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Soft tissue tumors range from very common lipomas to some of the rarest tumors in medicine.  These tumors are derived from soft tissue and benign tumors far outnumber malignant tumors.  Malignant tumors are termed sarcomas and only about 5700 cases are diagnosed annually in the United States.  Within recent years, the AIDS epidemic has introduced us to what was previously a very rare sarcoma, Kaposi's sarcoma.  Other soft tissue tumors may be associated with genetic syndromes such as neurofibromatosis.  Although exceedingly rare, these soft tissue sarcomas may also arise within organs. A pathologist often utilizes a variety of special stains and immunohistochemistry to elucidate the nature of the originating cell.  Within recent years, some of these sarcomas have shown unique translocations and other molecular genetic defects, providing another diagnostic tool as well as shedding light into the pathogenesis of these rare but fascinating tumors.

Alveolar Soft Part Sarcoma
Angioblastoma, Giant Cell Type
Angiofibroma, Giant Cell
Angiomyolipoma, Extrarenal
Angiomyxoma, Aggressive
Angiomyxoma, Superficial
Atypical Fibroxanthoma (AFX)
Calcifying Fibrous Pseudotumor (With Psammoma Bodies)
Chondroma (Soft Tissue Chondroma)
Chondrosarcoma, Extraskeletal
Clear Cell Myomelanocytic Tumor of the Falciform Ligament/Ligamentum Teres
Clear Cell Sarcoma (Melanoma of Soft Parts)
Dabska Tumor (Malignant Endovascular Papillary Angioendothelioima)
Dermatofibrosarcoma protuberans (DFSP)
Desmoplastic Small Round Blue Cell Tumor
Eccrine Angiomatous Hamartoma
Epithelioid Sarcoma
Ewing's Sarcoma
Extragastrointestinal stromal tumors
Extrarenal Malignant Rhabdoid Tumors
Fasciitis, Nodular
Fasciitis, Plantar
Fibromatosis (Includes Dupuytren's, Peyronie's Disease, and Desmoid Tumors)
Fibro-Osseous Pseudotumor of the Digits
Fibrous Histiocytoma, Benign (Dermatofibroma)
Fibrous Histiocytoma, Malignant (MFH, Malignant Fibrous Histiocytoma)
Follicular Dendritic Cell Tumor/Sarcoma
Giant Cell Angioblastoma
Giant Cell Fibroblastoma
Giant Cell Tumor of Soft Tissue/Soft Parts
Giant Cell Tumor of Tendon Sheath
Glomus Tumor
Granular Cell Tumor
Hyalinizing Spindle Cell Tumor with Giant Rosettes
Idiopathic Retroperitoneal Fibrosis
Inflammatory Myofibroblastic Tumor (Inflammatory Pseudotumor)
Interdigitating Dendritic Cell Sarcoma (Reticulum Cell Sarcoma)
Intimal Sarcoma (Aortic Intimal Sarcoma, Arterial Sarcoma, Intimal Angiosarcoma)
Juvenile Hyaline Fibromatosis (Murray-Puretic Syndrome)
Juvenile Xanthogranuloma
Kaposi's sarcoma
Leiomyoma (Outside of the Uterus)
Low-grade fibromyxoid sarcoma
Lymphangioendothelioma (Acquired Progressive Lymphangioma)
Malignant Peripheral Nerve Sheath Tumor (MPNST)
Malignant Rhabdoid Tumor (Extra-renal)
Melanotic Neuroectodermal Tumor (of Infancy)
Multinucleate Cell Angiohistiocytoma
Myofibroma (Myofibromatosis, Infantile Myofibromatosis)

Myxoinflammatory Fibroblastic Sarcoma
Myxoma (Soft Tissue)
Neuroblastoma (Olfactory, Esthesioneuroblastoma)
Neurothekeoma (Nerve Sheath Myxoma)
Ossifying Fibromyxoid Tumor of Soft Parts
Peritoneal Serous Carcinoma
Perivascular Epithelioid Cell Tumors (PEC Tumors, Clear Cell Sugar Tumors)
Phosphaturic Mesenchymal Tumor (Oncogenic Osteomalacia)
Pleomorphic Hyalinizing Angiectatic Tumor of Soft Parts (PHAT)
Plexiform Fibrohistiocytic Tumor
Primitive Neuroectodermal Tumor (Peripheral Neuroepithelioma, PNET)
Pyogenic Granuloma (Lobular Capillary Hemangioma)
Rhabdoid Tumor
Sacrococcygeal Teratoma
Sinus Pericranii
Small Round Blue Cell Tumor of Childhood
Solitary Fibrous Tumors
Synovial Sarcoma


Laboratory/Radiologic/Other Diagnostic Testing  
Gross Appearance and Clinical Variants  
Histopathological Features and Variants  
Special Stains/
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Differential Diagnosis  
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Aberration of epidermal growth factor receptor expression in bone and soft-tissue tumors: protein overexpression, gene amplification and activation of downstream molecules.

Dobashi Y, Takei N, Suzuki S, Yoneyama H, Hanawa M, Ooi A.

1Department of Pathology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan.

Mod Pathol. 2004 Dec;17(12):1497-505. Abstract quote  

In order to evaluate the involvement of epidermal growth factor receptor, and to analyze the correlation between gene aberration and protein expression in mesenchymal tumors, we examined protein expression by immunohistochemistry in 125 cases of bone and soft-tissue tumors. Furthermore, amplification of epidermal growth factor receptor gene was determined by fluorescence in situ hybridization.

Positive immunostaining was found in 23 cases (18.4%). Among these 23 cases, one of malignant fibrous histiocytoma showed the highest degree (3+) of protein overexpression and gene amplification as clusters of hybridization signals, indicating homogeneously staining regions. The second case of malignant fibrous histiocytoma also showed a higher degree (2+) of overexpression and coamplification of the epidermal growth factor receptor gene with the centromeric regions, indicating polysomy of chromosome 7. The levels of expression observed in immunohistochemistry were confirmed by immunoblotting and found to be comparable. Moreover, although expression of phosphorylated epidermal growth factor receptor was detected in those two cases of malignant fibrous histiocytoma, constitutive activation of extracellular signal-related protein kinase 1/2 was not observed, suggesting that activation of epidermal growth factor receptor does not necessarily and constantly lead to signal transduction to the downstream molecules. In the remaining 123 cases, including 21 cases exhibiting weak (1+) immunoreactivity, no gene amplification nor polysomy was found. Collectively, expression of epidermal growth factor receptor was observed not infrequently in mesenchymal tumors, but 'overexpression' is rare and can be attributed to an increase in gene copy number, resulting from amplification or polysomy.

Although cases that scored positive for protein expression and/or gene amplification could be qualified candidates for antiepidermal growth factor receptor therapies, further examination of the status of downstream molecules in the signal cascade, such as phosphorylated epidermal growth factor receptor and extracellular signal-related protein kinase 1/2, may be required as the process of therapeutic strategy.
Molecular diagnosis of sarcomas: chromosomal translocations in sarcomas.

Lazar A, Abruzzo LV, Pollock RE, Lee S, Czerniak B.

Department of Pathology, University of Texas M. D. Anderson Cancer Center, Houston, Tex 77030, USA.


Arch Pathol Lab Med. 2006 Aug;130(8):1199-1207 Abstract quote

CONTEXT: Sarcomas are rare, numerous in type, and often difficult to definitively classify. Work in the last 2 decades has revealed that a significant subset of sarcomas are associated with specific chromosomal translocations producing chimeric (fusion) genes that play a role in the sarcomas' biology and are helpful in their differential diagnosis.

OBJECTIVE: To briefly review the sarcomas associated with specific translocations presenting Ewing sarcoma and synovial sarcoma as archetypes and to further explain how cytogenetic and molecular biologic approaches are being used in the diagnosis of sarcomas.

DATA SOURCES: This work is based on a selected review of the relevant medical and scientific literature and our extensive experience with molecular testing in sarcomas.

CONCLUSIONS: In addition to, and complementing, the traditional diagnostic methods of examination of hematoxylin-eosin stained slides, immunohistochemistry, and sound clinical-pathologic correlation, additional cytogenetic and molecular biologic methods are being increasingly utilized and relied on in sarcoma pathology. These methods include chromosomal karyotyping, fluorescence in-situ hybridization, spectral karyotyping, and polymerase chain reaction- based methods for demonstrating specific chromosomal translocations and fusion genes. Understanding the basis of these methods and their application is critical to better provide accurate and validated specific diagnoses of sarcomas.

Primary Soft Tissue Sarcoma and Its Local Recurrence: Genetic Changes Studied by Comparative Genomic Hybridization

Pentscho Popov, M.D., Mortti Virolainen, M.D., Ph.D., Erkki Tukiainen, M.D., Ph.D., Sirpa Asko-Scljavaara, M.D., Ph.D., Riikka Huuhtanen, M.D., Ph.D., Sakari Knuutila, Ph.D. and Maija Tarkkanen, M.D. Ph.D.

Department of Plastic Surgery (PPET, SA-S), Töölö Hospital, Helsinki University Central Hospital; Department of Oncology (MV, RH), Helsinki University Central Hospital; Department of Medical Genetics (SK, MT), Haartman Institute, University of Helsinki; and Laboratory of Medical Genetics (SK, MT), Helsinki University Central Hospital

Mod Pathol 2001;14:978-984 Abstract quote

The aims of this study were to compare genetic aberrations in primary soft-tissue sarcomas and their local recurrences and to evaluate the genetic changes occurring during tumor progression.

A primary soft-tissue sarcoma and its subsequent local recurrence were analyzed in 20 tumor pairs by comparative genomic hybridization.

The samples were obtained before application of radio- or chemotherapy. Copy number aberrations were detected in 50% of the primary tumors and in 70% of the local recurrences. In primary tumors, the mean number of changes was 2.45 (range, 0 to 11) whereas in local recurrences, it was 5.05 (range, 0 to 17). The mean increase of changes from primary tumor to local recurrence was 2.6 per tumor pair (P = .02). Gains predominated over losses in both primary tumors and their local recurrences. The number of high-level amplifications was twofold in local recurrences. The most frequent gain affected 5p14-p15.1 (10% of primary tumors, 25% of local recurrences) and the most frequent loss, 9p (9p21-pter in 5% of primary tumors; 9p22-pter in 30% of local recurrences). In conclusion, our results show an increase in the number of genetic changes in local recurrences, due to tumor progression. Loss at 9p and gains at 5p and 20q were more frequent in local recurrences, and high-level amplification of 18p11.3 was not detected in any of the primary tumors.

Although all these alterations were not specific to local recurrences, they may represent changes important during tumor progression. PA


Expression of E-Cadherin and p53 Proteins in Human Soft Tissue Sarcomas

Jinyoung Yoo, MD, PhD, Sonya Park;, Chang Suk Kang, MD, PhD, Seok Jin Kang, MD, PhD, and Byung Kee Kim, MD, PhD

From the Department of Pathology, St Vincent's Hospital, Catholic University, Kyungkido, South Korea.

Arch Pathol Lab Med 2002;Vol. 126, No. 1, pp. 33–38. Abstract quote

Objective.—To investigate the expression of E-cadherin in human soft tissue sarcomas and its potential relationship to p53 alterations.

