and the expression of MMR proteins. MSI was studied using fluorescence-based multiplexed PCR of five loci. Immunohistochemistry was evaluated on formalin-fixed paraffin-embedded tissue for hMLH1, hMHS2 and hMSH6. MSI was present in only 1/9 (11%) clear cell sarcoma case and in 8/11 (73%) melanoma cases. Immunostaining for hMLH1 and hMSH2 was preserved in all the clear cell sarcomas but loss of immunostaining for one or both proteins was seen in 6/11 melanomas (55%). hMSH6 was detected in 7/9 (78%) clear cell sarcomas and 10/11 (91%) of melanomas. Clear cell sarcoma and metastatic melanoma differed significantly with respect to the presence of MSI (P=0.010) and staining for hMLH1 and/or hMSH2 (P=0.014) but not hMSH6 (P=0.57). Mismatch repair, and consequently genomic instability may contribute to tumorigenesis in melanoma but not clear cell sarcoma. Immunostaining for hMLH1 and hMSH2 and MSI analysis may be helpful in the differential diagnosis of large soft tissue or visceral malignancies with melanocytic differentiation.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Calponin and h-caldesmon expression in synovial sarcoma; the use of calponin in diagnosis.

AIMS: To assess the frequency of expression and potential diagnostic utility of calponin and caldesmon in synovial sarcomas. METHODS AND RESULTS: Immunohistochemistry with antibodies to calponin and h-caldesmon was undertaken in paraffin sections from 50 synovial sarcomas (19 biphasic and 31 monophasic, of which one biphasic and eight monophasic tumours had poorly differentiated areas), 10 each of malignant peripheral nerve sheath tumour (MPNST), solitary fibrous tumour (SFT), dermatofibrosarcoma (DFSP), Ewing's sarcoma (ES/PNET), and neuroblastoma, eight alveolar rhabdomyosarcomas, five adult fibrosarcomas and five carcinosarcomas. Nine of 19 biphasic synovial sarcomas were positive for calponin in spindle and glandular areas, nine in spindle cells only, and one in glands only. All monophasic synovial sarcomas and poorly differentiated areas expressed calponin; in monophasic tumours this was focally (29% of cases), moderately (39%), or diffusely (32%) positive and the poorly differentiated areas were usually moderately or diffusely positive. Four synovial sarcomas showed focal reactivity for h-caldesmon. Calponin was found in 4/10 MPNST, 7/10 SFT, 4/10 DFSP, 3/5 fibrosarcomas and the spindle component of the carcinosarcomas. H-caldesmon was weakly positive in 1/10 MPNST, 4/10 SFT, 0/10 DFSP, 0/5 fibrosarcomas and 1/5 carcinosarcomas (glands only). Both markers were negative in the other small round cell tumours. CONCLUSIONS: Calponin can be used as an additional marker for synovial sarcoma. Its absence argues against the diagnosis. The presence of calponin might be useful in distinguishing poorly differentiated synovial sarcoma from other small round cell tumours. H-caldesmon is not helpful in diagnosis of synovial sarcoma.

Biomarkers, Tumor↗
PubMed2000

Iron chelators inhibit the growth and induce the apoptosis of Kaposi's sarcoma cells and of their putative endothelial precursors.

Iron is suspected to be involved in the induction and/or progression of various human tumors. More particularly, iron may be involved in the pathogenesis of Kaposi's sarcoma, a tumor of probable vascular origin. This study was designed to investigate the effect of iron deprivation on Kaposi's sarcoma. The effects of iron chelators and iron deprivation associated with serum withdrawal were investigated on Kaposi's sarcoma-derived spindle cells, on a transformed Kaposi's sarcoma cell line (Kaposi's sarcoma Y-1) and on endothelial cells, which are the probable progenitors of Kaposi's sarcoma cells. Desferrioxamine and deferiprone, two chemically unrelated iron chelators, induced a time- and concentration-dependent inhibition of endothelial and Kaposi's sarcoma cell growth. The inhibition of cell growth was associated with a decrease in Ki-67 and in both stable and total proliferating cell nuclear antigen expression. Inhibition of the progression through the G1-phase of the cell cycle was further evidenced by decreased expression of cyclin D1 and of p34 cyclin-dependent kinase 4. Terminal deoxynucleotidyl transferase-mediated desoxyuridinetriphosphate nick end labeling assay, flow cytometry with annexin-V-fluorescein and morphologic analysis indicated that iron chelation also induced a time- and concentration-dependent apoptosis. This apoptotic effect was prevented by the addition of exogenous iron. Induction of iron deprivation in the culture medium by serum withdrawal led to similar cell cycle effects, which, however, could only be partly reverted by the addition of exogenous iron. In conclusion, these results show that iron deprivation inhibits the growth and induces the apoptosis of Kaposi's sarcoma cells and of their putative endothelial precursors. This suggests that iron chelators may represent a potential therapeutic approach for the treatment of Kaposi's sarcoma.

