Robin Reid

Clinicopathologic and molecular genetic characterization of low-grade fibromyxoid sarcoma, and cloning of a novel FUS/CREB3L1 fusion gene.

Low-grade fibromyxoid sarcoma (LGFMS) is an indolent, late-metastasizing malignant soft-tissue tumor that is often mistaken for either more benign or more malignant tumor types. Cytogenetic analyses have identified a recurrent balanced translocation t(7;16) (q32–34;p11), later shown by molecular genetic approaches to result in a FUS/CREB3L2 fusion gene. Whereas preliminary studies suggest that this gene rearrangement is specific for LGFMS, its incidence in this tumor type and the possible existence of variant fusion genes have not yet been addressed. For this purpose, a series of potential LGFMS were obtained from nine different soft-tissue tumor centres and subjected to molecular analysis as well as careful histopathologic review. Reverse transcriptase-polymerase chain reaction analysis disclosed a FUS/CREB3L2 fusion transcript in 22 of the 23 (96%) cases that remained classified as LGFMS after the histologic re-evaluation and from which RNA of sufficient quality could be extracted, whereas none of the cases that were classified as other tumor types was fusion-positive. In one of the tumors with typical LGFMS appearance, we found that FUS was fused to the CREB3L1 gene instead of CREB3L2. The proteins encoded by these genes both belong to the same basic leucine-zipper family of transcription factors, and display extensive sequence homology in their DNA-binding domains. Thus, it is expected that the novel FUS/CREB3L1 chimera will have a similar impact at the cellular level as the much more common FUS/CREB3L2 fusion protein. Taken together, the results indicate that virtually all LGFMS are characterized by a chimeric FUS/CREB3L2 gene, and that rare cases may display a variant FUS/CREB3L1 fusion.

Gastrointestinal stromal tumors (GIST): C-kit mutations, CD117 expression, differential diagnosis and targeted cancer therapy with imatinib

Gastrointestinal stromal tumors (GISTs) have been recognised as a biologically distinctive tumor type, different from smooth muscle and neural tumors of the gastrointestinal tract. They constitute the majority of gastrointestinal mesenchymal tumors. They are defined and diagnosed by the expression of a protooncogene protein called CD117 detected by immunohistochemistry. It is now believed that GISTs originate from gastrointestinal pacemaker cells known as interstitial cells of Cajal, that control gut motility or from a precursor of these cells. The identification of mutations mostly in exon 11 and to a lesser extent in exons 9 and 13 of the c-kit protooncogene coding for c-kit (CD117) in many GISTs, has resulted in a better understanding of their oncogenic mechanisms. The finding of remarkable antitumor effects of the molecular inhibitor, imatinib (Glivec™) in metastatic and inoperable GISTs, has necessitated accurate diagnosis of GISTs and their distinction from other gastrointestinal mesenchymal tumors. To achieve this, pathologists need to be familiar with the spectrum of histological appearances shown by GISTs and have a high index of suspicion for these tumors. This review summarises recent advances in knowledge regarding the histogenesis, pathology, molecular biology, genetics and differential diagnosis of GISTs and the basis for the novel targeted cancer therapy with imatinib.

Low-grade fibromyxoid sarcoma and hyalinizing spindle cell tumor with giant rosettes share a common t(7;16)(q34;p11) translocation.

Low-grade fibromyxoid sarcoma (LGFMS) is a rare metastasizing soft tissue tumor with deceptively bland histologic features. The hyalinizing spindle cell tumor with giant rosettes (HSCT) is thought to be a closely related tumor differing only by the presence of collagen rosettes. We report the occurrence of a common t(7;16)(q34;p11) translocation in 2 cases of HSCT and 2 cases of LGFMS, thereby providing the first cytogenetic proof that LGFMS and HSCT are variants of the same entity. The tumors occurred in the thighs of 2 females and in the buttock and supraclavicular fossa of 2 males. One HSCT had a spectrum of unusual histologic features, including the presence of plump epithelioid cells with abundant cytoplasm and strands and nests of clear epithelioid cells separated by eosinophilic hyalinized stroma. Two cases showed a hitherto unreported, focal staining with epithelial membrane antigen, thus adding to the immunohistochemical profile of these tumors. LGFMS and HSCT probably have a wider spectrum of morphologic features than previously thought, the awareness of which will help pathologists to avoid diagnostic pitfalls. Demonstration of the t(7;16)(q34;p11) translocation will help to diagnose difficult cases with unusual histologic features.