Design.—Tissue sections of 91 soft tissue sarcomas were analyzed by immunohistochemistry for E-cadherin and p53 proteins. Sixty-one tumors were investigated further by the application of the polymerase chain reaction technique and a direct sequence analysis procedure of exons 5 through 8 in the p53 gene.

Setting.—Tertiary-care teaching hospital.

Patients.—Ninety-one patients with soft tissue tumor were treated surgically. Thirteen of these patients had tumors with epithelial differentiation.

Results.—E-Cadherin was expressed at the cell-cell boundaries in 11 samples (12%): 9/13 (69%) with and 2/78 (3%) without histologic evidence of epithelial elements. Other sarcomas were completely negative for E-cadherin. Overexpression of p53 was detected in 30 cases (33%), 7 of which also demonstrated mutations in the p53 gene. The frequencies of p53 abnormalities in tumors with and without epithelial components were 8% and 37%, respectively. No association was established between E-cadherin immunoreactivity and p53 abnormalities (P = .13). Tumor grade strongly correlated with p53 alterations (P = .01), but not with E-cadherin expression (P = .07).

Conclusions.—These data support the involvement of p53 alterations in the pathogenesis of soft tissue sarcomas. The lack of E-cadherin expression in these tumors, with the exception of lesions showing epithelial differentiation, indicates that E-cadherin is not an important factor involved in cell-cell adhesion in sarcomas. It is, however, suggested that E-cadherin may play a role in the development and/or maintenance of epithelial architecture in sarcomas, regardless of p53 status.

Altered expression of g1 regulatory proteins in human soft tissue sarcomas.

Yoo J, Park SY, Kang SJ, Shim SI, Kim BK.

Department of Pathology, St Vincent's Hospital, Catholic University, South Korea.

Arch Pathol Lab Med 2002 May;126(5):567-73 Abstract quote

Context.-Soft tissue sarcomas constitute a heterogeneous group of tumors for which tumorigenesis is not fully understood. Altered cell-cycle regulation may underlie the development and/or progression of human malignancies. However, data concerning the occurrence of cell-cycle aberrations in soft tissue sarcomas are very limited.

Objectives.-To detect the abnormal features of cell-cycle regulatory proteins in soft tissue sarcomas and to determine the potential role of these proteins in clinical behavior.

Design.-The p53 and Rb-cyclin D pathways were investigated by immunohistochemical studies of p53, mdm2, pRb, p16, cyclin D1, and cdk4 proteins, respectively.

Results.-Of the 67 sarcomas analyzed, nuclear accumulation of p53 was detected in 25 samples (37%), and overexpression of mdm2 was found in 16 samples (24%). Both p53 and mdm2 expression correlated with tumor grade. Abnormalities involving the Rb-cyclin D pathway were identified in all of the tumors by the altered expression of either pRb (72%) or p16 (94%). Fourteen (21%) and 64 (96%) cases demonstrated cyclin D1 or cdk4 expression, respectively. Overexpression of cyclin D1 showed an association with pRb and p53. There was no correlation between pRb, p16, cyclin D1, or cdk4 and tumor grade or relapse.

Conclusion.-Disturbance in the cell-cycle regulatory system involving the p53 pathway and the Rb-cyclin D pathway is relatively frequent in soft tissue sarcomas and may be a contributing factor in the tumorigenesis of these tumors. The alterations in the Rb-cyclin D pathway probably constitute an early event, whereas the abnormalities in the p53 pathway seem to be involved in tumor progression. It is noteworthy that cyclin D1 may play a key role in linking both pathways.



Increased risk of soft tissue sarcoma after radiotherapy in women with breast carcinoma.

Huang J, Mackillop WJ.

The Radiation Oncology Research Unit, Department of Oncology, Queen's University, Kingston Regional Cancer Center, Kingston, Ontario, Canada.

Cancer 2001 Jul 1;92(1):172-80 Abstract quote

BACKGROUND: Numerous studies to date have suggested an association between radiation exposure and the development of soft tissue sarcoma. The current study was performed to quantify the risk of soft tissue sarcoma in the vicinity of previously irradiated anatomic regions in women with breast carcinoma.

METHODS: In this population-based, retrospective cohort study, 194,798 women who were diagnosed with invasive breast carcinoma (exclusive of those with distant metastasis) between 1973--1995 were identified, and subsequent soft tissue sarcoma cases utilizing the data from the Surveillance, Epidemiology, and End Results Program (SEER) were ascertained. Poisson regression analysis was used to calculate age standardized incidence ratios (SIR) and to model the influence of radiotherapy (RT) on the relative risk (RR) between the RT and non-RT cohorts.

RESULTS: A total of 54 women in the RT cohort and 81 women in the non-RT cohort subsequently developed soft tissue sarcoma. In the RT cohort, the SIR was 26.2 (95% confidence interval [95% CI], 16.5--41.4) for angiosarcoma and was 2.5 (95% CI, 1.8--3.5) for other sarcomas; in the non-RT cohort, the SIRs were 2.1 (95% CI, 1.0--4.4) and 1.3 (95% CI, 1.0--1.7), respectively. The RT cohort demonstrated a higher risk of developing both angiosarcoma (RR: 15.9; 95% CI, 6.6--38.1) and other sarcomas (RR: 2.2; 95% CI, 1.4--3.3) compared with the non-RT cohort, and the largest increase was observed in the chest wall/breast. The elevated RR was significant even within 5 years of RT, but it reached a maximum between 5--10 years.

CONCLUSIONS: The risk of soft tissue sarcoma, especially angiosarcoma, was elevated after RT in women with breast carcinoma.


Prosthetic implant associated sarcomas: A case report emphasizing surface evaluation and spectroscopic trace metal analysis.

Adams JE, Jaffe KA, Lemons JE, Siegal GP.

Department of Pathology, and the Division of Orthopaedic Surgery, University of Alabama at Birmingham; and Alabama Sports Medicine and Orthopedics Center, Birmingham, AL.

Ann Diagn Pathol 2003 Feb;7(1):35-46 Abstract quote

Advances with implantation of synthetic biomaterials in the setting of orthopedic surgery have clearly resulted in improvements in patient outcomes. However, all implants have been shown to have associated risks. For example, ionic and particulate debris from implants have been shown to engage in biological interactions with the native tissue, and have been associated with a wide range of metabolic, bacteriologic, immunologic, and oncogenic effects.

The propensity of synthetic biomaterials to undergo degradation, producing an inflammatory reaction or other sequelae, has been well recognized. The use of porous implants, which allow for a greater interface area between native tissue and the prosthesis, may magnify the interaction between biologically active tissue and synthetic devices in some situations, giving rise to new and intriguing issues concerning biocorrosion and biocompatibility. In this article, we report the case of a high-grade conventional osteosarcoma occurring at the site of a modular porous-surfaced titanium and cobalt alloy total hip prosthesis 3 years after device implantation.

Detailed spectroscopic trace metal analysis was performed and elevated levels of both vanadium and chromium, but not aluminum, nickel, or titanium were identified in the tumor.

Orthopaedic Implant-Related Sarcoma: A Study of Twelve Cases

Suzanne B. Keel, M.D., Kenneth A. Jaffe, M.D., G. Petur Nielsen, M.D. and Andrew E. Rosenberg, M.D.

The James Homer Wright Pathology Laboratories (SBKGPN, AER), Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; and the Department of Orthopaedic Surgery (KAJ), University of Alabama Medical Center, Birmingham, Alabama

Mod Pathol 2001;14:969-977 Abstract quote

Sarcoma developing in association with a metallic orthopaedic prosthesis or hardware is an uncommon, but well recognized complication.

We review 12 cases of sarcomas arising in bone or soft tissue at the site of orthopaedic hardware or a prosthetic joint.

Nine patients were male, and three were female. Their ages ranged from 18 to 85 (mean 55) years at the time of diagnosis of the malignancy. Five patients had undergone hip arthroplasty for degenerative joint disease, four had been treated with intramedullary nail placement for fracture, two had staples placed for fixation of osteotomy, and one had hardware placed for fracture fixation followed years later by a hip arthroplasty. The time interval between the placement of hardware and diagnosis of sarcoma was known in 11 cases and ranged from 2.5 to 33 (mean 11) years. The patients presented with pain, swelling, or loosening of hardware and were found to have a destructive bone or soft tissue mass on radiography. Two sarcomas were located primarily in the soft tissue and 10 in bone. Seven patients developed osteosarcoma, four malignant fibrous histiocytoma, and one a malignant peripheral nerve sheath tumor. All sarcomas were high grade. Three patients had metastatic disease at the time of diagnosis. Follow-up was available on eight patients: five patients died of disease 2 months to 8 years (mean 26 months) after diagnosis; two patients died without evidence of disease 7 and 30 months after diagnosis; and one patient is alive and free of disease 8 years after diagnosis.

Sarcomas that occur adjacent to orthopaedic prostheses or hardware are of varied types, but are usually osteosarcoma or malignant fibrous histiocytoma. They behave aggressively and frequently metastasize. Clinically, they should be distinguished from non-neoplastic reactions associated with implants, such as infection and a reaction to prosthetic wear debris.


Soft tissue tumors following traumatic injury: two observations of interest for the medicolegal causality.

Delpla PA, Rouge D, Durroux R, Rouquette I, Arbus L.

Unite Medico-Judiciaire, CHU Rangueil, Toulouse, France.

J Forensic Med Pathol 1998 Jun;19(2):152-6 Abstract quote

Two cases of tumors of the soft tissues developing at the site of a previous traumatic injury occurring a few years earlier are reported. One was finally diagnosed as aggressive fibromatosis and the other as low-grade fibrosarcoma.

Among the pathogenic mechanisms and the etiologic factors involved in such tumors, the posttraumatic causality is discussed, and in addition to the initial trauma, the role of iterative surgery in the first case and mineral muscular inclusions in the second case are examined. The different therapeutic approaches of such lesions are also reviewed.



Practical Application of Molecular Genetic Testing as an Aid to the Surgical Pathologic Diagnosis of Sarcomas: A Prospective Study

D. Ashley Hill, M.D.; Maureen J. O'Sullivan, M.D.; Xiaopei Zhu, M.D.; Robin T. Vollmer, M.D.; Peter A. Humphrey, M.D., Ph.D.; Louis P. Dehner, M.D.; John D. Pfeifer, M.D., Ph.D.

American Journal of Surgical Pathology 2002; 26(8):965-977 Abstract quote

The strong correlation of specific reciprocal translocations with individual tumor types and the demonstration that polymerase chain reaction (PCR)-based methods can detect translocations in tissue samples have stimulated interest in the role of molecular genetic testing in diagnostic surgical pathology.

To evaluate the clinical utility of PCR-based molecular analysis of soft tissue neoplasms in routine surgical pathology, 131 consecutive soft tissue tumors submitted for molecular genetic testing at a tertiary care teaching hospital were prospectively analyzed over a 36-month period. RT-PCR was used to test tumor RNA for fusion transcripts characteristic of malignant round cell tumors (including Ewing sarcoma/primitive neuroectodermal tumor, desmoplastic small round cell tumor, and alveolar rhabdomyosarcoma), spindle cell tumors (including synovial sarcoma and congenital fibrosarcoma), and fatty tumors (myxoid liposarcoma). DNA sequence analysis was used to confirm the identity of all PCR products, and the PCR results were compared with the histopathologic diagnosis.

