[New insights in the classification of soft tissue tumors]. / Nieuwe inzichten bij de classificatie van wekedelentumoren.

Soft tissue tumours are rare and form some of the most difficult pathological subjects in medicine. The diagnosis of a soft tissue tumour goes hand-in-hand with a number of clinically relevant questions related to the therapy and prognosis (what is the classifying diagnosis?, is the proliferation reactive or neoplastic?; in the case of neoplasia: is it benign or malignant?, what is the grade of malignancy?, what is the expected clinical course?). Due to new insights in tumour diversity at a morphologic level, developments in immunohistochemistry and increasing (cyto)genetic knowledge about tumour-specific abnormalities, the known histological groups of tumours have been better characterised at the clinicopathological level, new tumour entities have been defined, old terms have been abandoned and a better understanding of tumour histogenesis has been established.

Reticular perineurioma: a distinctive variant of soft tissue perineurioma.

Soft tissue perineurioma is a relatively recently characterized, uncommon tumor composed of perineurial cells exhibiting immunoreactivity for epithelial membrane antigen (EMA). These lesions occur preferentially in adults and may arise in a wide variety of anatomic sites. We report the clinicopathologic, immunohistochemical, and ultrastructural features of six cases of a poorly recognized morphologic variant of soft tissue perineurioma, characterized by a highly distinctive reticular growth pattern. Four of the patients were women, two were men (age range, 34-61 yrs; median, 43 yrs). Four of the cases arose in the subcutis of the upper extremity; three were located distally (thumb, finger, palm), whereas one was situated more proximally near the elbow region. One case each was located in the gingiva and subcutaneous tissue of the inguinal region, respectively. In those cases in which clinical information was available (n = 5), the lesions were asymptomatic and had been present from 4 months to 10 years before resection. Tumor size ranged from 1.5 cm to 10 cm (median size, 4.25 cm). Microscopically the lesions demonstrated a predominantly lace-like or reticular growth pattern composed of anastomosing cords of fusiform cells with bipolar cytoplasmic processes and palely eosinophilic cytoplasm. Nuclei were centrally placed, ovoid to fusiform in shape, and no mitoses were seen. Transition to more cellular areas was focally present in all cases. The stroma was variably collagenous to myxoid. Immunohistochemically all six cases stained positively for EMA but not for S-100 protein. Two cases demonstrated focal positive cytoplasmic staining for cytokeratin, whereas one case was focally desmin positive. Ultrastructural examination of two tumors showed typical features of perineurial cells. Follow up (available in only two cases) showed no evidence of recurrence. Reticular perineurioma of soft tissue represents an unusual morphologic variant within the perineurioma group, which should be distinguished from myoepithelial tumors, extraskeletal myxoid chondrosarcoma, and myxoid synovial sarcoma.

Malignant melanoma is genetically distinct from clear cell sarcoma of tendons and aponeurosis (malignant melanoma of soft parts).

Clear cell sarcoma of tendons and aponeuroses (malignant melanoma of soft parts) and conventional malignant melanoma may demonstrate significant morphologic overlap at the light microscopic and ultrastructural level. Consequently, the clinically relevant distinction between primary clear cell sarcoma and metastatic melanoma in the absence of a known primary cutaneous, mucosal or ocular tumour may occasionally cause diagnostic problems. A balanced translocation, t(12;22)(q13;q13), which can be detected, amongst others, using the reverse transcriptase polymerase chain reaction (RT-PCR) or fluorescent in situ hybridization (FISH), has been identified in a high percentage (50-75%) of clear cell sarcomas and is presumed to be tumour specific. Whether this chromosomal rearrangement is present in malignant melanoma has, to date, not as yet been studied by molecular genetic or molecular cytogenetic techniques. Using RT-PCR and FISH, a series of metastases from 25 known cutaneous melanomas and 8 melanoma cell lines (5 uveal and 3 cutaneous) were screened for the t(12;22)(q13;q13) translocation. Primers for RT-PCR were chosen based upon published breakpoint sequences. The Cosmids G9 and CCS2.2, corresponding to the 5' region of EWS and 3' region of ATF-1 respectively, were used as probes. The translocation was not identified in any of the melanomas or melanoma cell lines analysed in this study; in contrast this translocation was identified in 3 out of 5 clear cell sarcomas using these techniques. This allows distinction between translocation positive cases of clear cell sarcoma and malignant melanoma at a molecular genetic level. Consequently, in diagnostically challenging cases, this represents a valuable tool for the clinicopathologic differentiation between these two entities, with an important impact on patient management and prognosis.

