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The biological behaviour of a gastrointestinal stromal tumor (GIST) cannot be easily predicted from preoperative clinical examination alone. As a result, there is little standardization in the surgical treatment of GIST. In this study, we analyzed the clinicopathology and immunohistochemistry of 20 cases of GIST to clarify factors associated with tumors showing malignant potential. Immunohistochemical analysis of KIT, CD34, vimentin, alpha-smooth muscle actin (SMA), s-100, p53, ki-67, bcl-2 and bax expression was performed on 20 surgically resected GIST. An apoptotic index (AI) was calculated for each sample using a TdT-mediated dUTP-biotin nick end-labeling method. With regard to bcl-2, t(14;18) translocations were also investigated using a polymerase chain reaction based method. Finally, the relationship between these biological results and clinicopathological data was analyzed. Of the 20 cases studied, two patients died due to lung or liver metastasis. All cases stained positive for vimentin, nine cases were positive for alpha-SMA and three cases positive for s-100. All cases were stained for both KIT and CD34, which tended to correlate with malignant potential. There was significant difference in frequency of bcl-2 overexpression (p<0.05) and trend in Ki-67 labeling index (p=0.098) between benign and malignant cases. However, with regard to bcl-2, no chromosomal t(14;18) translocations were detected in four analyzed cases. In GIST, overexpression of bcl-2 may play an important role in increasing malignant potential. Furthermore, Ki-67 L.I. and bcl-2 overexpression may be useful in predicting malignant potential, and therefore help to determine the surgical treatment, follow-up manner, and the necessity of adjuvant therapy.
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PMID:Biological analysis of gastrointestinal stromal tumors. 1237 34

An inflammatory pseudotumor (IPT), known as a plasma cell granuloma, is a relatively uncommon neoplasm with an unidentified etiology. To our knowledge, an early relapse with multiple lung nodules following lung resection and occurrences in multiple organs is extremely rare. The patient was a 49-year-old man who presented with left chest pain and fever. A chest film demonstrated an 8x8 cm mass in the left lower lobe. During thoracotomy in April 2001, a mass was seen to have invaded the diaphragm with remarkable pleural adhesion. The intraoperative pathological diagnosis was infiltration of inflammatory cells with no malignancy. Therefore, a partial resection of the left lower lobe was performed. Three months after the thoracotomy, a chest CT scan disclosed multiple nodular opacities bilaterally, and an open lung-biopsy of the right lung was performed in January 2002. His past history included an excision of a mass on the penis in another hospital in 1994 and a subcutaneous mass that appeared on the right thigh and disappeared spontaneously following a needle biopsy in 1999. Pathologically there was no fundamental difference among his present lesion and the former two. The pathological diagnosis at each occurrence was inflammatory pseudotumor (IPT). In immunohistochemical study, the staining with smooth muscle actin cells was positive, but was negative for the staining with anaplastic lymphoma kinase (ALK). With no evidence of a neoplastic process, these histopathological and immunohistochemical findings could imply that this case may be a postinflammatory reparative reaction, although his condition exhibited the clinically aggressive behavior of suspected lung metastasis.
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PMID:A case report of inflammatory pseudotumor of the lung: rapid recurrence appearing as multiple lung nodules. 1247 87

We report a rare case of solitary fibrous tumor of the parotid gland. A 47-year-old woman presented with a 3-year-history of left-sided subauricular swelling. Computed tomographic scans and magnetic resonance images revealed a well-defined and dumbbell-shaped mass, measuring about 30 mm in its greatest dimension, in the left parotid gland. Because the tumor occupied both superficial and deep lobes of the gland, she underwent total parotidectomy with preservation of the facial nerve. The microscopic finding showed short-spindle and ovoid cells arranged in a haphazard pattern with interspersed thin collagen fibrils. Immunohistochemically, the tumor cells were strongly positive for CD34, bcl-2 and vimentin, whereas stains for S-100, cytokeratin, smooth muscle actin, collagen type IV and CD117 (KIT) were negative. On the basis of these findings, the tumor was diagnosed as solitary fibrous tumor. Her post-operative course was uneventful, and she is currently free from disease 14 months after surgery. Diagnosis, clinical behavior and treatment of solitary fibrous tumor are reviewed from perusal of the literature.
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PMID:A case of solitary fibrous tumor of the parotid gland: review of the literatures. 1249 13

Fifty canine gastrointestinal (GI) mesenchymal tumors were examined to determine the occurrence of leiomyomas (LM) and GI stromal tumors and to compare their clinicopathologic features. Twenty-one tumors (42%) were histologically reclassified as gastrointestinal stromal tumors (GISTs) and 29 tumors (58%) as LMs on the basis of their histologic similarity with homologous human tumors. The GISTs occurred equally in males and females, with a mean age of 11 years (range 5-14 years). Five GISTs (24%) were associated with clinical signs and six (29%) had metastasis in liver or abdominal cavity. The GISTs occurred in large intestine (10, 48%), small bowel (six, 29%), stomach (four, 19%), and mesentery of small intestine (one, 5%). Histologically, they were highly cellular spindle, or less commonly epithelioid tumors with mitotic rates ranging from 0 to 19 per 10 HPF. Eleven tumors (52%) were positive for CD117 (KIT); seven (33%) were positive for smooth muscle actin but none for desmin and S-100 protein. Sequences of KIT exon 11, often mutated in human GISTs, were evaluated from four GISTs. Deletion of Try556-Lys557 coexisting with duplication of Gln555 in one case of GIST and T to C transition resulting in substitution of Pro for Leu575 in another were identified. The LMs occurred predominantly in males (82%) with a mean age of 11 years (range 8-17 years). Nine tumors (31%) had associated clinical signs. They occurred in the stomach (22, 76%), esophagus (four, 14%), and intestines (three, 10%); all were paucicellular, had no mitoses, and were composed of mature smooth muscle cells. Twenty-eight (97%) were positive for smooth muscle actin and 18 (62%) for desmin but none for CD117 and S-100. Both GISTs and true LMs occur in the GI tract of dogs. Both tumors have distinctive pathologic features.
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PMID:Gastrointestinal stromal tumors and leiomyomas in the dog: a histopathologic, immunohistochemical, and molecular genetic study of 50 cases. 1262 12