We found that sufficient RNA for RT-PCR-based testing was recovered from 96% of the 131 cases and the percentage of tumors that tested positive for the associated characteristic fusion transcript was in general agreement with those reported in the literature. DNA sequence analysis of PCR products identified both variant transcripts and spurious PCR products, underscoring the value of product confirmation steps when testing formalin-fixed, paraffin-embedded tissue. Only in rare cases did testing yield a genetic result that was discordant with the histopathologic diagnosis.

We conclude that PCR-based testing is a useful adjunct for the diagnosis of malignant small round cell tumors, spindle cell tumors, and other miscellaneous neoplasms in routine surgical pathology practice.


CHIPing Soft Tissue Tumors: Will the Paradigms Be Changed?: On: Nielsen T, West R, Linn S, et al. Molecular characterization of soft tissue tumors: a gene expression study. Lancet 2002; 359:1301-1307.

Oliveira AM, Fletcher JA.

Adv Anat Pathol 2003 Jan;10(1):1-7 Abstract quote

Soft tissue tumor pathology is an actively evolving field. Novel clinicopathologic entities are reported each year, and ongoing histological, immunohistochemical, and molecular reappraisals lead to evolution in the categories to which each tumor type is assigned. In some cases, the advent of new nonmorphological information suggests that some soft tissue tumors, previously regarded as different, are in fact closely related entities in a common spectrum of disease. Needless to say, sometimes there are substantial differences of opinion, amongst experts, as to which tumor types should be regarded as distinct, and which are closely related to each other.

Therefore, critical and ongoing reassessment of the myriad of soft tissue tumor categories is intrinsic to the field. Most such evaluations are based primarily on skillful histopathologic assessment integrated with judicious application of ancillary techniques.

Recently, Nielsen et al. explored the intricate lattice of soft tissue tumors using cDNA microarray technology. cDNA expression profiles of different soft tissue tumors were consistent with current morphology-based categorizations. Importantly, the profiles revealed new constellations of tumor markers that should lead to refinements in soft tissue tumor classification, and ultimately to predictors of prognosis and therapeutic response.



Primary Sarcomas of the Brain and Spinal Cord: A Study of 18 Cases

Andre M. Oliveira, M.D.; Bernd W. Scheithauer, M.D.; Diva R. Salomao, M.D.; Joseph E. Parisi, M.D.; Peter C. Burger, M.D.; Antonio G. Nascimento, M.D.

Am J Surg Pathol2002; 26(8):1056-1063 Abstract quote

Primary sarcomas of the central nervous system are exceedingly rare.

We reviewed the clinicopathologic features of 18 primary central nervous system sarcomas diagnosed from 1959 through 1999. Median age at diagnosis of the nine female and nine male patients was 28 years (range 3-63 years). Median tumor size was 4 cm (range 1.3-8 cm). Fifteen tumors arose in the cerebrum (83%), two in the cerebellum, and one in the spinal cord.

Histopathologically, the most common tumor types included fibrosarcoma (six), malignant fibrous histiocytoma (five), and undifferentiated sarcoma (three). Immunohistochemical and ultrastructural studies supported the histologic diagnosis in 17 and six cases, respectively. All patients had subtotal to gross total tumor resection; 16 also received radiotherapy and/or chemotherapy. Twelve tumors (67%) were high-grade. Follow-up was obtained in all instances (median 2.3 years). Nine patients died of the disease, eight with high-grade tumors. Survival at 5 years for patients with high-grade tumors was 28% compared with 83% for those with low-grade neoplasms (p = 0.03).

Primary central nervous system sarcomas most often affect young and middle-aged adults. Most involve the cerebrum and show fibrous, "fibrohistiocytic," or no specific differentiation. The prognosis for high-grade sarcomas seems better than that for glioblastoma multiforme.


Treatment Effects in Pediatric Soft Tissue and Bone Tumors
Practical Considerations for the Pathologist

Cheryl M. Coffin, MD, Amy Lowichik, MD, PhD, and Holly Zhou, MD
Am J Clin Pathol 2005;123:75-90 Abstract quote

Dramatic improvements in survival for children with cancer have led to increased numbers of posttreatment pathologic specimens, particularly in bone and soft tissue sarcomas. Current therapeutic protocols in North America require specific pathologic classification and stratify patients based on clinical, biologic, and pathologic features. For osteosarcoma, the pathologic response to therapy predicts prognosis and modifies the treatment regimen. Ongoing studies aim to assess the response to therapy and outcome in other types of soft tissue and bone tumors.

The pathologic evaluation of pretreatment and posttreatment specimens is critical for therapeutic decisions and prognostic assessment. A standardized approach to posttherapy pathologic specimens, with attention to appropriate use of ancillary tests, and assessment of clinical and biologic significance of therapy-induced pathologic changes has significance for patient management and treatment protocols.

Consultative (Expert) Second Opinions in Soft Tissue Pathology Analysis of Problem-Prone Diagnostic Situations

Zoya K. Arbiser, MD, Andrew L. Folpe, MD, and Sharon W. Weiss, MD

Am J Clin Pathol 2001;116:473-476 Abstract quote

We reviewed 500 consecutive soft tissue lesions referred for expert consultation to determine types of lesions and/or situations in which major discrepancies occur.

Of 266 cases (53.2%) accompanied by a diagnosis, essential agreement with the second opinion was noted in 68%, minor discrepancy in 7%, and major discrepancy in 25%. The 65 major discrepancies were distributed proportionally to the referring sources and could be divided into 4 groups: benign mesenchymal lesions diagnosed as sarcomas (45%), sarcomas diagnosed as benign tumors (23%), nonmesenchymal lesions diagnosed as sarcoma (20%), and major grading discrepancies (12%). Relatively few lesions accounted for a major proportion of major discrepancies. Problematic lesions were lipoma and fasciitis and their variants and desmoplastic-neurotropic melanoma. Needle biopsy specimens were somewhat more likely to be associated with a discrepant opinion. With the exception of nonmesenchymal lesions, the diagnosis for all major discrepant cases could be made on the basis of the H&E-stained slides, suggesting that failure to perform immunostains did not account for discrepancies.

Lack of familiarity with rare or unusual lesions is probably more significant in explaining diagnostic discrepancies than is the increasing use of needle biopsy or the failure to perform immunohistochemical analysis.

Validity and reproducibility of histologic diagnosis and grading for adult soft-tissue sarcomas

Tadashi Hasegawa, MD
Seiichiro Yamamoto, PhD
Takayuki Nojima, MD
Takanori Hirose, MD
Takashi Nikaido, MD
Katsushige Yamashiro, MD
Yoshihiro Matsuno, MD

Hum Pathol 2002;33:111-115. Abstract quote

Soft-tissue sarcomas in adults show great variations in histologic type and grade. A valid and reproducible prognostication system is needed to select patients with soft-tissue sarcomas who could benefit from adjuvant chemotherapy.

This study was conducted to assess the validity and reproducibility of diagnosis of the histologic type, MIB-1 grade, and mitosis grade, as well as of the 3 components of these grading systems. MIB-1 grade is a recently proposed grading system for predicting the prognosis of patients with adult soft-tissue sarcomas on the basis of 3 criteria (tumor differentiation, necrosis, and MIB-1 score) and replaces the mitotic count in the French system with MIB-1 immunohistochemical staining. Four surgical pathologists from 4 institutions who had experience in diagnostic soft-tissue tumor pathology reviewed 130 cases of soft-tissue sarcoma and independently determined histologic type and grade. The validity of histologic diagnosis was measured by sensitivity and specificity, and that of grading was measured by statistics and percentage agreement with the diagnosis of the expert panel at the National Cancer Center, which was defined as a gold standard. Interobserver reproducibility was measured by and by percentage agreement between the diagnoses of the 4 pathologists. The validity of the diagnosis of histologic type was high for synovial sarcoma, small round-cell sarcoma, and liposarcoma (sensitivity 89% to 100%; specificity, 98% to 100%) but low for malignant fibrous histiocytoma (MFH) and spindle-cell sarcoma (73% to 75%; 93% to 95%). For the grading, the validity of the MIB-1 grade was substantial ( = 0.68; agreement, 79%) and higher than that of the mitosis grade (0.54; 69%). The most valid component was tumor differentiation ( = 0.79), followed by tumor necrosis (0.66), MIB-1 score (0.59), and mitotic score (0.37). Interobserver reproducibility of histologic diagnosis was high for small round-cell sarcoma, synovial sarcoma, and liposarcoma ( = 0.92, 0.90, 0.87; percentage agreement = 99%, 97%, 96%, respectively); for grading, reproducibility was highest for tumor differentiation (0.78; 87%) and second highest for MIB-1 grade (0.68; 79%).

We conclude that diagnosis of the type of soft-tissue sarcoma for synovial sarcoma, small round-cell sarcoma, and liposarcoma and the MIB-1 grading system based on tumor differentiation are highly valid and reproducible among Japanese pathologists who are familiar with the grading system, whereas re-evaluation of histologic criteria is essential for other histologic types such as MFH and spindle-cell sarcoma.

Fibrous hamartoma of infancy: an Italian multi-institutional experience.

Carretto E, Dall'Igna P, Alaggio R, Siracusa F, Granata C, Ferrari A, Cecchetto G.

Division of Paediatric Surgery, Department of Paediatrics, University of Padua, Padua, Italy.

J Am Acad Dermatol. 2006 May;54(5):800-3. Abstract quote  

BACKGROUND: Fibrous hamartoma (FH) of infancy is a benign mesenchymal tumor, occurring as a superficial mass. Complete excision is curative.
OBJECTIVE AND METHODS: The clinical features and treatment results of 18 children with FH are described.
RESULTS: Local excision was the most common procedure. Surgery was radical in 10 patients, with microscopic residual disease in 6; all of them are alive with no evidence of disease 2 to 49 months after diagnosis. One patient, treated with a local reexcision for macroscopic residual disease (and chemotherapy for a synchronous desmoid fibromatosis) is well 83 months after diagnosis; the last patient, with a lesion of the labia majora, only underwent biopsy and is doing well, awaiting plastic surgery.
LIMITATIONS: The results did not reach statistical significance due to difficulties in collecting cases.
CONCLUSIONS: FH should be treated by complete excision; in our experience a nonradical excision was also able to achieve the cure. An aggressive approach should be avoided, as the overall prognosis is excellent.
Subdermal fibrous hamartoma of infancy: pathology of 40 cases and differential diagnosis.

Sotelo-Avila C, Bale PM.

Histopathology Department, Royal Alexandra Hospital for Children, Sydney, Australia.