Apoptosis↗
PubMed2001

Early- and late-stage Kaposi's sarcoma-derived cells but not activated endothelial cells can invade de-epidermized dermis.

Whether Kaposi's sarcoma is a true neoplasm or a reactive endothelial cell outgrowth triggered by inflammatory cytokines remains unclear. In this study, we investigated the differential invasive properties of activated endothelial cells and Kaposi's sarcoma cells in a model of de-epidermized dermis, supplying the cells with matrix barriers similar to those found in vivo. Cells derived from early "patch-stage" and from late "nodular-stage" Kaposi's sarcoma lesions exhibited similar invasive properties, which indicates that cells with an invasive potential are present in the early stages of tumor development. Slow accumulation of the cells into the extracellular matrix, together with a low proliferation index and with expression of anti-apoptotic proteins, suggest that the progression of Kaposi's sarcoma may be related to escape from cell death rather than to increased proliferation. The Kaposi's sarcoma-Y1 cell line, which is tumorigenic in nude mice, also exhibited invasive properties. By contrast to the Kaposi's sarcoma-derived spindle cells, however, which were scattered between the collagen bundles, the Kaposi's sarcoma-Y1 cell population had a higher proliferation index and displayed a multilayer arrangement. Inflammatory cytokines and Kaposi's sarcoma cell supernatant could activate and stimulate the growth of human dermal microvascular endothelial cell, but could not induce their invasion in this model, showing that activated endothelial cells do not fit all the requirements to traverse the various barriers found in the dermal extracellular matrix. These results confer to Kaposi's sarcoma cells a tumor phenotype and suggest that the in vivo dominant endothelial cell population represents a reactive hyperplasia rather than the true tumor process.

Cell Division↗
PubMed1997

Prognostic factors in soft tissue sarcoma.

Several prognostic markers have been identified for soft tissue sarcomas. However, there reproducibility as regards both classification by different examiners and prognostic strength, as evaluated in different tumor series is poorly documented. Relevant factors and their strength differ in different subtypes of sarcoma. Thus, there is no generally accepted prognostic/staging system for soft tissue sarcoma. It seems possible that highly malignant soft tissue sarcomas behave like highly malignant bone tumors, such as osteosarcoma and Ewing sarcoma-i.e., almost all patients have metatastic disease when the primary tumor is diagnosed, although in most cases it is not detectable with today's imaging techniques. The highly malignant character of these tumors is defined by their histotype alone and the microscopic diagnosis is almost always easy. In contrast, no soft tissue sarcoma histotype is per se associated with such a poor prognosis: further prognostic markers are needed. The ideal prognostication system includes only two groups of patients; after removal of the primary tumor, one group has 100% survival and the other 0% survival. In the latter group, the tumor has metastasized and adjuvant therapy is necessary to improve survival. Meaningful chemotherapy trials requires reliable identification of high-risk patients; only these should be included. Inclusion of also low-risk patients is disadvantageous for two reasons: chemotherapy may have serious side-effects and positive effects may be difficult to detect when the trial is diluted by low-risk patients. Prognostication in soft tissue sarcoma has improved, but it may a long time before soft tissue sarcoma histotypes as highly malignant as osteosarcoma and Ewing sarcoma can be defined. Another approach would be to ignore efforts to characterize prognostic features of the primary tumor and instead, with some type of tracer technique (see pp x-y in this issue), focus on whether it has metastasized or not.

