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C D Fletcher

Publications and source records attributed to C D Fletcher.

At least 19 recordsLinked to original sources
PubMed2001

KIT activation is a ubiquitous feature of gastrointestinal stromal tumors.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract, and they are generally resistant to chemotherapy and radiation therapy. Most GISTs express the KIT receptor tyrosine kinase protein, and a subset of GISTs contain activating mutations within the KIT juxtamembrane region. We evaluated 48 GISTs, including 10 benign, 10 borderline, and 28 malignant cases, to determine whether KIT expression and activation are general properties of these tumors. Immunohistochemical KIT expression was demonstrated in each case. Somatic KIT mutations were found in 44 tumors (92%), of which 34 (71%) had juxtamembrane region mutations. Other GISTs had KIT mutations in the extracellular region (n = 6) and in two different regions in the tyrosine kinase domain (n = 4). Contrary to previous reports, KIT mutations were not identified preferentially in higher-grade tumors: indeed, they were found in each of 10 histologically benign GISTs. Notably, mutations in all KIT domains were associated with high-level KIT activation/phosphorylation, and KIT activation was also demonstrated in the four GISTs that lacked detectable KIT genomic and cDNA mutations. These studies underscore the role of KIT activation in GIST pathogenesis, and they suggest that activated KIT might represent a universal therapeutic target in GISTs.

Adult↗
PubMed2001

STI571 inactivation of the gastrointestinal stromal tumor c-KIT oncoprotein: biological and clinical implications.

Mutations in the c-KIT receptor occur somatically in many sporadic Gastrointestinal Stromal Tumors (GIST), and similar mutations have been identified at the germline level in kindreds with multiple GISTs. These mutations activate the tyrosine kinase activity of c-KIT and induce constitutive signaling. To investigate the function of activated c-KIT in GIST, we established a human GIST cell line, GIST882, which expresses an activating KIT mutation (K642E) in the first part of the cytoplasmic split tyrosine kinase domain. Notably, the K642E substitution is encoded by a homozygous exon 13 missense mutation, and, therefore, GIST882 cells do not express native KIT. GIST882 c-KIT protein is constitutively tyrosine phosphorylated, but tyrosine phosphorylation was rapidly and completely abolished after incubating the cells with the selective tyrosine kinase inhibitor STI571. Furthermore, GIST882 cells evidenced decreased proliferation and the onset of apoptotic cell death after prolonged incubation with STI571. Similar results were obtained after administering STI571 to a primary GIST cell culture that expressed a c-KIT exon 11 juxtamembrane mutation (K558NP). These cell-culture-based studies support an important role for c-KIT signaling in GIST and suggest therapeutic potential for STI571 in patients afflicted by this chemoresistant tumor.

Apoptosis↗
PubMed2001

Clinicopathologic re-evaluation of 100 malignant fibrous histiocytomas: prognostic relevance of subclassification.

PURPOSE: Malignant fibrous histiocytoma (MFH) has been regarded as the most common soft tissue sarcoma (STS) in adults. Yet its true nature and the validity of this diagnostic concept have increasingly been questioned. Available data suggest that most patients with MFH can be subclassified into specific STS types, but the clinical relevance of such categorization has been argued. In a retrospective study, we reclassified 100 tumors of the extremity and trunk wall primarily diagnosed as MFH and analyzed the outcome. PATIENTS AND METHODS: Patients were adults (median age, 70 years; range, 32 to 94 years). The median tumor size was 8 cm (range, 1 to 30 cm), and the thigh was the most common tumor location (n = 31). Median follow-up was 8 years (range, 3 to 16 years). The overall 5-year metastasis-free survival rate was 0.64. The tumors were reanalyzed histologically, immunohistochemically, and, where available, ultrastructurally, and were classified according to strict diagnostic criteria. Patients were staged according to the American Joint Committee on Cancer system, and prognoses were compared among different groups of the reclassified diagnoses, paying special attention to myogenic tumors. RESULTS: In 84 of 100 tumors, a specific line of differentiation was either proved or strongly suggested. The most common diagnoses were myxofibrosarcoma (n = 22) and leiomyosarcoma (n = 20). Overall, 30 tumors could be grouped as some form of myogenic sarcoma. These tumors had a worse prognosis, even within the same American Joint Committee on Cancer stage, and a shorter time to metastasis than nonmyogenic tumors. CONCLUSION: This retrospective study confirms that most so-called MFH can be subclassified by defined criteria; it provides evidence that such classification is clinically important. Specifically, pleomorphic STS showing myogenic differentiation are significantly more aggressive, a finding that allows planning future therapeutic trials.