Pediatr Pathol. 1994 Jan-Feb;14(1):39-52. Abstract quote  

Forty subdermal fibrous hamartomas of infancy occurred in 29 males and 11 females who were 7 months to 4 years of age at surgery.
At least 4 were congenital. The lesions were situated in axilla, chest wall, and breast (17 cases); abdominal wall, inguinal region, and scrotum (8); buttock and lower limb (6); upper limb (4); neck and scalp (3); and low back (2). They were 0.7 to 10 cm, ill defined, and five underwent reexcision, which was curative in all. All had the characteristic mixture of fibrous and adipose tissue and nests of immature mesenchyme in different proportions, and nearly all showed lymphocytes and thick patent capillaries in the mesenchyme.
However, the fibrous component varied considerably in amount, pattern, and cellularity, so that lesions that were typical in some areas, in others resembled collagenizing vascular granulation tissue, deep fibrous histiocytoma, or fibromatosis. Those in which adipose tissue predominated were distinguished from fibrolipoma by foci of immature mesenchyme and from lipoblastoma by their lack of a capsule and of a lobular pattern.
Clinicopathological features of untreated fibrous hamartoma of infancy.

Efem SE, Ekpo MD.

University Department of Surgery, University Teaching Hospital, Calabar Cross River State, Nigeria.

J Clin Pathol. 1993 Jun;46(6):522-4. Abstract quote  

AIM--To study the clinicopathological features of fibrous hamartoma of infancy in Nigerian children.

METHODS--Six children aged between 6 months and 10 years were studied. All specimens were stained with haemotoxylin and eosin and examined routinely. The children were followed up for between one and three years.

RESULTS--In four of the children lesions were present at birth; in the other two they appeared by the age of 1 year. Some of the children had had the lesion for between three and 10 years. All lesions were located in the subcutis. They were solitary and varied in size and shape. They had grown rapidly up to the age of 5, after which growth decelerated, but did not stop or regress. The younger the child the less clearly demarcated was the tumour on the deep surface. In the older children the capsule was more developed.

CONCLUSIONS--Fibrous hamartoma of infancy is rare, but it is important for clinicians to know that it is benign and readily amenable to treatment.
Superficial acral fibromyxoma: clinical and pathological features.

Andre J, Theunis A, Richert B, de Saint-Aubain N.

Department of Dermatology, CHU Saint-Pierre, 1000 Brussels, Belgium.
Am J Dermatopathol. 2004 Dec;26(6):472-4. Abstract quote  

Superficial acral fibromyxoma (SAFM) is a recently recognized myxoid tumor that usually occurs on the fingers and toes of middle-aged adults. We report on the typical case of a 50-year-old woman with a SAFM in the right big toenail that had been slowly growing for more than 10 years. To our knowledge, this case is the first reported case for which clinical pictures are available.

Histologically, the lesion was non-encapsulated and was composed of stellate and spindle cells, arranged in a myxoid matrix. No atypia or mitotic figures were found. Neoplastic cells showed positive staining for CD34 and negative staining for epithelial membrane antigen (EMA), actin, desmin, keratins, S100 protein, CD99, and HMB45.

Differential diagnosis encompasses benign and malignant myxoid and spindle cells tumors such as myxoid neurofibroma, sclerosing perineurioma, superficial angiomyxoma, and several low-grade myxoid sarcomas.

Cartilaginous differentiation in peritoneal tissues: a report of two cases and a review of the literature.

Fadare O, Bifulco C, Carter D, Parkash V.

Departments of Pathology, Yale University School of Medicine (OF, DC, VP), New Haven, Connecticut and Istituto Nazionale Tumori (CB), Milano, Italy.

Mod Pathol 2002 Jul;15(7):777-80 Abstract quote

Two cases of cartilaginous differentiation of the peritoneum not associated with an intraabdominal malignancy are described.

This is the first detailed report of cartilaginous metaplasia of the peritoneum. The patients were female, ages 53 (Patient 1) and 77 years (Patient 2). Prior medical histories were significant for a culdotomy (to drain pelvic abscesses associated with pelvic inflammatory disease) in Patient 1 and for an open abdominal surgery in Patient 2. The peritoneal lesions were incidental findings in both cases. In Patient 1, surgery was performed for a septated ovarian cyst; the other patient underwent surgery to relieve obstructive bowel symptoms. In Patient 1, multiple firm, white lesions ranging from 2.0 to 7.0 mm were present on the serosal surfaces and the mesenteries of the small and large bowel. In Patient 2, a single firm, white lesion measuring 2 cm in maximum dimension was removed from the mesentery of the ileum.

Microscopically, the lesions consisted of small nodules of mature hyaline cartilage surrounded by nondescript fibrous tissue and covered by mesothelium. There was no foreign body giant cell reaction, inflammation, or other reactive changes in the surrounding adipose tissue.

These may represent metaplastic lesions of the secondary mullerian system, or a unique peritoneal response to previous surgical manipulation. Alternatively, these may represent benign neoplastic lesions (chondroma) of the submesothelium.



Alpha-inhibin immunoreactivity in soft-tissue neoplasia.

Schraith DF, Hahm GK, Niemann TH, DeYoung BR.

Department of Pathology, University of Iowa Hospitals and Clinics, Iowa City, Iowa 52242, USA.

Mod Pathol. 2003 Dec;16(12):1205-9. Abstract quote  

Antibodies directed against alpha-inhibin have been previously reported as staining both sex cord-stromal neoplasms as well as adrenal cortical tumors.

This relatively restricted immunoreactivity pattern is useful in the assessment of retroperitoneal masses, especially in a setting of limited tissue (e.g., needle biopsy). However, no study to date has evaluated alpha-inhibin immunoreactivity in soft-tissue neoplasms, which frequently enter the differential diagnosis of retroperitoneal masses. We investigate the incidence of alpha-inhibin staining in a variety of soft-tissue neoplasms by using formalin-fixed, paraffin-embedded tissue sections from 282 previously classified soft-tissue neoplasms with anti-alpha-inhibin (Serotec, 1:75). A modified avidin-biotin complex method was used after heat-induced epitope retrieval. Cytoplasmic granular staining was considered positive.

Of the 282 tumors studied, a total of 8 (2.8%) demonstrated positive staining with anti-alpha-inhibin antibody. These included 4 of 25 liposarcomas (16%), 2 of 18 angiosarcomas (11%), 1 of 48 lipomas (2.1%), and 1 of 1 rhabdomyoma (100%). Negative staining was noted among hemangiomas (0/28), schwannomas (0/32), leiomyomas (0/16), fibrosarcomas (0/2), fibromas (0/11), dermatofibromas (0/9), neurofibromas (0/6), synovial sarcomas (0/15), rhabdomyosarcomas (0/10), Triton tumors (0/2), and malignant fibrous histiocytomas (0/59).

We conclude that rare soft-tissue tumors, especially those exhibiting either lipomatous or vascular differentiation, demonstrate alpha-inhibin immunoreactivity. These findings re-emphasize the need for a well-construed antibody panel when immunohistochemical methods are employed in the evaluation of retroperitoneal neoplasms. However, the rarity of alpha-inhibin expression by soft-tissue neoplasms provides further support for its overall specificity as a marker of adrenal cortical differentiation in the biopsy evaluation of a retroperitoneal mass.
Expression of anaplastic lymphoma kinase in soft tissue tumors: An immunohistochemical and molecular study of 249 cases.

Li XQ, Hisaoka M, Shi DR, Zhu XZ, Hashimoto H.
Hum Pathol. 2004 Jun;35(6):711-21. Abstract quote  

Although anaplastic lymphoma kinase (ALK) has been considered a diagnostic marker specifying a subset of anaplastic large cell lymphomas and inflammatory myofibroblastic tumors (IMTs), the existence of this receptor in some other mesenchymal malignancies has been recently reported.

We examined a wider variety of soft tissue tumors to further advance the survey of ALK status in mesenchymal lesions. ALK protein expression was evaluated immunohistochemically with 2 specific antibodies (ALK1 and 5A4) in 249 benign and malignant soft tissue tumors, and the expression of ALK transcripts and 8 types of ALK fusion transcripts was assessed using reverse transcription-polymerase chain reaction (RT-PCR) in 165 and 100 tumors, respectively. Moreover, ALK gene status was analyzed by interphase fluorescence in situ hybridization (FISH) in 17 tumors with ALK expression. Immunohistochemically, ALK protein was detected in 69 cases (28%), including IMTs (4 of 4), rhabdomyosarcomas (4 of 7), various lipogenic tumors (35 of 65), Ewing's sarcoma/peripheral primitive neuroectodermal tumors (6 of 10), malignant fibrous histiocytomas (8 of 37), leiomyosarcomas (3 of 18), and other non-IMT tumors (9 of 108); however, most of these, except the IMTs, displayed merely low-level expression. Although ALK transcripts were identified in 85 (52%) of the 165 cases examined by RT-PCR, the full-length (wild-type) ALK, rather than the truncated or chimeric forms detected in IMTs, predominated in most non-IMT tumors. Except for 2 IMTs, all cases with the expression of ALK messages displayed no detectable ALK fusion transcripts.

More than 67% of the cases analyzed by both RT-PCR and immunohistochemical assays demonstrated concordant results. ALK gene amplification was found in 4 non-IMT tumors (2 leiomyosarcomas and 1 case each of rhadomyosarcoma and malignant fibrous histiocytoma) analyzed by FISH, and the rearrangement of this gene was identified in 2 IMTs.

The current data expands the variety of non-IMT soft tissue tumors with ALK expression, and warrants further investigation of its underlying molecular mechanisms.
Apo D in Soft Tissue Tumors: A Novel Marker for Dermatofibrosarcoma Protuberans.

West RB, Harvell J, Linn SC, Lui CL, Prapong W, Hernandez-Boussard T, Montgomery K, Nielsen TO, Rubin BP, Patel R, Goldblum JR, Brown PO, Van De Rijn M.

Departments of *Pathology and paragraph signBiochemistry and Howard Hughes Medical Institute, Stanford University Medical Center, Stanford, CA; daggerDepartment of Pathology and Genetic Pathology Evaluation Centre, Vancouver General Hospital, Vancouver, British Columbia, Canada; double daggerDepartment of Anatomical Pathology, University of Washington Medical Center, Seattle, WA; and section signDepartment of Anatomic Pathology, Cleveland Clinic Foundation, Cleveland, OH.

Am J Surg Pathol. 2004 Aug;28(8):1063-1069. Abstract quote  

Using gene microarray expression profiling, we previously found that apolipoprotein D (Apo D) was highly expressed in dermatofibrosarcoma protuberans (DFSP).

In this study, we confirm that Apo D is highly and relatively specifically expressed in DFSP using immunohistochemistry. A tissue microarray containing 421 soft tissue tumors was constructed and stained with antibodies against Apo D and CD34. Cytoplasmic immunostaining for Apo D was found in 9 of 10 typical DFSPs. In addition, 3 of 3 Bednar tumors and 2 of 3 giant cell fibroblastomas stained in conventional sections. In contrast, Apo D was immunoreactive in only a very small subset of a diverse collection of other soft tissue tumors, including Malignant Fibrous Histiocytoma (MFH), glomus tumor, neurofibroma, and malignant peripheral nerve sheath tumors. Immunostains for Apo D were negative in conventional sections of 16 fibrous histiocytomas, and an additional 12 variants of fibrous histiocytoma. Digital images of all immunohistochemical and hematoxylin and eosin tissue microarray stains are available at the accompanying website (http://microarray-pubs.stanford.edu/tma_portal/apod/).