Chemotherapy, Adjuvant↗
PubMed1997

Expression of human herpesvirus 8-encoded cyclin D in Kaposi's sarcoma spindle cells.

BACKGROUND: Human herpesvirus 8 (HHV-8) DNA sequences have been detected in Kaposi's sarcoma, in primary effusion lymphoma (an unusual high-grade non-Hodgkin's lymphoma seen primarily in patients with acquired immunodeficiency syndrome [AIDS]), and in Castleman's disease (a rare lymphoproliferative disorder); however, proof that HHV-8 is involved in the pathogenesis of these diseases remains to be established. HHV-8 contains a gene, i.e., v-cyclin D, that is a homologue of the cellular cyclin D2 gene, which encodes a protein that promotes passage through G1 phase of the cell cycle. Previous studies have identified v-cyclin D messenger RNA (mRNA) in biopsy specimens of Kaposi's sarcoma. In this study, we isolated a full-length v-cyclin D complementary DNA and characterized the pattern of v-cyclin D mRNA expression in Kaposi's sarcoma. METHODS: Standard methods were used to construct and to screen HHV-8 genomic and complementary DNA libraries. Reverse transcription-polymerase chain reaction (RT-PCR) methods and in situ hybridization with RNA probes were used to examine v-cyclin D mRNA expression. RESULTS: RT-PCR demonstrated the presence of v-cyclin D mRNA in biopsy specimens of AIDS-related Kaposi's sarcoma, in early-passage spindle cells from classical (i.e., not AIDS-related) Kaposi's sarcoma, and in spindle cells isolated from the peripheral blood of patients with AIDS-related Kaposi's sarcoma. In situ hybridization indicated that mRNAs for v-cyclin D and kaposin, an HHV-8 latency-associated gene, were present in approximately 1% of the spindle cells in early patch lesions and approximately 60% of the spindle cells in late nodular lesions of Kaposi's sarcoma. CONCLUSIONS: Spindle cells of Kaposi's sarcoma, which have been regarded as the tumor cells of this cancer, contain v-cyclin D mRNA. Expression of v-cyclin D protein may be involved in the pathogenesis of Kaposi's sarcoma by promoting cell proliferation.

Blotting, Southern↗
PubMed1990

Kaposi's sarcoma in a cohort of homosexual and bisexual men. Epidemiology and analysis for cofactors.

Acquired immunodeficiency syndrome (AIDS) surveillance data for both the United States and San Francisco indicate that Kaposi's sarcoma is more common in homosexual and bisexual men with AIDS than in other adults with AIDS, and that the proportion of newly diagnosed AIDS cases presenting with Kaposi's sarcoma has been significantly declining over time. The changing epidemiology of Kaposi's sarcoma was analyzed in a well-characterized cohort of homosexual and bisexual men; laboratory and interview data from a sample of these men were evaluated for determinants of and cofactors associated with Kaposi's sarcoma. Among 1,341 men with AIDS, the proportion presenting with Kaposi's sarcoma declined from 79% in 1981 to 25% in 1989. Compared with other men with AIDS, men with Kaposi's sarcoma had a shorter interval from human immunodeficiency virus (HIV) seroconversion to AIDS diagnosis (median, 77 vs. 86 months). Men with and without Kaposi's sarcoma did not significantly differ with respect to number of sexual partners, history of certain sexually transmitted or enteric diseases, use of certain recreational drugs (including nitrite inhalants), or participation in certain specific sexual practices. The decline in Kaposi's sarcoma may at least partly be due to a shorter latency period from infection to disease. Although cofactors for the development of Kaposi's sarcoma may exist, many previously hypothesized agents were not supported by this analysis.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Composite risk score for Kaposi's sarcoma based on a case-control and longitudinal study in the Multicenter AIDS Cohort Study (MACS) population.

