Jeanne M. Meis-Kindblom

Malignant granular cell tumor of soft tissue. Diagnostic criteria and clinicopathologic correlation

Seventy-three cases of malignant, atypical, and multicentric granular cell tumors of soft tissue were studied to clarify criteria for malignancy and prognostic factors. Six histologic criteria were assessed: necrosis, spindling, vesicular nuclei with large nucleoli, increased mitotic activity (> 2 mitoses/10 high-power fields at 200x magnification), high nuclear to cytoplasmic (N:C) ratio, and pleomorphism. Neoplasms that met three or more of these criteria were classified as histologically malignant; those that met one or two criteria were classified as atypical; and those that displayed only focal pleomorphism but fulfilled none of the other criteria were classified as benign. Hence, 46 cases were classified as histologically malignant, 21 as atypical (3 were multicentric), and 6 as benign (all were multicentric). The patients with benign multicentric and atypical granular cell tumors had no metastases and there were no tumor deaths. In contrast, 11 of 28 patients (39%) with malignant granular cell tumor with follow-up information died of disease at a median interval of 3 years; 8 of 28 (29%) were alive with disease, and 9/28 (32%) were disease free (median intervals, 2 and 7 years, respectively). There were local recurrences in 9 of 28 malignant cases (32%) and metastases in 14 of 28 (50%) (median intervals, each 2 years). Forty-eight cases were studied immunohistochemically; 100% expressed vimentin, 98% S-100 protein, 98% neuron-specific enolase, 69% CD57, and 65% CD68. Alpha-smooth muscle actin, desmin, epithelial membrane antigen (EMA), cytokeratins (with CAM 5.2 and KL-1), chromogranin, and HMB45 were not detected. The proliferative index with Ki67 (MIB 1) was 10-50% in 14 of 25 malignant tumors (56%), and immunostaining for p53 was detected in 50% or more of tumor cells in 17 of 25 (68%); both of these factors were statistically significant with regard to the histologic classification as benign, atypical, or malignant. Ultrastructural examination of 13 benign, atypical, and malignant granular cell tumors showed engorgement of the cytoplasm with complex granules and lysosomes, as well as Schwannian features. By flow cytometric DNA analysis, two of six malignant tumors were aneuploid, two were hyperdiploid, and two were diploid. One atypical tumor was aneuploid and all 11 benign tumors were either diploid (9 cases) or hyperdiploid (2 cases). Statistically significant adverse prognostic factors with regard to survival included local recurrence, metastasis, larger tumor size, older patient age, histologic classification as malignant, presence of necrosis, increased mitotic activity, spindling of tumor cells, vesicular nuclei with large nucleoli, and Ki67 values greater [corrected] than 10%. This study defines clinical and morphologic criteria for malignancy in granular cell tumors and shows that malignant granular cell tumor is a high-grade sarcoma with a high rate of metastases and a short survival.

NF1-associated gastrointestinal stromal tumors have unique clinical, phenotypic, and genotypic characteristics

Gastrointestinal stromal tumors (GIST) have been reported to occasionally occur in patients with neurofibromatosis type 1 (NF1). This study aims to describe the phenotypic and genotypic characteristics of GIST in NF1 patients and attempts to elucidate the relationship between them. We analyzed GIST arising in 15 NF1 patients (8 males and 7 females, 19-82 years of age). Eleven patients had multiple GISTs (3 to >100 tumors) ranging from 1 mm to 10 cm in size and predominantly involving the small intestine including the duodenum. Tumors were symptomatic in 8 patients and incidental findings in the remaining 7 patients. Microscopically, the tumors cells were typically spindled and the mitotic rate low; 9 patients had tumors classified as very low or low risk and 6 as intermediate risk GIST. Nine patients were treated surgically and none developed metastases or died of disease. Immunohistochemical stains for CD117 were strongly positive in 47 of 50 GIST; they also accentuated hyperplastic foci (diffuse and focal) of the interstitial cells of Cajal that were often associated with microscopic GIST in the surrounding intestinal muscle wall. No KIT or PDGFRA mutations were detected in 24 GIST from 12 patients using dHPLC analysis and DNA sequencing. We conclude that patients with NF1 have a high risk of developing GIST. NF1-associated GIST are also phenotypically and genotypically distinct from sporadic GIST, indicating that different pathogenetic mechanisms are involved in their evolution.