Adult↗
PubMed2001

The association between tumour progression and vascularity in myxofibrosarcoma and myxoid/round cell liposarcoma.

Angiogenesis is an important factor in the morphological progression and metastasis of many solid tumours. We studied two homogeneous series of myxofibrosarcoma (MFS) and myxoid/round liposarcoma (MRLS), characterised by distinct vascular patterns and correlated the intratumoral microvessel density (IMD) with morphologic progression in both types of sarcoma. In our study, 43 cases of MFS and 42 cases of MRLS were graded according to established diagnostic criteria. For evaluation of IMD, representative sections were stained immunohistochemically for CD31. After selection of "neovascular hot spots", IMD was calculated by measuring the endothelial surface within twenty 200x fields in relation to the total analysed area. In addition to the correlation of IMD with histological grades of malignancy, a correlation of IMD with the inflammatory infiltrate in MFS was done. To determine whether vascular endothelial growth factor (VEGF) and its receptors, KDR and flt-1, may play a role in the progression of both types of sarcomas, we used mRNA in situ hybridisation (ISH) to study VEGF, KDR and flt-1 expression in selected cases. In addition, the expression of thrombospondin-1, which has been reported to inhibit angiogenesis, and of collagen type I was studied using mRNA ISH. Cases of MFS varied histologically from hypocellular, mainly myxoid, neoplasms (low-grade malignant, 18 cases) to intermediate-grade malignant lesions with increased cellularity and mitotic activity (13 cases), and high-grade malignant cases with marked pleomorphism, high proliferative activity and areas of necrosis in many cases (12 cases). Cases of purely low-grade myxoid liposarcoma (16 cases) were characterised by low-cellularity, mucin pooling and plexiform vasculature. In combined MRLS, these hypocellular areas were admixed with hypercellular, round cell areas (5-80% of the analysed tumour area; 23 cases), and in round cell liposarcoma (three cases) rounded tumour cells predominated (>80% of the analysed tumour area). The average IMD in intermediate and high-grade malignant MFS (4.03 and 4.09, respectively) was significantly higher than in low-grade malignant MFS (2.73). Correlation of vascularity with the inflammatory infiltrate in MFS showed increased IMD only in cases with abundant neutrophils; most of these cases were high-grade malignant neoplasms. In contrast, no statistical correlation between morphological progression and IMD was seen in myxoid liposarcoma (6.08), MRLS (6.57) and round cell liposarcoma (4.07). VEGF mRNA was expressed by tumour cells in all histological grades of MFS and MRLS. VEGF receptor mRNA was weakly expressed by endothelia of newly formed blood vessels in both entities. Interestingly, tumour cells of all analysed cases of MFS strongly expressed collagen type I and thrombospondin-1, while these proteins were not detected in tumour cells of MRLS. In conclusion, morphologic tumour progression in MFS is associated with increased IMD, whereas, in MRLS, no such correlation is seen. Whereas VEGF and VEGF receptor mRNA were expressed in both entities, a characteristic expression profile of collagen type I and thrombospondin-1 in MFS emerged. Further studies are necessary to correlate vascularity and clinical course in MFS and MRLS.