The possibility that an agent in addition to human immunodeficiency virus type 1 may be involved in the etiology of Kaposi's sarcoma in acquired immunodeficiency syndrome (AIDS) patients was investigated between 1984 and 1992 in this nested case-control analysis from the Multicenter AIDS Cohort Study (MACS) of homosexual and bisexual men. A total of 316 cases of Kaposi's sarcoma were identified and compared with 510 participants with AIDS and no evidence of cancer. More of the Kaposi's sarcoma cases were from Los Angeles and used a higher number of recreational drugs. The Kaposi's sarcoma cases were also more active sexually. There was a dose-response relation between Kaposi's sarcoma and the number of sexual partners, with an odds ratio of 2 between the most and least sexually active subgroups. The odds ratio for Kaposi's sarcoma increased to 4.18 (95% confidence interval 1.29-14.1) in the presence of a history of five infections. Hepatitis and gonorrhea contributed the most to this relation. The various observed odds ratios did not change after multivariate adjustment for the other risk factors. A model was developed combining all predictive associations into a composite risk score ranging from one to 12 and based on history of infections, sexual activity, use of poppers/nitrites, and having had sexual partners from the West Coast of the United States. The subgroup with the highest scores, compared to the subgroup with the lowest score, had an odds ratio of 8.93 (95% confidence interval 3.21-30.44) for Kaposi's sarcoma. A longitudinal proportional hazards analysis among all 2,190 human immunodeficiency virus type 1-seroprevalent men at study entry, based on this risk score and CD4 cells at baseline, confirmed these findings. Identifying these specific subgroups that are at high and low risk for Kaposi's sarcoma will help future investigations to be more focused in their search for an additional etiologic factor for Kaposi's sarcoma in AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Seroconversion for human herpesvirus 8 during HIV infection is highly predictive of Kaposi's sarcoma.

BACKGROUND: The finding of antibodies against human herpesvirus 8 (HHV-8) is associated with the occurrence of Kaposi's sarcoma in persons infected with HIV. However, the predictive value of HHV-8 antibodies for Kaposi's sarcoma in HIV infection is unknown. METHODS: The Amsterdam Cohort Studies on HIV infection and AIDS started in 1984 for homosexual men and in 1985 for injecting drug users. Serum samples from 1459 homosexual men and 1167 drug users were tested for antibodies to recombinant HHV-8 lytic-phase capsid (ORF65) antigen and latent-phase nuclear (ORF73) antigen. Individuals were retrospectively identified as HHV-8-positive or HHV-8-negative at enrolment or HHV-8 seroconverter during the study. Kaposi's sarcoma-free survival time was compared between HIV-infected men who were positive for HHV-8 at enrolment and those who later seroconverted for HHV-8. Hazard ratios were estimated for Kaposi's sarcoma, lymphoma, and opportunistic infection according to the HHV-8 serostatus. RESULTS: The incidence of HHV-8 seroconversion among drugs users was 0.7 per 100 person-years based on 31 seroconversions, whereas an incidence of 3.6 was found among homosexual men based on 215 seroconversions. The hazard ratio for Kaposi's sarcoma was 3.15 (95% CI: 1.89-5.25) in HIV-infected individuals if HHV-8 antibodies were present either at enrolment or at HIV seroconversion. In HIV-infected persons who later seroconverted to HHV-8, Kaposi's sarcoma developed more rapidly: hazard ratio of 5.04 (95% CI: 2.94-8.64), an additional risk of 1.60 (95% CI: 1.01-2.53; P = 0.04). Time-dependent adjustment for CD4+ cell count and HIV RNA had no impact on the additional risk, although the CD4+ cell count was an independent risk factor for Kaposi's sarcoma. HHV-8 infection did not increase the risk of AIDS-related lymphoma or opportunistic infections. CONCLUSIONS: The incidence of HHV-8 infection is higher in homosexual men than in drug users. The presence of HHV-8 antibodies in HIV-infected persons increases the risk of Kaposi's sarcoma. Among HIV-infected persons, those who subsequently seroconvert for HHV-8 are at highest risk. These results strongly confirm the causal role of HHV-8 in Kaposi's sarcoma and emphasize the clinical relevance of HHV-8 seroconversion before and after the HIV infection.

Adult↗
PubMed2005

Kaposi's sarcoma of an intraparotid lymph node leading to a diagnosis of HIV.