Extraskeletal myxoid chondrosarcoma: A reappraisal of its morphologic spectrum and prognostic factors based on 117 cases

Extraskeletal myxoid chondrosarcoma (EMC), a phenotypically and genotypically distinctive entity, has generally been viewed as a low-grade sarcoma. No studies regarding clinical and morphologic prognostic factors have been performed on a large series of cases with long-term follow-up because of the rarity and protracted clinical course of EMC. The clinical, morphologic, and immunohistochemical features of 117 previously unreported cases were studied and statistically analyzed. The male-to-female ratio was 2:1. The median patient age was 52 years (range, 6-89 years), and the median tumor size was 7 cm (range, 1.1-25 cm). All tumors occurred within the deep subcutis or deeper soft tissues, with 80% occurring in the proximal extremities or limb girdles and 20% in the trunk. Most initial tumor excisions were intralesional or marginal. Follow-up information was available in 99 cases (median, 9 years: range, 2 months-22 years). Forty-eight patients were disease-free, and 41 patients had evidence of disease (18 of these had died of disease). Ten additional patients survived, but their disease status was unknown. There were local recurrences in 40 (48%) of 83 patients, 23 (58%) of whom had multiple local recurrences. Metastases occurred in 35 (46%) of 76 patients. The estimated 5-, 10-, and 15-year survival rates were 90%, 70%, and 60%, respectively. All cases had histologic features characteristic of classical EMC, at least focally. Cellular foci devoid of myxoid matrix and reminiscent of chondroblastoma, Ewings sarcoma, monophasic and poorly differentiated synovial sarcoma, fibrosarcoma, and rhabdoid tumor were identified in 29% cases. Older patient age, larger tumor size, and tumor location in the proximal extremity or limb girdle were adverse prognostic factors identified by multivariate analysis. Metastasis also adversely affected survival, although local recurrence did not. This study shows that EMC has a unique clinical course, including a high rate of local recurrence, prolonged survival after metastasis in some cases, and eventually a high rate of death due to tumor. These features distinguish EMC from low-grade sarcomas. This study shows that histologic grading is of no prognostic value in EMC because prognosis is dictated primarily by certain clinical features. Histologic recognition of classical EMC and cellular and solid, nonmyxoid variants is important, however, in view of EMCs distinctive biologic behavior.

Acral Myxoinflammatory Fibroblastic Sarcoma: A Low-grade Tumor of the Hands and Feet

Acral myxoinflammatory fibroblastic sarcoma is a unique low-grade tumor of modified fibroblasts. It characteristically occurs in the distal extremities and has a propensity to recur locally. Forty-four cases that occurred in 22 males and 22 females from 20 to 91 years of age (median, 53 years) were studied. The lesions, which were 1-6 cm (median, 3 cm), occurred in the hands (64%), the feet (20%), the ankles (11%), and the wrists (5%). The patients usually had a long history of a painless mass (median duration, 1 year). Clinically they were suspected to be ganglion cysts, tenosyonovitis, or giant cell tumors of tendon sheath. Initial histologic diagnoses, in most cases, included pigmented villonodular tenosynovitis or various reactive fibroinflammatory processes. Histologically, the lesions were multinodular, poorly delineated, and characterized by a prominent myxoid matrix containing numerous inflammatory cells, including polymorphonuclear leukocytes, eosinophils, lymphocytes, and plasma cells, as well as fibrosis. Amidst the prominent inflammation, and sometimes obscured by it, were scattered, large, bizarre tumor cells with vesicular nuclei, prominent inclusion-like nucleoli, and abundant eosinophilic cytoplasm, which was homogeneous to vacuolated and often contained intracytoplasmic inflammatory cells. Ultrastructurally, the bizarre tumor cells had features of modified fibroblasts, including an abundance of intermediate filaments and dilated rough endoplasmic reticulum. Immunohistochemically, the neoplastic cells revealed strong positivity for vimentin (25 of 25), focal positivity for CD68 antigen (17 of 25) and CD34 (7 of 25); the tumor cells did not express neuroectodermal, epithelial, or lymphoid markers. The Ki67 labeling index with MIB1 was less than 1% in 20 of 25 cases; p53 immunoreactivity (20-90%) was observed in 7 of 25 primary tumors and in 2 of 3 local recurrences. Follow-up information was available in 36 of 44 cases (median, 5 years). Most excisions were either intralesional or marginal. Ten patients underwent amputation, usually after repeated local recurrences. Radiation therapy and chemotherapy were administered in five and two cases, respectively. Twenty-four cases (67%) had at least one local recurrence. A histologically proven lymph node metastasis developed in one patient, whereas another was stated to have lung metastases, although these were not documented histologically. At last follow-up, 23 patients were alive and well, 11 were alive with disease, and 2 were dead of other causes without evidence of tumor. The prominent inflammation and fibrosis seen histologically in acral myxoinflammatory fibroblastic sarcoma simulate a reactive process. The presence of myxoid foci and scattered bizarre cells, which are occasionally multivacuolated, may cause confusion with malignant fibrous histiocytoma and liposarcoma. Based on the protracted clinical course, a high rate of local recurrence (sometimes necessitating amputation), and a low rate of metastasis, we believe these tumors are low-grade sarcomas. The intimate relationship with the synovium, the frequent association with tenosynovitis, and the prominent inflammatory infiltrate suggest that inflammation may play a role in the pathogenesis of acral myxoinflammatory fibroblastic sarcoma.