The histopathological differential diagnosis of gastrointestinal stromal tumours.

Gastrointestinal stromal tumours (GISTs), initially presumed to be of "true" smooth muscle origin, encompass a heterogeneous, and as yet incompletely understood, group of mesenchymal tumours with respect to their origin, cellular differentiation, and prognosis. Cellular morphology ranges from predominantly spindle shaped to epithelioid in character, whereas differentiation pathways, as determined primarily by immunohistochemistry and ultrastructure, can vary from indeterminate to myoid and/or neural. Recent work has indicated that the interstitial cells of Cajal, a complex cellular network postulated to act as pacemaker cells of the gastrointestinal tract, which exhibit both myoid and neural features, could be candidates for tumour histogenesis. This would provide a plausible and attractive explanation for the variable differentiation pathways identified in the GIST category to date. Nevertheless, the occasional but undisputed location of GISTs outside the gastrointestinal tract (omentum, peritoneum, and retroperitoneum) might mitigate against such an origin, and their histogenesis remains open to debate. The c-kit proto-oncogene, encoding a growth factor receptor with tyrosine kinase activity, has been postulated to play an important role in tumorigenesis because "gain of function" mutations in this gene, localised to chromosome 4q11-21, are being increasingly identified in hereditary and sporadic cases. Monoclonal and polyclonal antibodies directed at the c-kit gene product expressed on the cell surface (CD117/c-kit) appear to be increasingly helpful in resolving the histopathological differential diagnosis between GISTs and true gastrointestinal smooth muscle neoplasms, schwannomas, and other far less frequently occurring mesenchymal tumours at this site. Although tumours with a clinically benign course appear to be more common than their malignant counterparts, no specific histological criteria have as yet been identified to enable an unambiguous prediction of biological behaviour. Increasing tumour size and mitotic activity favour aggressive tumour behaviour, whereas the prognostic value of germline and somatic mutations within the c-kit proto-oncogene remains to be elucidated further. It is the aim of this synopsis to highlight the relevant fundamental and diagnostic developments with respect to this complex group of neoplasms.

An update of diagnostic strategies using molecular genetic and magnetic resonance imaging techniques for musculoskeletal tumors.

Rheumatologists may be incidentally confronted by bone and soft tissue lesions presenting in and around joints that require early recognition and appropriate referral. The diagnostic and therapeutic management of patients with musculoskeletal tumors is critically dependent on a multidisciplinary approach. Advances, particularly in the fields of histopathology, molecular (cyto)genetics and radiologic imaging techniques, have resulted in significant improvements in reaching a correct (differential) diagnosis, essential for implementing optimal treatment modalities. Magnetic resonance imaging is becoming increasingly important in planning preoperative and postoperative management strategies, and should precede all invasive procedures. Improvements in the fields of immunohistochemistry, together with the realization that certain tumor groups may be associated with specific genetic alterations, has significantly improved diagnostic accuracy. Additionally, the presence of certain genetic alterations within the tumoral genome have been found to be of prognostic value, and the hereditary context recognized for a number of specific bone and soft tissue tumors should be taken into account in the management of a patient with such a neoplasm. It is envisaged that an increasing understanding of the molecular biology and histogenesis of individual musculoskeletal tumor types will lead to tailor-made therapeutic options and consequently prognostic improvements. This update serves to highlight some important recent developments in fundamental and diagnostic aspects of musculoskeletal tumors.

Diagnostic and prognostic implications of the unfolding molecular biology of bone and soft tissue tumours.