OBJECTIVE: Kaposi's sarcoma is a common malignancy in patients infected with HIV but is rarely seen in the major salivary glands. If a patient is known to be HIV-positive, however, Kaposi's sarcoma must be considered in the differential diagnosis of salivary gland masses in addition to the benign and malignant neoplasms that occur in immunocompetent patients. We present a unique case in which an otherwise healthy patient was diagnosed with HIV after resection of his enlarged parotid gland revealed Kaposi's sarcoma. STUDY DESIGN: Case report. METHODS: A 58-year-old man presented with slowly enlarging bilateral parotid masses of approximately 3 years' duration. The patient's presentation, workup, and final diagnosis of Kaposi's sarcoma are discussed. RESULTS: A magnetic resonance imaging scan of the neck showed two right parotid lesions and one left parotid mass. The patient underwent a right superficial parotidectomy for a suspected diagnosis of Warthin's tumor, given the bilaterality of the lesions. Histologic evaluation of the surgical specimen revealed spindle-shaped cells with extravasated erythrocytes typical of Kaposi's sarcoma. After discussion of the results with the patient, HIV risk factors were elucidated, and subsequent testing revealed the patient to be HIV-positive. CONCLUSIONS: Although Kaposi's sarcoma is common in AIDS patients, there are few case reports of this malignancy arising in the salivary glands. Previously reported cases include salivary gland Kaposi's sarcoma in known HIV-positive patients and a handful of reports in patients without confirmed immunocompromise. The patient presented here is unique because the diagnosis of parotid gland Kaposi's sarcoma led to a new diagnosis of HIV. This interesting case reiterates the need for complete history taking and the inclusion of Kaposi's sarcoma in the differential diagnosis of salivary gland masses in the appropriate patient population.

Adenolymphoma↗
PubMed2004

Procholecystokinin as marker of human Ewing sarcomas.

PURPOSE: Ewing sarcoma is a rapidly growing mesenchymal tumor in young adults. Although it was shown previously to express the cholecystokinin (CCK) gene, it is unknown whether CCK gene expression is detectable at protein level in Ewing sarcoma tumor cell lines, in tumor tissue, and in plasma from Ewing sarcoma patients, and, if so, whether CCK peptides might play a role as tumor markers. EXPERIMENTAL DESIGN: CCK gene expression was evaluated with in situ hybridization or reverse transcription-PCR in tumor tissue. CCK precursors and bioactive CCK were measured with specific RIAs in tumor tissue, in cell culture medium, and in plasma of Ewing sarcoma patients before and after chemotherapy as well as after tumor recurrence. RESULTS: CCK mRNA was identified in 12 Ewing sarcoma biopsies sampled in two series and in four Ewing sarcoma cell lines but not in unrelated neoplasia. Immunoreactive proCCK was identified in the culturing medium of all Ewing sarcoma cell lines but not in the media from unrelated tumor cell lines. Moreover, in plasma from Ewing sarcoma patients, precursors and mature forms of CCK, in particular proCCK, were detected; several fold elevation of the total proCCK product was found in plasma from patients before treatment and after tumor recurrence, whereas successful chemotherapy reduced proCCK to basal concentrations. Plasma concentrations of proCCK paralleled the respective tumor size. CONCLUSIONS: This is the first study that consistently documents an altered CCK metabolism in human cancer; Ewing sarcomas synthesize and secrete proCCK that can be identified in plasma as circulating tumor marker.

Biomarkers, Tumor↗
PubMed1996

Synovial sarcoma: prognostic significance of tumor size, margin of resection, and mitotic activity for survival.