Chondrosarcoma of small bones of the hand.

A clinicopathological review of 23 patients (mean age, 67 years; range, 42–85 years) with chondrosarcoma of the bones of the hand was done. The mean follow up was 8.5 years. Eleven patients presented with a progressive painless swelling, 26% having had symptoms for over 10 years. The proximal phalanx was the commonest site. Initial clinical misdiagnosis as ganglion, bursa, gout, rheumatoid arthritis and a cyst occurred in five patients. Radiologically most lesions showed bone expansion, cortical destruction and soft-tissue extension. The majority was of high histologic grade (Evan’s grade 2 & 3) with extensive myxoid areas. Five out of eight patients who were originally treated by curettage or excision had local recurrences compared to none treated by ray resection or amputation of phalanx (P=0.002). None had metastases. The low risk of metastases despite the high histologic grade indicates that chondrosarcomas of the hand behave differently from chondrosarcomas elsewhere.

Myositis Ossificans and Fibroosseous Pseudotumor of Digits: A Clinicopathological Review of 64 Cases with Emphasis on Diagnostic Pitfalls

Myositis ossificans (MO) and fibroosseous pseudotumor of digits (FP) are pseudotumoral mimics of malignancy. A review of 50 cases of MO and 14 cases of FP showed that a malignant diagnosis was suggested by referring pathologists in 23% of MO and 9% of FP. The most common misdiagnosis was osteosarcoma. Awareness of the spectrum of clinicopathological features of MO and FP will help pathologists avoid misdiagnoses. A comparison of the clinicopathological features of MO and FP showed that most features were similar, but FP involved an older age group (p<0.001). MO showed a statistically significant higher tendency to contain fibrinous material (p=0.007), edematous lymphangioma-like areas (p=0.01 3), and cartilage (p=0.017) and FP to contain excessive immature osteoid (p=0.029). These differences may be related to the site of occurrence

Chondroblastoma: Varied Histologic Appearance, Potential Diagnostic Pitfalls, and Clinicopathologic Features Associated With Local Recurrence

Chondroblastoma is a rare, benign bone tumor. Although it has distinctive clinicopathologic features, its wide morphologic spectrum may pose diagnostic problems. We present the clinicopathologic features of 42 patients (28 males, 14 females; age range, 8 to 66 years), with emphasis on unusual histologic features, potential diagnostic pitfalls, and factors associated with recurrence. Thirty-four tumors were in long bones, with the most common site being the proximal femur. Unusual histologic features included the presence of atypical, epithelioid, spindle, and foamy cells and necrosis and a diffuse basophilic myxoid matrix. Tumors with focal osteoclast-like giant cell rich areas (n = 11), prominent cystic change (n = 8) and extensive fibromyxoid areas (n = 3) resembled giant cell tumors, aneurysmal bone cysts, and chondromyxoid fibromas, respectively. The diagnosis of referring pathologists was inaccurate in 34% of cases. Six patients (14%) had local recurrence. The only clinical feature significantly associated with increased risk of local recurrence was duration of symptoms for less than 6 months (log rank P =.003). None of the histologic features was significantly associated with recurrence. These included worrisome features such as cellular atypia, necrosis, and mitoses. None of the patients had metastases. An increased awareness of the morphologic spectrum of chondroblastomas will enable pathologists to avoid diagnostic pitfalls. We emphasize the need for a combined clinical, radiologic and histologic approach to the diagnosis of chondroblastomas.

Imatinib in the Management of Multiple Gastrointestinal Stromal Tumors Associated With a Germline KIT K642E Mutation

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gut and are distinguished by expression of CD117 (c-Kit). Oncogenic mutations in the KIT or PDGFRA gene are detected in approximately 85% of sporadic GISTs. In recent years, examples of familial GIST have been reported in which germline mutations of KIT or PDGFRA result in multiple GISTs, skin disorders, and other abnormalities. The most common germline mutations are in KIT exon 11, mutations in exons 8 and 17 have also been described, and there are 2 families with germline PDGFRA mutations. We present a case in which a germline KIT exon 13 mutation (K642E) was discovered in a patient with multiple GISTs of rectum, small intestine, and esophagus, as well as diffuse hyperplasia of the interstitial cells of Cajal. To our knowledge, this is only the second germline example of this particular mutation. The patients esophageal tumors were stabilized with imatinib.