We conclude that Apo D is strongly expressed in DFSPs and neural lesions and may be useful in differentiating DFSP from fibrous histiocytoma.

Epithelial-Type and Neural-Type Cadherin Expression in Malignant Noncarcinomatous Neoplasms With Epithelioid Features That Involve the Soft Tissues
William B. Laskin, MD and Markku Miettinen, MD

From the Department of Pathology, Northwestern University Medical School, Chicago, Ill (Dr Laskin); and the Department of Soft Tissue Pathology, Armed Forces Institute of Pathology, Washington, DC (Dr Miettinen)

Arch Pathol Lab Med 2002;126, No. 4, pp. 425–431. Abstract quote

Context.—Transmembrane adhesion molecules, epithelial-type cadherin (ECAD) and neural-type cadherin (NCAD), help in regulating transformations between epithelial and mesenchymal cells in the developing embryo and in maintaining the epithelioid phenotype. Consequently, the presence of epithelioid cells in certain malignant noncarcinomatous neoplasms raises speculation that the expression of ECAD and NCAD in these neoplasms may have diagnostic significance.

Objective.—To investigate the utility of ECAD and NCAD immunoexpression in distinguishing malignant (noncarcinomatous) neoplasms with epithelioid features that involve the soft tissues.

Design.—Membranous immunoreactivity of anti-ECAD and anti-NCAD was evaluated on archived cases selected from the files of the Armed Forces Institute of Pathology.

Results.—Epithelial-type cadherin was found in biphasic synovial sarcoma (35 of 35 cases), malignant melanoma (13/21), monophasic fibrous synovial sarcoma (13/26), clear cell sarcoma (4/9), poorly differentiated synovial sarcoma (3/13), diffuse mesothelioma (4/20), malignant epithelioid peripheral nerve sheath tumor (1/6), and epithelioid sarcoma (5/62). Neural-type cadherin was observed in chordoma (11/11), biphasic synovial sarcoma (30/35), diffuse mesothelioma (14/20), malignant melanoma (14/25), epithelioid sarcoma (24/63), epithelioid angiosarcoma (1/4), poorly differentiated synovial sarcoma (2/13), clear cell sarcoma (1/10), and monophasic fibrous synovial sarcoma (1/26). Eighteen cases of primary cutaneous squamous cell carcinomas all tested positive for ECAD, whereas NCAD was focally observed in 5 cases. No expression of either molecule was observed in cases of epithelioid hemangioendothelioma (n = 9), alveolar soft part sarcoma (n = 8), and extraskeletal myxoid chondrosarcoma (n = 7).

Conclusions.—Epithelial-type and neural-type cadherins are found in a variety of noncarcinomatous neoplasms with epithelioid features that involve the soft tissues and can be utilized, in association with other immunomarkers, in distinguishing chordoma (100% NCAD) from extraskeletal myxoid chondrosarcoma and conventional chondrosarcoma of bone (0% NCAD), squamous cell carcinoma (100% ECAD) from epithelioid sarcoma (8% ECAD), and biphasic synovial sarcoma (100% ECAD) from diffuse mesothelioma (20% ECAD).


Caveolin Expression is Common among Benign and Malignant Smooth Muscle and Adipocyte Neoplasms

Ilene Bayer-Garner, M.D., Michael Morgan, M.D. and Bruce R. Smoller, M.D.

Departments of Pathology (IB-G, BRS) and Dermatology (BRS), University of Arkansas for Medical Sciences, Little Rock, Arkansas; and Department of Pathology (MM), James Haley Veterans Administration Hospital, Tampa, Florida

Mod Pathol 2002;15:1-5 Abstract quote

The caveolins belong to a newly described group of membrane-scaffolding proteins. Their presence in benign endothelial cells has been used to discriminate benign from malignant vascular neoplasms. The extent of caveolin expression in cutaneous mesenchymal neoplasms has not yet been evaluated, and thus the diagnostic utility of these antibodies is not yet known. In our study, we immunohistochemically examined a spectrum of tumors derived from smooth muscle and adipocytes for caveolin expression.

We found that both benign and malignant smooth muscle tumors and tumors comprised of adipocytes expressed caveolins. The presence of this protein in a range of mesenchymal neoplasms is important to know about as this decreases the reported specificity of a positive finding. It is doubtful that caveolin down-regulation contributes to the pathogenesis of liposarcomas and leiomyosarcomas. This finding also may suggest a common origin between endothelial cells and other mesenchymal cells.


Immunohistochemical Staining for KIT (CD117) in Soft Tissue Sarcomas Is Very Limited in Distribution

Jason L. Hornick, MD, PhD, and Christopher D.M. Fletcher, MD, FRCPath

Am J Clin Pathol 2002;117:188-193 Abstract quote

We performed immunohistochemical analysis for KIT in 365 soft tissue sarcomas.

Most tumors evaluated were completely negative for KIT, including all cases of leiomyosarcoma, rhabdomyosarcoma, myxofibrosarcoma, liposarcoma, solitary fibrous tumor, synovial sarcoma, dermatofibrosarcoma protuberans, schwannoma, malignant peripheral nerve sheath tumor, clear cell sarcoma, low-grade endometrial stromal sarcoma, and follicular dendritic cell sarcoma.

Tumors showing occasional immunoreactivity for KIT included extraskeletal myxoid chondrosarcoma (2/20), Ewing sarcoma/malignant primitive peripheral neuroectodermal tumor (4/20), melanotic schwannoma (3/5), metastatic melanoma (4/20), and angiosarcoma (5/20). In most cases, staining for KIT was focal.

Rare tumor cells showing KIT positivity were identified in a small number of other tumors.

This study demonstrates very limited expression of KIT in soft tissue tumors other than gastrointestinal stromal tumors and underscores the discriminatory value of KIT immunohistochemical analysis for differential diagnosis. As some of these findings differ markedly from previous reports, it is evident again that variations in immunohistochemical technique can lead to major discrepancies in positive staining. Since treatment eligibility for selective tyrosine kinase inhibitors such as STI571 hinges on positive immunostaining, standardization and reproducibility of meaningful results are critically important.

Matrix metalloproteinase expression is related to angiogenesis and histologic grade in spindle cell soft tissue neoplasms of the extremities.

Roebuck MM, Helliwell TR, Chaudhry IH, Kalogrianitis S, Carter S, Kemp GJ, Ritchie DA, Jane MJ, Frostick SP.

Department of Musculoskeletal Science, University of Liverpool, Liverpool, England.
Am J Clin Pathol. 2005 Mar;123(3):405-14. Abstract quote  

We defined the immunocytochemical expression of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in benign soft tissue neoplasms, fibromatoses, and sarcomas, together with the activity of gelatinase MMPs and TIMPs measured by zymography and reverse zymography in a subset of cases.

The most strongly expressed MMP in all tumors was MMP-1, with weaker expression of MMP-10, MMP-11, and MMP-14 in most tumors. Nuclear expression of MMP-1, MMP-8, and MMP-13 was an unusual feature. TIMP-2 was expressed in all tumors, with stronger expression in fibromatoses than in sarcomas. Fibromatoses and high-grade sarcomas showed greater MMP-1 expression than other groups, and endothelial MMP-2 expression was more extensive in sarcomas.

Differences in MMP and TIMP expression might be linked to the biologic behavior of soft tissue neoplasms. The activation of endothelial MMP-2 linked to widespread MMP-14 expression provides a mechanism for sarcomas to modulate their matrix and facilitate angiogenesis.
Reproducibility of MDM2 and CDK4 Staining in Soft Tissue Tumors

Matthieu Bui Nguyen Binh, MD, etal.
Am J Clin Pathol 2006;125:693-697
Abstract quote

MDM2 and CDK4 immunostaining can be useful adjuncts in diagnosing liposarcoma among soft tissue neoplasms.

We examined the reproducibility of MDM2 and CDK4 staining between 2 laboratories and between tissue microarrays and whole tissue sections. Sixty-two soft tissue tumors were immunostained at the Bergonié Institute, Bordeaux, France, and the Curie Institute, Paris, France. We also examined 203 soft tissue neoplasms on standard tissue sections and tissue microarrays.
There was high concordance of results obtained from the 2 laboratories (with 2 different pathologists) for MDM2 (k, 0.93) and CDK4 (k, 0.8) staining. There also was excellent concordance between results on tissue microarray and on whole tissue sections for MDM2 (k, 0.80) and CDK4 (k, 0.93).

Immunostaining for MDM2 and CDK4 is a reproducible technique that may be exported to different laboratories for routine use. Tissue microarray is indicated for studying large series.

Detection and diagnostic utilization of placental alkaline phosphatase in muscular tissue and tumors with myogenic differentiation.

Goldsmith JD, Pawel B, Goldblum JR, Pasha TL, Roberts S, Nelson P, Khurana JS, Barr FG, Zhang PJ.


Am J Surg Pathol 2002 Dec;26(12):1627-33 Abstract quote

Placental alkaline phosphatase (PLAP) is normally produced by primordial germ cells and syncytiotrophoblasts, and the detection of its expression has been useful in the diagnosis of germ cell tumors. We have recently observed PLAP immunoreactivity in normal human adult and fetal muscle tissue. Based on this observation, we explored the possible role of PLAP in the diagnosis of soft tissue tumors. A total of 271 tumors were studied. These included tumors with myogenic, neural, fibrous, myofibroblastic, lipomatous, neuroepithelial, perivascular, and epithelial differentiation.

A formalin-fixed, paraffin-embedded section from each tumor was stained with PLAP monoclonal antibody using standard immunohistochemical methods preceded by antigen retrieval. In addition, western blotting with PLAP monoclonal antibodies was performed on fresh samples from a uterine leiomyoma, grossly normal myometrium, and placenta. Also, formalin-fixed sections of fetal skeletal muscle were labeled with double immunohistochemistry techniques using antibodies to myogenin and PLAP.

Cytoplasmic PLAP reactivity was detected in all leiomyomas and rhabdomyosarcomas (100%), 7 of 15 (46%) leiomyosarcomas, 15 of 19 (79%) desmoplastic small round cell tumors, 2 of 15 (13%) gastrointestinal stromal tumors, 1 of 8 (13%) Wilms' tumors, 1 of 9 synovial sarcomas (9%), and 2 of 7 (29%) myofibroblastic tumors. No PLAP reactivity was detected in hyperplastic scars, nodular fasciitis, or the other remaining soft tissue and epithelial tumors. Double immunohistochemistry studies showed coexpression of myogenin and PLAP in fetal skeletal muscle cells, and western blot analysis showed a 70-kDa band in samples derived from grossly normal placenta, benign myometrium, and a uterine leiomyoma. PLAP immunoreactivity is detected in soft tissue tumors with known myogenic differentiation. PLAP immunoreactivity seems to relate to the degree of myogenic differentiation in soft tissue tumors and is more frequently expressed in cells with skeletal muscle differentiation and least in those with myofibroblastic features.