PURPOSE: The present study serves to describe outcomes-based prognostic variables characteristic of synovial cell sarcoma. PATIENTS AND METHODS: An analysis was performed of a prospectively compiled data base of 48 consecutive patients with extremity and truncal synovial sarcomas seen between 1966 and 1994. RESULTS: No local recurrences were observed among 27 patients who presented with localized primary disease. Patients with synovial sarcoma less than 5 cm in size has a cancer-specific survival rate at 10 years of 100%, compared with a 10-year survival rate of 32% and 0% for those with sarcoma 5 to 10 cm and greater than 10 cm, respectively (P = .002). Patients with synovial sarcoma with less than 10 mitoses per 10 high-power fields (hpf) had a 10-year cancer-specific survival rate of 46%, compared with a 10-year survival rate of 14% for those with sarcomas with greater than 10 mitoses per hpf (P = .04). Patients with a clean margin of excision were found to have a 10-year cancer-specific survival rate of 43%, compared with 0% for those with microscopic positive margins (P = .03). Among 14 patients treated with neoadjuvant chemotherapy, seven (50%) had objective responses. CONCLUSION: Local control for patients with nonmetastatic disease was excellent. The overall cancer-specific survival rate for patients with localized synovial sarcoma was 34% at 10 years. Primary tumor size, margin of resection, and mean mitotic activity were prognostic factors for survival in synovial sarcoma. There was a high objective response rate to treatment with neoadjuvant chemotherapy; however, there was no detectable beneficial effects on survival in the subset of patients treated with chemotherapy versus nonrandomized patients who received no chemotherapy. Patients with synovial sarcoma > or = 5 cm in size, microscopic positive margins, and/or mean mitotic activity greater than 10 mitoses per 10 hpf should be targeted for new therapeutic studies.

Adult↗
PubMed2007

Isolated limb perfusion with melphalan and tumor necrosis factor alpha for advanced melanoma and soft-tissue sarcoma.

BACKGROUND: Isolated limb perfusion (ILP) with melphalan is used in the treatment of advanced in-transit melanoma but has no real efficacy for irresectable soft tissue sarcomas arising in the extremities. The addition of tumor necrosis factor (TNF)-alpha may increase response rates for bulky melanoma and for sarcoma, but the potential for major systemic toxicity has limited its use. METHODS: Between October 2000 and April 2004, 49 ILPs were performed with melphalan and TNF-alpha. All procedures were performed with continuous leakage monitoring and regional hyperthermia. RESULTS: Forty-nine ILPs were performed for melanoma (n = 30), sarcoma (n = 16), or other tumors (n = 3). The most common indications were widespread in-transit disease for melanoma (n = 29) and irresectable primary disease for sarcoma (n = 9). Complete and partial responses for melanoma were 40% and 37%, and for sarcoma they were 20% and 33%. At a median follow-up of 14 months, 66% of melanoma patients who responded had not experienced local progression, compared with only 37% of sarcoma patients. Progression-free survival was significantly less for patients with sarcoma than melanoma (P = .0476). Four of 16 patients with sarcoma subsequently required amputation for progressive disease. CONCLUSIONS: ILP with melphalan and TNF-alpha is a valuable treatment for advanced in-transit melanoma. Significant response rates were also seen in irresectable sarcoma, although the duration of response was limited.

Adult↗
PubMed1999

Delay in the diagnosis and treatment of primary bone sarcoma of the pelvis.

BACKGROUND: Symptoms arising from primary bone sarcoma of the pelvic girdle are often insidious in onset and nonspecific in nature. To make the subtle initial signs and symptoms of these tumors more apparent to clinicians, we studied a cohort of patients who had a primary bone sarcoma of the pelvic girdle. Our purpose was to describe the initial clinical findings and to evaluate the duration, frequency, and implications of delays in the treatment of these tumors. METHODS: We retrospectively analyzed the data on sixty-eight patients who had a primary bone sarcoma of the pelvic girdle. The data that we reviewed included demographic characteristics; histological diagnosis; anatomical location, size, and stage of the tumor; characteristics of the biopsy specimen; duration and description of symptoms before an accurate diagnosis was made; delay before recognition of the tumor on radiographs; results of diagnostic imaging; inaccurate diagnoses; type of intervention based on these inaccurate diagnoses; and outcome with regard to survival. There were forty high-grade sarcomas and twenty-eight low-grade sarcomas. RESULTS: Excluding two asymptomatic patients in whom the sarcoma was noted incidentally, the average duration of symptoms before an accurate diagnosis was made was ten months (median, six months; range, one month to four years). Common symptoms and findings on physical examination included pain in the buttock (twenty-three patients; 35 percent), a mass (twenty patients; 30 percent), sciatica (nineteen patients; 29 percent), pain in the hip (seventeen patients; 26 percent), pain in the groin (thirteen patients; 20 percent), and low-back pain (fourteen patients; 21 percent). In thirty (44 percent) of the sixty-eight patients, the pelvic sarcoma was not recognized initially and an inaccurate diagnosis was made. The misdiagnoses included a herniated lumbar disc, spinal stenosis, spondylolisthesis, tendinitis, bursitis, an inguinal hernia, a stress fracture, a pilonidal cyst, a recurrent urinary-tract infection, and degenerative arthritis of the spine, hip, and knee. Inappropriate treatment for these misdiagnoses included seven operative procedures (two laminectomies, two debridements, one hip arthrotomy, one total knee replacement, and one inguinal herniorrhaphy), six courses of nonsteroidal anti-inflammatory medications, five chiropractic adjustments, four trials of physical therapy, and three local injections of steroids. It took an average of seven months for the clinicians to arrive at the diagnosis of primary pelvic sarcoma. With the numbers available, no significant association between the duration of symptoms before an accurate diagnosis was made and the grade or the stage of the tumor could be detected. In addition, no association between the duration of symptoms and the survival of the patient (p = 0.54) could be determined, with univariate analysis. The grade and the stage of the tumor were strongly associated with the outcome, with a low tumor grade proving to be a favorable prognostic indicator for survival (p = 0.006). CONCLUSIONS: Patients who have a primary bone sarcoma of the pelvis often have had symptoms for a long duration that mimic those of more commonly encountered non-neoplastic musculoskeletal conditions. When a patient has symptoms that appear to be out of the ordinary, particularly refractory pain or pain at rest, physicians should include the pelvic girdle in the evaluation and should carefully examine a high-quality radiograph of the entire pelvis.