Paget Sarcoma of the Spine : Scottish Bone Tumor Registry Experience

Study Design. Retrospective case study of 13 cases of Paget sarcoma of the spine accrued from a prospectively collected Tumor Registry database. Objectives. To analyze the clinical, radiologic, and histologic features of Paget sarcoma of the spine and to determine the factors influencing the prognosis. Summary of Background Data. Paget disease of bone is a common disorder with the spine being involved in over 50% of patients. However, sarcomatous degeneration in the vertebral column is an extremely rare complication. There is very little in the literature with regard to clinical presentation and prognosis of patients with Paget sarcoma affecting the vertebral column. Methods. Between January 1944 and December 2003, 89 patients were registered with a diagnosis of Paget sarcoma in the Scottish Bone Tumor Registry. Thirteen patients with Paget sarcoma of the spine were analyzed with regard to their clinical, radiologic, and histopathologic features along with the prognostic predictors. Results. The mean age was 66.9 years (range: 56–79 years). There were 10 males and three females. There were seven cases involving the sacral spine (63.6%), three cases involving lumbar vertebrae, two affecting the dorsal spine, and one with diffuse dorsolumbar involvement (D11–L3). The mode of presentation was progressively increasing low back pain (in all 13), unilateral sciatica (six; left-sided, five; right-sided, one), bilateral sciatica (two), lower limb weakness (eight), and autonomic dysfunction (four). Ten of 13 cases (76.9%) were osteosarcoma. The rest were chondrosarcoma (n = 1), fibrosarcoma (n = 1), and malignant fibrous histiocytoma (n = 1). Decompression laminectomy was performed in three patients with progressive neurologic deficit. Eight patients had received radiotherapy. The mean survival was 4.22 months. Conclusions. This series confirmed that Paget sarcoma of the spine has a very poor prognosis. We found a constellation of symptomatology in patients with sarcomatous Paget spine resulting from radiculomedullary compression, primarily lumbosacral involvement and predominantly osteosarcomatous histology. There was no significant difference observed on the overall prognosis of the patients with Paget sarcoma of the spine in the last 6 decades.

Prognostic factors associated with local recurrence, metastases, and tumor-related death in patients with synovial sarcoma.

Prognostic factors associated with local recurrence, metastases, and tumor-related death in synovial sarcoma were studied in 51 patients in the Scottish Bone Tumor Registry from 1955 to 1999. In a multivariate analysis, the presence of poorly differentiated (PD) areas was the strongest prognostic factor associated with local recurrence (Hazard ratio [HR] = 11.3, 95% CI 2.3, 122.5, p = 0.033), metastases (HR = 16.9, 95% CI 2.3,122.5, p = 0.005), and tumor-related death (HR = 6.9, 95% CI 1.1,41.8, p = 0.036). Other significant independent risk factors included bone invasion (HR = 16.6, 95% CI 1.1, 252.5, p = 0.043) and necrosis (HR = 5.1, 95% CI 1.4, 18.99, p = 0.016) for metastases and bone invasion (HR = 17.6, 95% CI 1.2, 253.2, p = 0.035) for tumor-related death. Increasing percentages of PD areas and necrosis were associated with increasing hazard ratios for metastases and death. In the univariate analysis, PD areas, tumor size, and a mitotic count over 10/10 high-power fields were significantly associated with recurrence, whereas necrosis, vascular invasion, and age more than 25 years were additional risk factors for metastases and death. Local recurrence was significantly associated with increased risks for metastases (OR = 6.8, 95% CI 1.6, 28.7, p = 0.006), and death (all cases). Histologic features such as PD areas, necrosis, vascular invasion, and bone invasion should be considered when deciding about adjuvant therapy.

Balloon cell metastatic melanoma : an important differential in the diagnosis of clear cell tumours

Two cases of metastatic balloon cell melanoma are reported. Each tumour was composed of large clear cells which did not contain melanin, glycogen or fat, but showed positive staining for S‐100 protein, NK/1‐C3 and HMB‐45. In each case the primary lesion was a cutaneous melanoma of typical morphology. It is essential to consider balloon cell melanoma in the differential diagnosis of clear cell tumours. These cases emphasize the need for an accurate clinical history.