Adolescent↗
PubMed2001

Clear cell sarcoma shows immunoreactivity for microphthalmia transcription factor: further evidence for melanocytic differentiation.

Microphthalmia transcription factor, a melanocytic nuclear protein critical for the embryonic development and postnatal viability of melanocytes, is a master regulator in modulating extracellular signals. Recently, microphthalmia transcription factor expression was shown to be both a sensitive and specific marker of epithelioid melanoma. We investigated the sensitivity of D5, an anti-microphthalmia transcription factor antibody, for diagnosis of clear cell sarcoma (also known as malignant melanoma of soft parts). Immunoreactivity in a nuclear pattern for D5 was present in 8 of 12 (75%) tumors. D5 staining was strong in three tumors, moderate in two, and weak in three. S-100 protein expression was seen in all 12 cases that had clear cell sarcoma examined. HMB-45 staining was seen in 11 of 12 (92%) tumors. Focal Melan-A positivity was seen in 3 of 7 (43%) tumors. Although D5 was shown in a previous study to be a highly sensitive and specific marker for epithelioid melanomas, the results of this study expand the spectrum of tumors showing immunoreactivity for D5. D5 immunoreactivity in clear cell sarcoma provides further evidence for melanocytic differentiation in this unusual tumor.

Adolescent↗
PubMed2001

Cellular myxoma of soft tissue: a clinicopathological study of 38 cases confirming indolent clinical behaviour.

AIMS: To characterize the clinicopathological features and biological potential of a group of soft tissue lesions with morphology intermediate between intramuscular myxoma and low-grade myxofibrosarcoma. METHODS AND RESULTS: Thirty-eight lesions in 37 patients were retrieved from the authors' consultation files. Clinical and follow-up data were obtained and the lesions were also studied immunohistochemically. Tumours occurred in adults aged 25-83 years (mean 51.9 years) with a slight predominance in females. All cases, except two, were solitary. The extremities were preferentially involved (18 lower limb; nine upper limb), with seven lesions arising around the upper (2/7) and lower limb (5/7) girdles and four lesions occurring at other locations. Twenty-nine of 31 of the tumours, for which the depth was known, were situated deep to the superficial fascia, although only 19 were strictly intramuscular. Histologically these lesions were both more cellular and more vascular than intramuscular myxoma, while lacking the cytological pleomorphism, nuclear atypia and curvilinear vascular pattern characteristic of low-grade myxofibrosarcoma. CD34 positivity in lesional cells was identified in 17/30 (57%) cases, probably reflecting their fibroblastic nature. Staining for alpha-smooth muscle actin was focally positive in 3/30 (10%) cases, while desmin and S100 protein staining were consistently negative. Clinical follow-up data (available in 22 cases; median duration 30 months) demonstrate that these lesions behave in a benign fashion with only a small risk of local recurrence if not excised completely; in this study only two tumours recurred, both of which originally had been incompletely excised. None metastasized. CONCLUSIONS: The risk of recurrence in this group of lesions which we have designated 'cellular myxoma' appears to be low. Consequently simple complete local excision is most often adequate treatment. Longer follow-up (5-10 years or more) in a larger number of cases will be important in more definitively confirming the natural history of these lesions.

Adult↗
PubMed2001

Primary liposarcoma of the orbit: a clinicopathologic study of seven cases.