Sarcomas account for approximately 1-2% of human malignant disease and are relatively uncommon. Histopathological study of these mesenchymal tumours at light microscopic and ultrastructural level may not always provide an unambiguous diagnosis. It has become apparent with the identification of increasing numbers of tumour specific genetic alterations that (cyto) genetic evaluation could become a very helpful adjunct to histopathological assessment in reaching a correct diagnosis. Thus, once the different tumour types can be accurately identified and classified, more meaningful clinical trials can be initiated to evaluate and select optimal methods of management. In addition, an increasing awareness and understanding of the molecular changes associated with, and the genetic variability in, the various tumour groups is beginning to provide important new information about clinical progression and prognosis.

Myxoid tumours of soft tissue.

Myxoid tumours of soft tissue encompass a heterogeneous group of lesions characterized by a marked abundance of extracellular mucoid (myxoid) matrix. This group of tumours demonstrate significant variability in their biological behaviour thus including tumours which are entirely harmless, tumours with a tendency to recur locally but not metastasize, and malignant tumours. There appears to be a considerable degree of overlap clinically and morphologically between the various tumour types in this group, generating potential diagnostic problems for the clinician and pathologist alike. While diligent microscopy remains the basis of diagnostic pathology, the continuous developments and refinements within the fields of immunohistochemistry and molecular cytogenetics are providing substantial new information, allowing the development of new diagnostic criteria and hence facilitating an accurate diagnosis. It is the aim of this short review to highlight the most prevalent soft tissue tumours with predominantly myxoid morphology, to describe the features by which the majority of these myxoid lesions may be identified, and to discuss the differential diagnosis where appropriate.

Adenocarcinoma arising within a tailgut cyst: clinicopathological description and follow up of an unusual case.

Full clinicopathological details and clinical follow up of a case of malignant transformation within a tailgut cyst are presented. A 43 year old woman presented with signs and symptoms of an imminent threatened abortion. Routine examination identified a coincidental, asymptomatic retrorectal/presacral mass. Following imaging studies, surgical resection was carried out and an adenocarcinoma arising within a pre-existent tailgut cyst was identified by microscopy. Four years later the patient presented with neurological symptoms consistent with local recurrence of the tumour. Surgical biopsies confirmed this diagnosis and she was subsequently started on chemotherapy. She died soon after from a cause unrelated to the disease, after declining further active intervention. Differential diagnosis of such cases includes (cystic) teratoma, epidermal cyst, rectal duplication cyst, anal gland cyst and carcinoma, extension of local carcinoma, and metastatic disease. It is recommended that these lesions be completely excised when detected incidentally.

Adult hypertrophic pyloric stenosis: case report and review.

A case of adult hypertrophic pyloric stenosis presented in an older female with no apparent predisposing factors which might be likely to precipitate the condition. There was a history of chronic dyspepsia and occasional episodes of vomiting. No contributory medical history was identified. Barium swallow and follow through showed a markedly reduced emptying time of the stomach. A partial gastrectomy was eventually done and on histopathological examination a diagnosis of adult hypertrophic pyloric stenosis was made.

Myoepithelial carcinoma (malignant myoepithelioma): first report of an occurrence in the maxillary sinus.

AIM: We document for the first time the occurrence of a malignant myoepithelioma at a site other than within the major and minor salivary glands. METHODS AND RESULTS: A 67-year-old male presented with progressive symptoms and signs of a space-occupying lesion in the right maxillary sinus. An initial biopsy identified a malignant (myo)epithelial lesion and a radical maxillectomy was performed. Histology, supplemented by immunohistochemistry, confirmed the presence of a malignant myoepithelioma. CONCLUSION: Malignant myoepithelioma is a very rare tumour composed almost exclusively of myoepithelial cells and, to date, has only been described arising in the the major and minor salivary glands. A variety of tumours of salivary tissue have been reported within the head and neck area at sites outside the major and minor salivary glands, probably arising within accessory salivary tissue. We report the first case of a malignant myoepithelioma occurring in the maxillary sinus, also presumably arising in accessory salivary tissue in this location.

Local recurrence of a phyllodes tumour of the breast presenting with widespread differentiation to a telangiectatic osteosarcoma.