Deregulation of the hedgehog signalling pathway: a possible role for the PTCH and SUFU genes in human rhabdomyoma and rhabdomyosarcoma development.

The naevoid basal cell carcinoma syndrome (NBCCS) is caused by mutations in the hedgehog receptor PTCH gene. It is characterized by developmental defects and a predisposition to the development of certain tumours, such as basal cell carcinoma, medulloblastoma and meningioma, and potentially fetal rhabdomyomas and embryonal rhabdomyosarcomas. This study aimed to analyse PTCH status in an NBCCS patient with fetal rhabdomyoma and to investigate whether deregulation of hedgehog signalling, as shown by altered expression of hedgehog pathway components and/or genetic imbalances, is a general finding in sporadic rhabdomyomas and rhabdomyosarcomas. The NBCCS patient had a novel PTCH germ‐line mutation, 1370insT, and developed a fetal rhabdomyoma that harboured a 30 bp in‐frame deletion in the second allele resulting in homozygous inactivation of PTCH. Sporadic rhabdomyomas and rhabdomyosarcomas showed overexpression of PTCH (43/43) and GLI1 (41/43) mRNA, as determined by in situ hybridization, indicating ongoing active hedgehog signalling. Immunohistochemical staining revealed a subgroup of fetal rhabdomyomas and embryonal rhabdomyosarcomas (12/34) lacking PTCH immunoreactivity. Four of nine informative fetal rhabdomyomas and embryonal rhabdomyosarcomas showed loss of heterozygosity (LOH) in the PTCH region with two of these (one fetal rhabdomyoma and one embryonal rhabdomyosarcoma) also showing LOH in the SUFU region. These findings suggest that haploinsufficiency for the two tumour suppressor genes PTCH and SUFU, which are both active in the same signalling pathway, may be important for tumour development. Based on our results we propose that the pathogenesis of rhabdomyoblastic tumours, particularly fetal rhabdomyomas and embryonal rhabdomyosarcomas, involves deregulation of the hedgehog signalling pathway. Copyright

Neoadjuvant, adjuvant and palliative treatment of gastrointestinal stromal tumours (GIST) with imatinib : a centre-based study of 17 patients

Malignant gastrointestinal stromal tumours (GIST) have a poor prognosis. Since these tumours are resistant to conventional radiation and chemotherapy, surgery has been the mainstay of treatment. However, surgery is usually inadequate for the treatment of malignant GIST. Imatinib, a KIT tyrosine kinase inhibitor, has recently been found to have a dramatic antitumour effect on GIST. In this centre-based study of 17 consecutive patients with high-risk or overtly malignant GIST, imatinib was used in three different settings – palliatively, adjuvantly, and neoadjuvantly. The treatment was found to be safe and particularly effective in tumours with activating mutations of exon 11 of the KIT gene. Clinical response to imatinib treatment correlated morphologically to tumour necrosis, hyalinisation, and reduced proliferative activity. The value of neoadjuvant imatinib treatment was illustrated in one case.