Adolescent↗
PubMed2006

Evaluation of dysregulation of the receptor tyrosine kinases Kit, Flt3, and Met in histiocytic sarcomas of dogs.

OBJECTIVE: To evaluate canine histiocytic sarcoma cell lines and tumor samples for dysregulation of the Kit/stem-cell factor (SCF), Flt3/Flt3 ligand (Flt3L), and Met/hepatocyte growth factor (HGF) receptor tyrosine kinase signaling pathways, as these are known to contribute to the differentiation and survival of normal dendritic cells as well as malignant transformation of dendritic cells in mouse models. SAMPLE POPULATION: 4 histiocytic sarcoma tumor cell lines and 35 formalin-fixed histiocytic sarcoma specimens obtained from dogs. PROCEDURE: Histiocytic sarcoma cell lines were evaluated for expression of Kit/SCF, Flt3/Flt3L, and Met/HGF by use of reverse transcriptase-PCR procedures. Histiocytic sarcoma cell lines and tumor samples were evaluated for mutations in Kit, Flt3, and Met by use of PCR analysis of genomic DNA, followed by both sequencing and fluorescent PAGE for deletions or internal tandem duplications. The ability of the multi-targeted split-kinase inhibitor SU11654 to block proliferation and induce apoptosis of histiocytic sarcoma cell lines was also evaluated. RESULTS: No mutations in Kit, Flt3, and Met were identified in any of the cell lines or tumor samples evaluated. Furthermore, SU11654 did not induce cell-cycle arrest or apoptosis of histiocytic sarcoma lines, even at supratherapeutic doses. CONCLUSIONS AND CLINICAL RELEVANCE: These data suggest that dysregulation of Kit/SCF, Flt3/Flt3L, and Met/HGF signaling pathways is unlikely to occur in histiocytic sarcomas of dogs and that inhibitors of the Kit, Flt3, and Met pathways are unlikely to provide clinical benefit to dogs with histiocytic sarcomas.

Animals↗
PubMed2006

Utility of CD117 immunoreactivity in differentiating metastatic melanoma from clear cell sarcoma.