The biologic function of PLAP in muscle and tumors with myogenic differentiation is unknown and merits further investigation. In addition to its role as a germ cell marker, PLAP may also be used as a myogenic marker in the diagnosis of soft tissue tumors.


Myxoid nodular fasciitis
Myxoid neurofibroma
Dermal myxoma
Dermal nerve sheath myxoma
Intramuscular myxoma
Superficial angiomxyoma
Ossifying fibromyxoid tumor

Aggressive angiomyxoma
Juxta-articular myxoma

Myxoid liposarcoma
Extraskeletal myxoid chondrosarcoma
Myxoid leiomyosarcoma
Myxoid malignant peripheral nerve sheath tumor
Myxoid dermatofibrosarcoma protuberans
Low grade fibromyxoid sarcoma



Prognostic factors for children and adolescents with surgically resected nonrhabdomyosarcoma soft tissue sarcoma: an analysis of 121 patients treated at St Jude Children's Research Hospital.

Spunt SL, Poquette CA, Hurt YS, Cain AM, Rao BN, Merchant TE, Jenkins JJ, Santana VM, Pratt CB, Pappo AS.

Departments of Hematology/Oncology, Biostatistics and Epidemiology, Surgery, Radiation Oncology, and Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105-2794, USA.

J Clin Oncol 1999 Dec;17(12):3697-705 Abstract quote

PURPOSE: The rarity and heterogeneity of pediatric nonrhabdomyosarcoma soft tissue sarcoma (NRSTS) has precluded meaningful analysis of prognostic factors associated with surgically resected disease. To define a population of patients at high risk of treatment failure who might benefit from adjuvant therapies, we evaluated the relationship between various clinicopathologic factors and clinical outcome of children and adolescents with resected NRSTS over a 27-year period at our institution.

PATIENTS AND METHODS: We analyzed the records of 121 consecutive patients with NRSTS who underwent surgical resection between August 1969 and December 1996. Demographic data, tumor characteristics, treatment, and outcomes were recorded. Univariate and multivariate analyses of prognostic factors for survival, event-free survival (EFS), and local and distant recurrence were performed.

RESULTS: At a median follow-up of 9.2 years, 5-year survival and EFS rates for the entire cohort were 89% +/- 3% and 77% +/- 4%, respectively. In univariate models, positive surgical margins (P =.004), tumor size > or = 5 cm (P <.001), invasivene (P =.002), high grade (P =.028), and intra-abdominal primary tumor site (P =.055) adversely affected EFS. All of these factors except invasiveness remained prognostic of EFS and survival in multivariate models. Positive surgical margins (P =.003), intra-abdominal primary tumor site (P =.028), and the omission of radiation therapy (P =.043) predicted local recurrence, whereas tumor size > or = 5 cm (P <.001), invasiveness (P <.001), and high grade (P =.004) predicted distant recurrence.

CONCLUSION: In this largest single-institution analysis of pediatric patients with surgically resected NRSTS, we identified clinicopathologic features predictive of poor outcome. These variables should be prospectively evaluated as risk-adapted therapies are developed.

Nonrhabdomyosarcoma soft tissue sarcomas in children: is age at diagnosis an important variable?

Hayes-Jordan AA, Spunt SL, Poquette CA, Cain AM, Rao BN, Pappo AS, Shochat SJ.

Department of Surgery, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.

J Pediatr Surg 2000 Jun;35(6):948-53 Abstract quote

PURPOSE: The associations between age at diagnosis, tumor characteristics, and outcome in children diagnosed with nonrhabdomyosarcoma soft tissue sarcoma (NRSTS) were studied.

METHODS: Retrospective review was conducted of 192 children from 1962 through 1996. Patients were divided into groups: birth to 1 year (n = 13), 1 to 5 years (n = 26), 5 to 10 years (n = 49), 10 to 15 years (n = 55), and older than 15 years (n = 49) of age at diagnosis. Characteristics including IRS group, histological grade and pattern, tumor size, and invasiveness were investigated. Survival rate was estimated by age group. The median follow-up was 8.8 years (range, 2 to 28 years).

RESULTS: There were 81 group I patients, 40 group II, 41 group III, and 30 group IV. A significant difference of IRS groups among the age groups was seen (P = .034). There were no IRS group IV patients less than 1 year of age; 50% of IRS group IV patients were older than 15 years. A significant difference in the distribution of histological grade among the age groups (P = .032) was seen. Ten of 13 (77%) children less than 1 year of age had low-grade tumors, whereas 42%, 45%, 60%, and 37% of patients aged 1 to 5, 5 to 10, 10 to 15, and older than 15 years, respectively, had low-grade tumors. Patients older than 15 years had the highest incidence of invasive tumors (59%). Histological pattern also varied with age. The most prevalent histology in the less-than-1-year age group was infantile fibrosarcoma. No predominant histology was seen in the 1- to 5-year age group. Malignant fibrous histiocytoma was the most frequent histological subtype in children between 5 and 10 years of age. In the 10- to 15-year age group and children older than 15 years the malignant peripheral nerve sheath tumor and synovial sarcoma were the most prevalent subtypes. Without adjusting for any other factors, age group was prognostic of survival (P = .007). Patients less than 1 year at diagnosis had the best outcome, with a 5-year survival rate of 92% +/- 9%. Five-year estimates were lowest for patients older than 15 years (49% +/- 7%).

CONCLUSIONS: Significant differences in IRS group, histological grade, and histological subtype were observed in different age groups. Infants with NRSTS were more likely to have low grade, less invasive, and lower stage tumors. These characteristics may account for their improved prognosis.

Improved prognostication in soft tissue sarcoma: independent information from vascular invasion, necrosis, growth pattern, and immunostaining using whole-tumor sections and tissue microarrays.

Engellau J, Bendahl PO, Persson A, Domanski HA, Akerman M, Gustafson P, Alvegard TA, Nilbert M, Rydholm A.

Department of Oncology, Lund University Hospital, SE-221 85 Lund, Sweden.

Hum Pathol. 2005 Sep;36(9):994-1002. Abstract quote  

In 140 mixed primary soft tissue sarcomas with a median follow-up of 6 years, the prognostic importance of tumor size, tumor depth, grade, necrosis, vascular invasion, and peripheral growth pattern (pushing versus infiltrating) was evaluated on whole-tumor sections. Immunohistochemical expression of Ki-67, p53, cyclin A, bcl-2, beta-catenin, CD44, and P-glycoprotein was determined using tissue microarray from the peripheral growth zone.

Local recurrences developed in 17% of the patients and correlated with necrosis, vascular invasion, and cyclin A expression. No local recurrence developed in tumors with a pushing growth pattern, regardless of tumor grade and depth. Metastasis developed in 39% of the patients. Vascular invasion was identified in 36% of the tumors and was the strongest prognostic factor for metastasis with a hazard ratio of 3.5. Growth pattern and tumor necrosis were also strong prognostic factors for metastasis, whereas malignancy grade, tumor size, and tumor depth did not have any independent prognostic value. Immunostaining showed independent prognostic information for Ki-67, beta-catenin, CD44, and P-glycoprotein.

The results indicate that whole-tumor sections could facilitate identification of vascular invasion, necrosis, and peripheral growth pattern and that immunohistochemical profiling from the growth zone also provides independent prognostic information for metastasis in soft tissue sarcoma.

Sarcoma metastatic to the brain: a series of 15 cases.

Salvati M, Cervoni L, Caruso R, Gagliardi FM, Delfini R.

Department of Neurosurgery, Neurological Mediterranean Neuromed Institute, IRCCS, Pozzilli (IS), Italy.

Surg Neurol 1998 Apr;49(4):441-4 Abstract quote

METHODS: We report on 15 patients surgically treated for intraparenchymal brain metastases from sarcoma, including six osteosarcomas, five leiomyosarcomas, two malignant fibrous histiocytomas, and two alveolar soft-part sarcomas (ASPS).

RESULT: Median survival after craniotomy was 9.3 months. Patients with a preoperative Karnofsky performance score of > 70 survived for 12.8 versus 5.3 months for those with a Karnofsky performance score < 70 (p=0.03). Patients with evidence of only lung metastases at the time of surgery (nine cases) survived 8.6 months, which was similar to the 10.4-month survival for patients with disease limited to the brain (p=0.1). The two patients with alveolar soft-part sarcomas are alive at 15 and 20 months after surgery.

CONCLUSION: We conclude that surgery is effective in treating selected patients with sarcoma metastatic to the brain and that patients with metastasis from ASPS may have a relatively good prognosis if they are surgically treated. The complete removal of all brain metastases and a Karnofsky performance score > 70 are associated with a favorable prognosis; the presence of concurrent lung metastases is not a contraindication to surgery.


Lymph node metastasis from soft tissue sarcoma in adults. Analysis of data from a prospective database of 1772 sarcoma patients.

Fong Y, Coit DG, Woodruff JM, Brennan MF.

Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York 10021.

Ann Surg 1993 Jan;217(1):72-7 Abstract quote

To examine the natural history of lymph node metastasis from sarcomas and the utility of therapeutic lymphadenectomy, clinical histories of all adult patients identified by a prospective sarcoma database for the 10-year period July 1982 to July 1991 were examined.

Of the 1772 sarcoma patients, 46 (2.6%) were identified with lymph node metastasis. Median follow-up of all patients from diagnosis of lymph node metastasis was 12.9 months (range, 0 to 100 months). Median survival for nonsurvivors was 12.7 months (range, 0 to 40.7). The tumor types with the highest incidence of lymph node metastasis are angiosarcoma (5/37 total cases; 13.5%), embryonal rhabdomyosarcoma (ERMS) (12/88 total cases; 13.6%), and epithelioid sarcoma (2/12 total cases; 16.7%). Lymph node metastasis from visceral primary (p = 0.004) and malignant fibrous histiocytomas (p = 0.006) were associated with particularly poor prognosis. Thirty-one patients underwent radical, therapeutic lymphadenectomy with curative intent, whereas 15 patients had less than curative procedures, in most cases biopsy only. Patients not treated with radical lymphadenectomy had a median survival of 4.3 months (range, 1 to 32) whereas radical lymphadenectomy was associated with a 16.3 month median survival and the only long-term survivors (46% 5-year survival by Kaplan-Meier).

The authors conclude that lymph node metastases from sarcoma are rare in adults, but vigilance is warranted, especially in angiosarcoma, ERMS, and epithelioid subtypes. Radical lymphadenectomy is appropriate treatment for isolated metastasis to regional lymph nodes and may provide long-term survival.


Skeletal metastases from soft-tissue sarcomas. Incidence, patterns, and radiological features.

Yoshikawa H, Ueda T, Mori S, Araki N, Kuratsu S, Uchida A, Ochi T.

Department of Orthopaedic Surgery, Osaka Medical Centre for Cancer and Cardiovascular Diseases and Osaka University Medical School, Japan.

J Bone Joint Surg Br 1997 Jul;79(4):548-52 Abstract quote

We reviewed 277 patients with soft-tissue sarcoma (STS) treated between 1975 and 1995 to study the incidence, distribution, time of appearance, and radiological findings of skeletal metastases.