Osteogenic sarcomas of the breast are extremely rare and need to be distinguished from a variety of breast lesions producing metaplastic bone. A 50 year old patient presented with a painless lump in her right breast after twice previously having undergone local excision of a phyllodes tumour at this site. Following radiological and cytological investigation, excision was advised. Histology showed focal remnants of the previously excised phyllodes tumour in continuity with areas of widespread differentiation towards a telangiectatic osteosarcoma. So far this is a unique morphological endpoint.

Clear cell sarcoma of tendons and aponeuroses (malignant melanoma of soft parts) and cutaneous melanoma: exploring the histogenetic relationship between these two clinicopathological entities.

Clear cell sarcoma of tendons and aponeuroses (CCS) has come to be recognized as a distinct histopathological entity in the last three to four decades. It shares a number of histological and ultrastructural features with cutaneous melanoma (MM), occasionally creating diagnostic difficulties with metastatic melanoma in the absence of a known primary cutaneous tumour. At a genetic level, a t(12;22) has been identified in 60-75 per cent of cases of CCS using karyotype analysis, while MM demonstrates a broad range of genetic alterations, most commonly appearing to involve chromosomes 1, 5, and 6. Although these two tumour types share many common microscopic, and thus histogenetic, similarities, the genotypic evidence supports two distinct histopathological entities.

FH Afrikaner-3 LDL receptor mutation results in defective LDL receptors and causes a mild form of familial hypercholesterolemia.

Three founder-related gene mutations (FH Afrikaner-1, -2, and -3) that affect the LDL receptor are responsible for 90% of the familial hypercholesterolemia (FH) in South African Afrikaners. Patients heterozygous for the FH Afrikaner-1 (FH1) mutation, which results in receptors having approximately 20% of normal receptor activity, have significantly lower plasma cholesterol levels and milder clinical symptoms than heterozygotes with the FH Afrikaner-2 mutation, which completely abolishes LDL receptor activity. In this study we re-created the FH3 mutation (Asp154-->Asn) in exon 4 by site-directed mutagenesis and analyzed the expression of the mutant receptors in Chinese hamster ovary cells. The mutation resulted in the formation of LDL receptors that are markedly defective in their ability to bind LDL, whereas binding of apoE-containing beta-VLDL is less affected. The mutant receptors are poorly expressed on the cell surface as a result of significant degradation of receptor precursors. The plasma cholesterol levels of 31 FH3 heterozygotes were similar to FH1 heterozygotes but significantly lower than FH2 heterozygotes. The FH1 and FH3 heterozygotes also tended to be less severely affected clinically (by coronary heart disease and xanthomata) than FH2 patients. This study demonstrates that mutational heterogeneity in the LDL receptor gene influences the phenotypic expression of heterozygous FH and that severity of expression correlates with the activity of the LDL receptor measured in vitro. The results further indicate that knowledge of the specific mutation underlying FH in heterozygotes is valuable in determining the potential risk of premature atherosclerosis and should influence the clinical management of FH patients.

Phenotypic variation among familial hypercholesterolemics heterozygous for either one of two Afrikaner founder LDL receptor mutations.

Two common founder-related gene mutations that affect the low-density lipoprotein receptor (LDLR) are responsible for approximately 80% of familial hypercholesterolemia (FH) in South African Afrikaners. The FH Afrikaner-1 (FH1) mutation (Asp206-->Glu) in exon 4 results in defective receptors with approximately 20% of normal activity, whereas the FH Afrikaner-2 (FH2) mutation (Val408-->Met) in exon 9 completely abolishes LDLR activity (< 2% normal activity). We analyzed the contribution of these mutations and other factors on the variation of hypercholesterolemia and clinical features in Afrikaner FH heterozygotes. The type of FH mutation, plasma triglyceride levels, and age of patients each contributed significantly to the variation in hypercholesterolemia, whereas smoking status, high-density lipoprotein cholesterol levels, and gender had no influence. Although all FH heterozygotes had frank hypercholesterolemia, patients with the FH1 mutation had significantly lower cholesterol levels than those with the FH2 mutation. FH1 heterozygotes also tended to have milder clinical features. The differences between the two FH groups could not be explained by a difference in the common apolipoprotein E variants. This study demonstrates that mutational heterogeneity in the LDLR gene influences the phenotypic expression of heterozygous FH.