Adjuvant imatinib treatment improves recurrence-free survival in patients with high-risk gastrointestinal stromal tumours (GIST)

Palliative imatinib treatment has dramatically improved survival in patients with malignant gastrointestinal stromal tumours, particularly in patients with tumours harbouring activating KIT mutations. To evaluate the effectiveness of adjuvant imatinib after radical surgery, a consecutive series of patients with high-risk tumours (n=23) was compared with historic controls (n=48) who were treated with surgery alone. The mean follow-up period was over 3 years in both groups. Only 1 out of 23 patients (4%) in the adjuvant treatment group developed recurrent disease compared to 32 out of 48 patients (67%) in the control group. This preliminary study indicates that 1 year of adjuvant treatment with imatinib dramatically improves recurrence-free survival. Confirmation of these findings awaits the results of ongoing randomised studies.

Growth hormone receptor is expressed in human breast cancer

Several clinical observations and experimental studies indicate that pituitary hormones, including growth hormone, play a role in the development of human breast cancer. We analyzed 48 human breast carcinomas using reverse transcription polymerase chain reaction, immunohistochemistry, and Western blotting techniques to assess growth hormone receptor expression. In 17 of these cases, adjacent normal breast tissue was similarly analyzed. These analyses revealed that growth hormone receptor (GHR) is expressed in human breast cancer and appears to be up-regulated compared to adjacent normal breast tissue. GHR expression correlated inversely with tumor grade and MIB-1 index. Progesterone receptor expression correlated positively with GHR expression. These findings, along with our observation of GHR expression in breast cancer stromal cells and previous reports of local production of growth hormone in breast carcinoma, suggest that GHR-mediated signaling pathways are involved in the development of human breast cancer, possibly via autocrine or paracrine mechanisms.

Ectomesenchymal chondromyxoid tumor of the anterior tongue: nineteen cases of a new clinicopathologic entity

We present 19 cases of a previously undescribed myxoid tumor of the anterior tongue. These lesions occurred in nine women and 10 men aged 9 to 78 years (median, 32 years). Most tumors were seen as slow growing, painless nodules in the anterior dorsal tongue. The duration of growth ranged from a few months of 10 years. All tumors were treated by surgical excision, and two recurred. Microscopically, they exhibited a lobular proliferation of ovoid and fusiform cells, which often had multilobated nuclei and occasional foci of atypia, in a chondromyxoid background. Some tumors entrapped muscle or nerve fibers and had a tendency for blunt infiltration of adjacent tissue. The cells were diffusely and intensely immunore active for glial fibrillary acidic protein (GFAP) and cytokeratin but were decorated less frequently with antibodies for smooth muscle actin and S-100 protein. Reactivity for epithelial membrane antigen and desmin was not found. We believe these tumors fail to meet established clinicopathologic criteria for any existing myxoid neoplasms of the tongue, including nerve sheath myxoma, myoepithelioma, benign mixed tumor, ossifying fibromyxoid tumor of soft parts, extraskeletal myxoid chondrosarcoma, and glial and chondroid choristomas or heterotopias. Although the histogenesis of this neoplasm is unclear, we suspect that a cell of undifferentiated ectomesenchyme is the progenitor and suggest the descriptive term ectomesenchymal chondromyxoid tumor (ECT) of the the anterior tongue be adopted.

Benign epithelioid schwannoma

Benign schwannoma (neurilemoma) has various morphologic patterns that may cause problems in differential diagnosis. Although an epithelioid variant of malignant schwannoma simulating carcinoma and melanoma is well recognized, a benign counterpart has not yet been defined. In the current study, we describe five cases of benign epithelioid schwannoma that were in the subcutis (four cases) and the neck of the urinary bladder (one case). The tumors occurred in adults 28-73 years of age, were 1-4.5 cm in diameter, were well circumscribed and cellular, and were composed of epithelioid cells arranged in cords and nests. The benign nature of the lesions was evident by a constellation of features, including small size, sharp circumscription, bland morphology, low proliferative activity (four of five had < or =1% Ki67 immunostaining), and a benign clinical course after either marginal or intralesional excision. All cases had some features of classic schwannoma light microscopically and a high degree of Schwann cell differentiation both ultrastructurally and immunohistochemically. The recognition of benign epithelioid schwannoma is important because it may be misinterpreted as a malignant neuroectodermal, mesenchymal, epithelioid, or melanocytic tumor.