Of these, 28 (10.1%) had metastases within a mean period of 18.6 months after admission. The incidence of skeletal metastases differed among the histological subtypes of sarcoma; alveolar soft-part sarcoma, dedifferentiated liposarcoma, angiosarcoma, and rhabdomyosarcoma tended to show higher incidences. The regional bones close to the primary tumour were affected in 13 (46.4%) of the 28 patients, and the axial bones in 18 (64.3%).

Radiologically, the metastatic bony lesions predominantly showed osteolytic changes, and there were pathological fractures in 21 of 44 lesions.


Proliferative activity (MIB-1 index) is an independent prognostic parameter in patients with high-grade soft tissue sarcomas of subtypes other than malignant fibrous histiocytomas: a retrospective immunohistological study including 216 soft tissue sarcomas.

Jensen V, Sorensen FB, Bentzen SM, Ladekarl M, Nielsen OS, Keller J, Jensen OM.

Centre for Bone and Soft Tissue Sarcomas, University Hospital of Aarhus, Denmark.

Histopathology 1998 Jun;32(6):536-46 Abstract quote

AIMS: To evaluate the prognostic value of tumour proliferative activity, p53 accumulation and bcl-2 expression in a retrospective series of 216 patients with soft tissue sarcomas (STS).

METHODS AND RESULTS: The immunohistochemical analyses were performed on formalin-fixed, paraffin-embedded tissue. The proliferative activity was assessed by use of the monoclonal antibody MIB-1 and evaluated in multiple, random systematic sampled fields of vision. The percentage of proliferating cells (the MIB-1 index) ranged between 1% and 85% (median 12%). A significant increase in mean MIB-1 index was seen with increasing histological malignancy grade. Variation in the incidence of p53 accumulation and bcl-2 positivity among different histological subtypes was observed. p53 accumulation was frequent in synovial sarcomas and leiomyo- and rhabdomyosarcomas, whereas bcl-2 preferentially was expressed in synovial sarcomas. Univariate analysis identified patient age, tumour size, histological grade of malignancy, MIB-1 index and p53 accumulation as significant prognostic parameters. Multivariate Cox analysis, including tests for interaction terms between histological subtypes and MIB-1 index, showed independent prognostic effect of MIB-1 index and tumour size in patients with high-grade tumours of other subtypes than malignant fibrous histiocytoma (MFH).

CONCLUSIONS: Histopathological malignancy grading is the most important single prognostic factor for overall survival in STS, but estimation of MIB-1 index is useful for identifying the least favourable subgroup of high grade STS of other subtypes than MFH, for whom adjuvant therapy may be indicated.


Local recurrence of soft tissue sarcoma a risk factor for late metastases. 379 patients followed for 0.5-20 years.

Trovik CS, Bauer HC.

Department of Orthopedics, Karolinska Hospital, Stockholm, Sweden.

Acta Orthop Scand 1994 Oct;65(5):553-8 Abstract quote

We performed a retrospective analysis of 379 adult patients treated for soft tissue sarcoma.

None had metastasis at the time of diagnosis and all were treated surgically. Patients who developed metastatic disease before the local recurrence were excluded. The 8-year metastasis-free survival rate in the group of 261 patients with local tumor control was 0.72, compared to 0.67 in the 118 patients with local recurrence (P 0.2). Multiple regression analysis showed that high-grade malignancy and large tumor size were risk factors for metastases. Local recurrence was not a risk factor. However, when patients with small and/or low-grade tumors were analyzed separately, local recurrence emerged as a risk factor. In this group of patients, the 8-year survival rate was 0.87 for those with local control and 0.64 for those with local recurrence (P 0.004).

Local recurrence appears to be a risk factor for the development of late metastases in patients who otherwise have a low risk of metastases.

Size and timing of local recurrence predicts metastasis in soft tissue sarcoma. Growth rate index retrospectively analyzed in 134 patients.

Choong PF, Gustafson P, Rydholm A.

Department of Orthopedics, University Hospital, Lund, Sweden.

Acta Orthop Scand 1995 Apr;66(2):147-52 Abstract quote

Our study combined size and timing of the first local recurrence to create a growth rate index (GRI-ratio of size (cm) to timing (mo)) which we analyzed for an association with metastasis.

We analyzed 134 locally recurrent tumors from a series of 460 adult patients with soft tissue sarcoma of the extremities and trunk wall who were diagnosed and treated between 1964 and 1990, with a median follow-up of 10 (2-28) years for survivors. None of the patients had metastases at diagnosis. One half (74) of local recurrences were from inadequately treated primaries, one half (71) were associated with metastases, and two thirds (89) were seen in non-center-treated patients. There were equal numbers of patients with GRI < or = 0.4 (low) and > 0.4 (high). Patients with a low GRI had a better 2-year metastasis-free survival (80 percent) than those with a high GRI (30 percent). High GRIs were associated with large, high grade primary tumors and a short metastasis-free interval in comparison to low GRI tumors. Time to local recurrence strongly correlated with the time to metastasis (R2 0.85, p < 0.001). GRI was a good discriminator of metastasis in patients with tumors larger than 5 cm and of malignancy grade IV.

Our study suggests that clinical characteristics (e.g., GRI) of local recurrence rather than presence, per se, are important in predicting tumor behavior.


The influence of anatomic location on outcome in patients with soft tissue sarcoma of the extremity.

Gerrand CH, Bell RS, Wunder JS, Kandel RA, O'Sullivan B, Catton CN, Griffin AM, Davis AM.

University Musculoskeletal Oncology Unit, Department of Surgery, Mount Sinai Hospital, the University of Toronto, Toronto, Ontario, Canada.

Cancer 2003 Jan 15;97(2):485-92 Abstract quote

BACKGROUND: The anatomic location of an extremity soft tissue sarcoma may influence the patient's presentation, management, and local and systemic recurrence rates. The objective of this study was to compare the presentation, management, and outcome of patients with soft tissue sarcomas of the upper extremity and the lower extremity.

METHODS: Prospectively collected data from patients who underwent limb-sparing surgery for extremity soft tissue sarcoma between January, 1986 and April, 1997 were analyzed. Local recurrence free rates and metastasis free rates were calculated using the method of Kaplan and Meier. Univariate and multivariate analyses of potential predictive factors were evaluated with the log-rank test and the Cox proportional hazards model.

RESULTS: Of 480 eligible patients, 48 patients (10.0%) had a local recurrence, and 131 patients (27.3%) developed distant metastasis. The median follow-up of survivors was 4.8 years (range, 0.1-12.9 years). Patients with upper extremity tumors had smaller lesions (6.0 cm vs. 9.3 cm; P < 0.001), more often underwent unplanned excision before referral (89 patients [64.0%] vs. 160 patients [46.9%]; P < 0.001), and less often received radiotherapy (98 patients [70.5%] vs. 289 patients [84.8%]; P < 0.001). The 5-year local recurrence free rate was 82% for patients with sarcomas of the upper extremity and 93% for patients with sarcomas of the lower extremity (P = 0.002). The 5-year metastasis free rate was 82% for patients with sarcomas of the upper extremity and 69% for patients with sarcomas of the lower extremity (P = 0.013).

CONCLUSIONS: Local recurrence was more frequent in patients who had sarcomas of the upper extremity compared with patients who had sarcomas of the lower extremity. Factors that contributed to this difference included histologic type, the use of radiotherapy, and local anatomy. Metastasis was more frequent among patients with sarcomas of the lower extremity, because those tumors tended to be large and deeper compared with upper extremity tumors.


Multifactorial analysis of the survival of patients with distant metastasis arising from primary extremity sarcoma.

Billingsley KG, Lewis JJ, Leung DH, Casper ES, Woodruff JM, Brennan MF.

Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.

Cancer 1999 Jan 15;85(2):389-95 Abstract quote

BACKGROUND: Despite optimal multimodality limb-sparing therapy for extremity soft tissue sarcoma (STS), a significant number of patients develop distant metastasis. The objective of this study was to analyze patterns of metastatic disease and define prognostic factors for survival in a large group of patients followed prospectively at a single institution.

METHODS: Between July 1, 1982, and June 30, 1996, all adult patients admitted to the Memorial Sloan-Kettering Cancer Center with primary extremity sarcoma were treated and prospectively followed. Patients who developed distant metastases constituted the study group. Prognostic factors were analyzed for postmetastasis survival. These included both factors related to the primary tumor and factors related to the pattern of metastasis. Postmetastasis survival was modeled using the Kaplan-Meier method. Statistical significance was evaluated using the log rank test for univariate analysis and the Cox proportional hazards model for multivariate analysis.

RESULTS: During the study period, the authors admitted and treated 994 patients with primary extremity STS. The median follow-up was 33 months. Distant metastasis developed in 230 patients (23%). Median survival after distant metastasis was 11.6 months. The lungs were the first metastatic site in 169 patients (73%). Other first sites of metastasis included the skin and soft tissues of the head and neck, trunk, and extremities. There was no statistically significant difference in survival between patients with pulmonary and those with nonpulmonary metastatic disease. In multivariate analysis, resection of metastatic disease, the length of the disease free interval, the presence of a preceding local recurrence, and patient age > 50 years all were significant predictors of postmetastasis survival. Other factors that defined the primary tumor, including histologic grade, depth, and microscopic margins, were not associated with postmetastasis survival.

CONCLUSIONS: Despite optimal multimodality therapy, 23% of the patients in this series with primary extremity sarcoma developed distant metastasis. Median survival after metastasis was approximately 1 year. After metastasis, the independent favorable factors that are associated with patient survival include resection of the metastases, a long disease free interval, the absence of preceding local recurrence, and patient age < 50 years. Although a definitive conclusion regarding the benefit of resection can be made only with a randomized clinical trial, these data suggest that resection of metastatic STS may contribute to patient survival, which in some cases may be long term.

Long-term outcome of patients with American Joint Committee on Cancer stage IIB extremity soft tissue sarcomas.

Fleming JB, Berman RS, Cheng SC, Chen NP, Hunt KK, Feig BW, Respondek PM, Yasko AW, Pollack A, Patel SR, Burgess MA, Papadopoulos NE, Plager C, Zagars G, Benjamin RS, Pollock RE, Pisters PW.

Sarcoma Center at The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030-4195, USA.

J Clin Oncol 1999 Sep;17(9):2772-80 Abstract quote

PURPOSE: It has been suggested that patients with small (< 5 cm), high-grade extremity soft tissue sarcomas (STS) have an excellent overall prognosis and, consequently, may not require adjuvant therapies.

PATIENTS AND METHODS: A comprehensive review of all patients with extremity STS treated at a tertiary care cancer hospital over a 9-year period (January 1984 to December 1992) was performed. Prognostic factors, treatment data, and long-term outcome were evaluated in the subset of 111 patients with American Joint Committee on Cancer stage IIB (G3/4, T1a/b) disease.