Liposarcoma, the most common soft tissue sarcoma in adults, will rarely involve the orbit, either primarily or as a metastasis. We describe seven primary orbital liposarcomas, representing the largest documented series of primary orbital liposarcoma to date. Affected patients were three males and four females ranging in age from 28 to 69 years (median, 51 years). Five patients presented with painless proptosis, one patient had painful proptosis, and no details of presenting symptoms are available in one case. The site distribution was retrobulbar (3 cases), lateral orbital wall (2 cases), medial wall (1 case), and unspecified (1 case). Radiologic impression included hemangioma, lipoma, and an inflammatory process. Lesional size ranged from 2.8 to 4 cm. Five liposarcomas were purely well-differentiated, one was dedifferentiated, and one was pleomorphic in type. The well-differentiated cases comprised the following subtypes: spindle cell (2 cases), adipocytic (2 cases), and combined adipocytic/sclerosing/inflammatory (1 case). Five patients underwent orbital exenteration (one followed by radiation) and two had marginal/partial excision of their tumors. Follow-up was available for five patients, ranging from 13 to 204 months (median 65 months). Four patients showed no evidence of recurrence, including the patient with pleomorphic liposarcoma who had a long, disease-free survival (65 months) following marginal excision. One patient has had multiple recurrences following initial partial excision. One patient died of an unrelated cause with no clinical evidence of recurrence. Despite the difficulty in obtaining wide surgical margins, the small tumor size at presentation and the apparent predominance of the well-differentiated type means that the prognosis for orbital liposarcoma is generally good. In view of the various morphologic patterns that may occur, liposarcoma should be considered in the differential diagnosis of any histologically unusual mesenchymal lesion in the orbit.

Adult↗
PubMed2001

Inflammatory pseudotumor of lymph node and spleen: an entity biologically distinct from inflammatory myofibroblastic tumor.

Inflammatory pseudotumors (IPTs) of the lymph node and spleen are an uncommon, benign cause of lymphadenopathy and/or splenomegaly that often bear striking clinicopathologic similarities to the inflammatory myofibroblastic tumors (IMTs) found in soft tissues. These tumors have classically been grouped together under the umbrella category of "inflammatory pseudotumor." Recent evidence shows that IMTs are in fact neoplastic processes that often harbor balanced chromosomal translocations involving the ALK kinase gene. These translocations result in expression of ALK kinase in IMTs as assessed by immunohistochemical studies. However, the relationship between IMT and IPT of the lymph node and spleen is uncertain. To determine if ALK tyrosine kinase expression is also present in IPT, 13 cases of IPT (9 involving lymph nodes, 4 splenic lesions) were examined for the presence of ALK tyrosine kinase by immunohistochemical staining on paraffin-embedded tissue. In addition, in situ hybridization studies for Epstein-Barr virus--encoded RNAs (EBER) and immunoperoxidase studies for human herpesvirus-8 (HHV8)--specific proteins were performed. All cases had clinical, morphologic, and immunophenotypic findings typical of IPT and had varying proportions of fibroblastic and inflammatory components. Age ranged from 11 to 75 (median, 40) years; 8 subjects were male, and 5 were female. None of the cases (0 of 13) had positive staining for ALK kinase or HHV8, and in 1 a lymph node (1 of 13) was focally positive for EBV (EBER) by in situ hybridization. The absence of ALK kinase as detected by immunohistochemical studies in IPT of the lymph node and spleen suggests that this entity is biologically distinct from the histologically similar IMT.

Adult↗
PubMed2001

"Juvenile" xanthogranuloma: an immunophenotypic study with a reappraisal of histogenesis.