CONTEXT: Clear cell sarcoma is a malignant soft tissue tumor with melanocytic differentiation. Molecular methods are sometimes necessary to identify the unique t(12; 22)(q13;q12) translocation and differentiate clear cell sarcoma from melanoma. OBJECTIVE: To determine whether CD117 immunoreactivity may be useful in separating melanoma from clear cell sarcoma. DESIGN: We identified 20 tumors listed in our surgical pathology files that were diagnosed as clear cell sarcoma or in which clear cell sarcoma was strongly considered. These were tested for the presence of the t(12;22) translocation by reverse transcriptase/polymerase chain reaction and sequencing from paraffin-embedded tissue. Tumors with a t(12;22) translocation were immunostained with an antibody to CD117 and compared with 16 similarly stained metastatic melanomas. RESULTS: Twelve tumors from 9 patients demonstrated t(12;22). No metastatic melanomas demonstrated t(12;22). None of the 12 clear cell sarcomas showed membrane or cytoplasmic staining for CD117. Conversely, 10 (63%) of 16 metastatic melanomas were, at least focally, positive for CD117; this difference was significant (P < .001). Interestingly, 3 tumors in which clear cell sarcoma was initially considered as a diagnosis, but which lacked t(12;22), were also positive for CD117. CONCLUSIONS: Reverse transcriptase/polymerase chain reaction, performed on paraffin-embedded tissue, is a useful, rapid tool for identifying the presence of t(12;22) in clear cell sarcoma. The CD117 immunoreactivity may prove useful in the differential diagnosis of deep soft tissue or visceral lesions with melanocytic differentiation; positive staining results exclude clear cell sarcoma, but are compatible with metastatic melanoma.

Adult↗
PubMed1985

Kaposi's sarcoma causing pulmonary infiltrates and respiratory failure in the acquired immunodeficiency syndrome.

Although an aggressive form of Kaposi's sarcoma often develops in patients with the acquired immunodeficiency syndrome, most patients die due to opportunistic infections rather than the direct effects of this tumor. Because Kaposi's sarcoma has caused pulmonary dysfunction in a number of our patients, we attempted to characterize features of pulmonary dysfunction induced by Kaposi's sarcoma. In 66 patients with Kaposi's sarcoma treated between 1982 and 1984 there were 30 episodes of pulmonary dysfunction that resulted in a biopsy. Six episodes were due to pulmonary Kaposi's sarcoma alone, and 6 additional episodes were due to Kaposi's sarcoma and associated opportunistic infections. Clinical and radiologic features of pulmonary Kaposi's sarcoma an infection were indistinguishable. Pulmonary Kaposi's sarcoma could only be documented in large tissue sections available from open-lung biopsy or autopsy samples. Because chemotherapy or radiation therapy appears to provide palliation, clinicians should recognize Kaposi's sarcoma as a cause of pulmonary disease in patients with the acquired immunodeficiency syndrome.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Anticancer drug sensitivity and expression of multidrug resistance markers in early passage human sarcomas.

We have established new human sarcoma lines and examined their sensitivity to common antitumor drugs and expression of putative multidrug resistance (MDR) proteins. Eighty-two sarcoma samples were transplanted in nude mice. Fourteen of these sarcomas were established as tumor cell lines. We determined a chemosensitivity profile to antitumor drugs (MDR drugs = doxorubicin, mitoxantrone, and vincristine; non-MDR drugs = cisplatin, ifosfamide, and bleomycin) for each tumor line in vivo. Response to chemotherapy with doxorubicin and ifosfamide was observed in 30-50% of these tumor lines. Our results obtained with xenotransplants are similar to the results documented in clinical trials in which doxorubicin and ifosfamide are effective in 30-50% of the patients. Furthermore, we examined expression of MDR-relevant markers like P-glycoprotein, MDR-associated protein, lung resistance protein, and mdr1 mRNA in these xenotransplants. A relationship between mdr1 mRNA expression and response to doxorubicin was demonstrated in >90% of our tumor lines. In six sarcomas with mdr1 mRNA expression, five were resistant against doxorubicin and cross-resistant against several other drugs, whereas from eight sarcomas, which lacked detectable mdr1 mRNA, seven were sensitive to doxorubicin and other drugs. We found lung resistance protein or MDR-associated protein expressed in three resistant and mdr1 mRNA-positive sarcomas. These results demonstrate that mdr1 mRNA expression is a putative marker for drug resistance in our sarcoma lines. We conclude, therefore, that inherent P-glycoprotein expression might be also responsible for drug resistance occurring in treatment of patients with sarcomas. The established tumor lines are useful for additional investigations on mechanisms of drug resistance in sarcomas and as models for preclinical screening of new antitumor drugs.

ATP Binding Cassette Transporter, Subfamily B, Mem↗