RESULTS: The median tumor size was 3.0 cm (range, 0.6 to 4.9 cm), and 55 tumors (50%) were deep in location. All patients underwent surgical resection; 68 (61%) received pre- or postoperative radiotherapy, and 32 (29%) received doxorubicin-based chemotherapy. The median follow-up was 76 months. Forty patients (36%) experienced 59 recurrences. First recurrences occurred at local, regional, and distant sites in 21, five, and 14 patients, respectively. The 5-year actuarial local recurrence-free, distant recurrence-free, disease-free, and overall survival rates were 82%, 83%, 68%, and 83%, respectively. The presence of a microscopically positive surgical margin was an independent adverse prognostic factor for both local recurrence (relative risk [RR] = 3.75; 95% confidence interval [CI], 1.25 to 11.25; P =.02) and disease-free survival (RR = 2.57; 95% CI, 1.33 to 4.98; P =.005).

CONCLUSION: Event-free outcome for this subset of patients with high-grade STS does not seem as favorable as previously reported by other investigators. Patients who undergo maximal surgical resection with microscopically positive margins represent a subset of T1 STS patients who warrant consideration for adjuvant therapies.

Prognostic index for extremity soft tissue sarcomas with isolated local recurrence.

Ramanathan RC, A'Hern R, Fisher C, Thomas JM.

Royal Marsden Hospital, London, United Kingdom.

Ann Surg Oncol 2001 May;8(4):278-89 Abstract quote

BACKGROUND: Local recurrence occurs in 10% to 20% of patients with extremity soft tissue sarcomas despite optimal treatment. The association of local recurrence with subsequent survival is controversial and conflicting. There is a need for a staging system to predict outcome in this subset of patients and also to plan optimal treatment, including adjuvant systemic therapy.

METHODS: Data collected from 110 patients with locally recurrent extremity soft tissue sarcomas were studied. The influence of clinical and pathologic factors on local recurrence, distant metastasis, and disease-specific survival were analyzed by univariate and multivariate techniques.

RESULTS: Of the 110 patients who presented with local recurrence, 92 had an isolated local recurrence and 18 had prior or concomitant distant metastases. The 5-year disease-specific survival for all patients was 63% and for those with isolated local recurrence, it was 69%. Histologic grade, malignant fibrous histiocytoma histology, pathologic margins, previous local recurrence, and prior radiotherapy were independent prognostic factors for subsequent local recurrence. Tumor size, histologic grade, and time to local recurrence were independent prognostic factors for distant metastasis and disease-specific survival. A prognostic index was calculated by assigning a score of 1 to 3 for each of the three independent prognostic factors for survival and added to give the prognostic index for each patient. As the prognostic index increased from 3 to 9, there was a progressive increase in the hazard ratios and a corresponding deterioration in survival. The patients were then categorized into three prognostic groups based on the hazard ratios for disease specific survival. The differences in the survival curves were highly statistically significant (P < .0001).

CONCLUSIONS: Tumor size, histologic grade, and time to local recurrence are the primary determinants of distant metastases and survival in locally recurrent extremity soft tissue sarcomas. The impact of local recurrence on survival varies considerably. The nature of the local recurrence, rather than its presence per se, is a more useful guide to prognosis. We propose a simple staging system based on size, grade, and time to recurrence that correlates extremely well with prognosis and may serve as a guide to make therapeutic decisions in patients with locally recurrent extremity soft tissue sarcomas.


Retroperitoneal soft-tissue sarcoma: analysis of 500 patients treated and followed at a single institution.

Lewis JJ, Leung D, Woodruff JM, Brennan MF.

Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York City, New York 10021, USA.

Ann Surg 1998 Sep;228(3):355-65 Abstract quote

OBJECTIVE: To analyze treatment and survival of a large cohort of patients with retroperitoneal soft-tissue sarcomas (STS) treated and prospectively followed at a single institution.

SUMMARY BACKGROUND DATA: Retroperitoneal STS are relatively uncommon and constitute a difficult management problem. Although surgical resection is often difficult or impossible, current chemotherapy is not effective and radiation is limited by toxicity to adjacent structures. Thus, complete surgical resection remains the most effective modality for selected primary and recurrent disease.

METHODS: Five hundred patients with retroperitoneal STS were admitted and treated between July 1, 1982, and September 30, 1997, and prospectively followed. Patient, tumor, and treatment variables were analyzed for disease-specific and disease-free survival. Survival was determined with the Kaplan-Meier method. Statistical significance was evaluated using the logrank test for univariate influence and Cox model stepwise regression for multivariate influence.

RESULTS: Two hundred seventy-eight patients (56%) had primary disease and 222 (44%) recurrent disease. Median follow-up was 28 months (range 1 to 172 months), 40 months for survivors. Median survival was 72 months for patients with primary disease, 28 months for those with local recurrence, and 10 months for those with metastasis. For patients with primary or locally recurrent tumors, unresectable disease, incomplete resection, and high-grade tumors significantly reduced survival time.

CONCLUSIONS: In this study of patients with retroperitoneal STS, stage at presentation, high histologic grade, unresectable primary tumor, and positive gross margin are strongly associated with the tumor mortality rate. Patients approached with curative intent should undergo aggressive attempts at complete surgical resection. Incomplete resection should be undertaken only for symptom relief.

Prognostic factors in retroperitoneal sarcoma: a multivariate analysis of a series of 165 patients of the French Cancer Center Federation Sarcoma Group.

Stoeckle E, Coindre JM, Bonvalot S, Kantor G, Terrier P, Bonichon F, Nguyen Bui B; French Federation of Cancer Centers Sarcoma Group.

Department of Surgery, Institut Bergonie, Bordeaux, France.

Cancer 2001 Jul 15;92(2):359-68 Abstract quote

BACKGROUND: Surgery is the main prognostic factor in retroperitoneal sarcoma. However, despite progress, surgery alone is rarely curative, and analysis of the causes of failures and of other prognostic factors are warranted to ascertain treatment orientations.

METHODS: Data of patients treated from 1.80 to 12.94 for primary retroperitoneal sarcoma were extracted from the French Federation of Cancer Centers Sarcoma Group registry. Univariate and multivariate analysis were performed for initial local control and for local and general outcome. One hundred sixty-five patients (median age, 54 years; range, 16--82 years) were identified. Median tumor size was 15 cm (range, 2--70 cm); 31% of tumors presented with neurovascular or bone involvement. Liposarcoma, leiomyosarcoma, and malignant fibrous histiocytoma represented 66% of the tumors. Eighty-four percent of the tumors were of high or intermediate grade. Twenty patients had initial metastases. Multimodality treatment included surgery (150 patients), radiotherapy (92 patients), and chemotherapy (77 patients). Complete excision was achieved in 94 of 145 nonmetastatic patients. Median follow-up was 47 months (range, 3--160 months).

RESULTS: Actuarial overall 5-year survival rate (median) was 46% (51 months). The main prognostic factors for survival were initial metastases and surgery, which represented the major treatment-linked factor. High-grade of tumors affected local recurrence, metastatic recurrence, and survival. Adjuvant radiotherapy was significantly associated with reduced local recurrence. Various evolutive patterns were observed with histologic subtypes.

CONCLUSIONS: Aggressive surgery remains mandatory in retroperitoneal sarcoma, but a randomized trial is needed to evaluate the place of radiotherapy for local control.


The management of retroperitoneal soft tissue sarcoma: a single institution experience with a review of the literature.

Pirayesh A, Chee Y, Helliwell TR, Hershman MJ, Leinster SJ, Fordham MV, Poston GJ.

Department of Surgery, Royal Liverpool University Hospital, Prescot St., Liverpool, L7 8XP, UK.

Eur J Surg Oncol 2001 Aug;27(5):491-7 Abstract quote

AIM: Ten percent of soft tissue sarcomas (STS) arise in the retroperitoneal tissues. The prognosis for patients with retroperitoneal sarcoma is poor with a 5-year survival rate between 12% and 70%. Stage at presentation, high histological grade, unresectable primary tumour and incomplete resection are associated with a less favourable outcome.

METHODS: Complete follow-up data were available on 22 patients who underwent surgery for retroperitoneal STS in our institution between 1990 and 2000. Patient, tumour and treatment variables were analysed including use of adjuvant therapy and survival status.

RESULTS: Eighteen patients underwent surgery for primary disease, four patients were treated for recurrent disease or metastases. Ten patients presented with pain, seven with an abdominal mass, other presentation included weight loss and haematuria. Thirteen patients presented with tumours larger than 10 cm. The tumours were seven liposarcomas, six leiomyosarcomas, three malignant fibrous histiocytomas, two rhabdomyosarcomas, two malignant schwannomas and two undifferentiated sarcomas. Six primary tumours were completely excised, five patients received radiotherapy and five received chemotherapy. Local recurrence rate was 45% and recurrence-free interval for 10 patients with recurrence was 11 months. Five patients received radiotherapy and five received chemotherapy. The median survival for patients with primary tumours was 36 months, and 5-year survival was 44%. Adjuvant therapy was not associated with higher survival rates.

CONCLUSION: This study re-emphasizes the poor outcome of patients with retroperitoneal STS. Adjuvant radiotherapy and chemotherapy do not appear to be any proven benefit and the single most important prognostic factor is aggressive successful en bloc resection of the primary tumour. Our resection rate and 5-year survival rates are comparable with previous reported UK series although lower than large reports from North American centres. This might partly be explained by difficulty in data collection in a retrospective analysis, but may reflect inadequate subspecialization in UK centres.


Human DNA topoisomerase I: An anticancer drug target present in human sarcomas.

Coleman LW, Rohr LR, Bronstein IB, Holden JA.

Department of Pathology, University of Utah Health Sciences Center, Salt Lake City, UT and the York Structural Biology Laboratory, Department of Chemistry, University of York, Heslington, York, UK.

Hum Pathol 2002 Jun;33(6):599-607 Abstract quote

New anticancer drugs targeting DNA topoisomerase I (topo I) are showing activity against human sarcomas. Laboratory studies have indicated that cells responsive to topo I-targeted drugs have elevated levels of topo I, require active DNA replication, and may require a functional apoptotic pathway.

In this study, we evaluated these potential markers of topo I-targeted drug sensitivity in 55 cases of human sarcoma (42 high grade, 4 intermediate grade, and 9 low grade). By immunohistochemical staining, we observed elevated topo I expression in 20 of 55 neoplasms (36%). Immunohistochemical staining for the proliferation marker DNA topoisomerase II-alpha (topo II-alpha), showed that 15 of 55 neoplasms (27%) had topo II-alpha indices >50, indicating a large number of actively cycling tumor cells. Abnormal p53 expression was observed in 19 of the 55 cases (35%). None of the cases were interpreted as positive for ALK-1. To complement our immunohistochemical staining of topo I, we isolated functionally active topo I from extracts of a human sarcoma. These isolates demonstrated that sarcoma topo I is sensitive to topo I-targeted anticancer drugs.

Of the 55 cases of human sarcoma, 7 (13%) had high levels of topo I, a large number of cycling tumor cells, and normal p53 expression. These are the molecular parameters that might suggest responsiveness to drugs targeting topo I.

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Commonly Used Terms

Herringbone-Pattern of tumor growth resembling a herring bone with spindled cells arranged at acute angles.

Palisading-Pattern of tumor growth with cell nuclei lining along parallel arrays.

Storiform-Pattern of tumor growth with spindled cells radiating from a central point, like a pinwheel.

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