The non-Langerhans histiocytoses, a nosologic category to which juvenile xanthogranuoma (JXG) belongs, represent a heterogenous collection of disorders related to the monocyte/macrophage lineage. The dermal dendrocyte was previously proposed as the cell of origin for JXG on the basis of Factor XIIIa reactivity, a suggestion that does not fully explain the occasional xanthogranulomatous proliferations localizing exclusively to extracutaneous sites. This study applies a panel of recently developed immunohistochemical markers to JXGs and relates the phenotype of this process to new concepts of monocyte/dendritic cell ontogeny. Twenty-seven JXG, ten dermatofibromas (DF), and ten age-matched normal skin specimens were stained using standard immunohistochemistry methods, and all JXGs were fascin+ and CD68+, although 26 of 27 were reactive for HLA-DR, 25 of 27 for Factor XIIIa, 25 of 27 for LCA, 21of 27 for CD4, and 8 of 27 for polyclonal s100. Six of those eight polyclonal S100+ cases were also reactive for monoclonal S100. None of those cases was reactive for CD1a, CD3, CD21, CD34, or CD35. Eight of ten dermatofibromas were FXIIIa+; all were negative for HLA-DR, LCA, CD4, and polyclonal s100. In controls, fascin+ dendritic cells were present but did not stain for Factor XIIIa, S100, or CD4. Based on the morphologic and phenotypic overlap of the lesional cells in JXGs and plasmacytoid monocytes, it would appear that the plasmacytoid monocyte might be considered the putative normal counterpart of the major cellular population of JXGs, a proposal that helps explain the extra-cutaneous, visceral, and soft tissue location that have been reported for occasional cases of JXG. We would also conclude that neither Factor XIIIa-nor S100+ results should preclude the diagnosis of JXG, and find that reactivity for CD4 and LCA may be used to distinguish JXG from DF when the latter is heavily lipidized or the former is not.

Adolescent↗
PubMed2001

Microphthalmia transcription factor: not a sensitive or specific marker for the diagnosis of desmoplastic melanoma and spindle cell (non-desmoplastic) melanoma.

Microphthalmia transcription factor (Mitf), a melanocytic nuclear protein critical for the embryonic development and postnatal viability of melanocytes, is a master lineage regulator and modulates extracellular signals. Recently, Mitf expression was shown to be both a sensitive and specific marker of epithelioid melanoma. Because loss of specific melanocytic markers in melanomas with spindle cell morphology is more common compared with those tumors with epithelioid morphology, we investigated the sensitivity of D5, an anti-Mitf antibody, for diagnosis in this diagnostically problematic subset of melanomas. Twenty of 21 (95%) spindle cell and desmoplastic melanomas examined were reactive for S-100 protein. Only 4 of 21 (19%) spindle cell and desmoplastic melanomas were reactive for HMB-45. Six of 21 tumors (29%) were reactive for D5, including one case that was non-reactive for S-100 and HMB-45. Melan-A reactivity was seen in 2 of 13 cases (15%) studied. Eight of 24 (33%) non-melanocytic spindle cell tumors were reactive for D5, including 4 of 6 dermatofibromas, 1 of 6 schwannomas, 1 of 2 leiomyomas, and 2 of 6 leiomyosarcomas. Although D5 was shown in a previous study to be a highly sensitive and specific marker for epithelioid melanomas, the results of this study show it is not a sensitive or specific marker of spindle cell and desmoplastic melanomas. Nevertheless, we believe that diffuse positive staining for D5 when taken in clinical, histologic and immunohistochemical context may be diagnostically useful in selected cases of melanoma.

Adult↗
PubMed2001

Expanding the spectrum of malignant change in schwannomas: epithelioid malignant change, epithelioid malignant peripheral nerve sheath tumor, and epithelioid angiosarcoma: a study of 17 cases.

Schwannomas (neurilemmomas) rarely undergo malignant change, most often in the form of either malignant peripheral nerve sheath tumor (MPNST) or angiosarcoma. We characterize the clinical features and the histopathologic spectrum of 17 schwannomas with evidence of malignant change. The study group comprised 7 males and 10 females with an age range of 16 to 76 years, (median, 40 yrs). None of the patients had neurofibromatosis. Lesions ranged in size from 0.6 to 10.5 cm (median, 4.0 cm) and arose mainly in the limbs/limb girdles (7 cases) or head and neck region (7 cases). All tumors contained areas of conventional benign schwannoma. Four cases of pure epithelioid malignant peripheral nerve sheath tumor (EMPNST) were identified, three of which showed immunopositivity for S-100 protein. Four angiosarcomas were identified, predominantly epithelioid-type. Ten schwannomas had an appearance that we have designated epithelioid malignant change (EMC) and, in one of these, EMC coexisted with EMPNST. Large epithelioid cells with abundant eosinophilic cytoplasm, vesicular chromatin, and prominent nucleoli (morphologically similar to cells of EMPNST) were distributed throughout the schwannoma--singly, in clusters, and in one case a microscopic nodule of such cells was also present. These large epithelioid cells were strongly positive for S-100 protein. Although follow-up data so far are limited, 1 of 5 patients with EMC in whom meaningful follow up was available developed repeated local recurrence (median follow up, 21 mos), one patient each with EMPNST and angiosarcoma died of local and metastatic disease. Pure EMPNST is rare; however, we confirm the tendency of MPNST to show epithelioid cytomorphology when arising in a benign schwannoma. We also confirm the distinctive (albeit infrequent) tendency of angiosarcoma to arise in schwannomas. We describe EMC in schwannomas and suggest that this represents a putative precursor lesion of EMPNST. At this time, we do not have an explanation for the tendency of schwannomas to show epithelioid cytomorphology when they undergo malignant change.

Adolescent↗
PubMed2001

Malignant epithelioid angiomyolipoma ('sarcoma ex angiomyolipoma') of the kidney: a case report and review of the literature.

Malignant epithelioid angiomyolipoma is a recently described rare tumor of the kidney. Its existence has been questioned, however, on the basis of incomplete evidence of malignant behavior, the absence of an associated classic angiomyolipoma component, or the absence of immunoreactivity for HMB-45 in some cases. We describe a case that was HMB-45-positive and arose in association with a classic angiomyolipoma. The patient was treated with a partial nephrectomy. Three years later, she developed rapidly enlarging liver nodules. A fine-needle aspiration of the liver confirmed the presence of pleomorphic epithelioid cells morphologically and immunohistochemically identical to those comprising the primary renal tumor. After two cycles of treatment with doxorubicin, there was a 50% reduction in the size of the tumors with marked improvement in performance status. We believe this case confirms the existence of a malignant epithelioid angiomyolipoma.

Angiomyolipoma↗
PubMed2001

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.

Adult↗
PubMed2001

Mammary-type myofibroblastoma of soft tissue: a tumor closely related to spindle cell lipoma.

Mammary myofibroblastoma is a benign breast tumor, with a reported predilection for older men. It is composed of fascicles of spindle cells having features of myofibroblasts, with intervening hyalinized collagenous stroma and a variably prominent component of adipose tissue. The spindle cells characteristically express both CD34 and desmin. Herein, we report the clinicopathologic features of nine tumors that were morphologically and immunohistochemically identical to myofibroblastoma of breast; however, they arose in subcutaneous soft tissue at extramammary sites. The study group comprised seven men and two women with an age range of 35-67 years (median 53 years). Lesions presented as either a slowly growing painless mass or were incidental findings at the time of surgery. The site distribution was as follows: inguinal/groin area (five cases) and one case each in posterior vaginal wall, buttock, anterior abdominal wall, and mid-back. Tumor size ranged from 2 to 13 cm (median 6 cm), and all lesions were well circumscribed. Eight tumors had a component of adipose tissue (ranging from 10% to 60%), within which some variation in adipocyte size was often seen. One case showed epithelioid cytomorphology and three cases showed rare atypical or multinucleated cells. Focal myxoid stromal change was seen in four cases. Tumor cells were positive for desmin (9 of 9 cases), CD34 (8 of 9 cases), and occasionally positive for smooth muscle actin (3 of 9 cases). Lesions were marginally excised with no recurrences to date, although follow-up is very limited. Lesions with morphologic and immunophenotypic features similar to myofibroblastoma of breast can arise at extramammary sites, with an apparent predilection for the inguinal area of older men. Both mammary and extramammary lesions show morphologic overlap with spindle cell lipoma and are likely closely related.

Adult↗