Although the majority of mesenchymal lesions of the gastrointestinal tract are neoplastic in nature, nonneoplastic reactive processes may involve the gastrointestinal tract and mesentery, causing diagnostic confusion with more aggressive neoplasms, such as fibromatosis or gastrointestinal stromal tumors. In this study, we report a series of fibroinflammatory lesions of the gastrointestinal tract that we think represent a relatively cohesive group of tumors and describe the clinical and pathologic features of this entity, which we have termed "reactive nodular fibrous pseudotumor." The tumors affected five patients (four male and one female patient) who ranged in age from 48 to 71 years (mean 56 years). Two patients presented with acute abdominal pain without a significant past medical history, two had incidental lesions discovered during evaluation for other medical conditions, and one was found to have an abdominal mass. Three patients had a history of abdominal surgery. The tumors were multiple in three patients and solitary in two patients. In four cases, at least one of the tumors involved the small intestine or colon, and the lesion was confined to the peripancreatic soft tissue in one case. The tumors were firm, tan-white, ranged in size from 4.3 to 6.5 cm in greatest dimension, and were grossly well circumscribed. All of the lesions were of low to moderate cellularity and composed of stellate or spindled fibroblasts arranged haphazardly or in intersecting fascicles. Three cases had microscopically infiltrative borders. The stroma was rich in collagen, which was wire-like, keloidal, or hyalinized. Intralesional mononuclear cells were sparse but were more numerous peripherally and frequently arranged in lymphoid aggregates. Immunohistochemical stains demonstrated that all of the tumors stained for vimentin, 80% stained for CD117 or muscle specific actin, 60% stained for smooth muscle actin or desmin, and none of the tumors stained for CD34, S-100 protein, or anaplastic lymphoma kinase-1. Follow-up information was available in all cases: four patients had no residual disease following surgical resection (mean follow-up 16.3 months) and one patient who had an incomplete surgical resection had stable disease at 26 months. In summary, we report a series of distinct intraabdominal fibroinflammatory pseudotumors that we have collectively termed "reactive nodular fibrous pseudotumors." These lesions are uncommon and may infiltrate the bowel wall, thereby mimicking primary bowel neoplasms or intraabdominal fibromatosis. Recognition of these nonneoplastic lesions is important, as they pursue a benign clinical course, but may be confused with other mesenchymal neoplasms that require more aggressive treatment.
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PMID:Reactive nodular fibrous pseudotumor of the gastrointestinal tract and mesentery: a clinicopathologic study of five cases. 1510 9

In this study we analyzed the clinicopathologic features of duodenal smooth muscle or stromal tumors, including 156 GISTs, 6 leiomyomas (LMs), and 5 leiomyosarcomas (LMSs) from the files of the Armed Forces Institute of Pathology and the Haartman Institute of the University of Helsinki. GISTs were documented as KIT positive (n = 109); 47 tumors were also included because of their histologic identity to KIT-positive cases. GIST-specific c-kit gene mutations were documented in exon 11 in 9 of 30 cases (30%) and exon 9 in 4 of 30 cases (13%). The GISTs occurred in patients with an age range of 10-88 years (median 56 years); 54% were male. Ten patients had neurofibromatosis type I; six of them had multiple GISTs. The GISTs ranged from small asymptomatic intramural or external nodules to large masses that extended into the retroperitoneum (median size 4.5 cm). They were mostly spindle cell tumors; three malignant GISTs had an epithelioid morphology, and 81 cases had skeinoid fibers. The tumors often coexpressed CD34 and KIT (54%) and were variably positive for smooth muscle actin (39%) and S-100 protein (20%) but never for desmin. A total of 86% of patients with tumors >5 cm with >5 mitoses/50 high power fields (HPF) (n = 21) died of disease, whereas no tumor <2 cm with <5 mitoses/50 HPF (n = 12) recurred or caused death. Long latency was common between primary operation and recurrences or metastases; either one occurred in 49 of 140 patients with follow-up (35%). No formula could accurately predict metastases, which occasionally developed even if mitotic activity was <5/50 HPF and size <5 cm. Metastases were in the abdominal cavity, liver, and rarely in bones and lungs but never in lymph nodes. Four actin- and desmin-positive and KIT-negative benign intramural LMs were similar to those more often seen in the esophagus. There were five LMSs, one of which formed a polypoid intraluminal mass; all were actin positive and KIT negative. The great majority of duodenal mesenchymal tumors are GISTs, which have a spectrum from small indolent tumors to overt sarcomas. LMs and LMSs are rare.
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PMID:Gastrointestinal stromal tumors, intramural leiomyomas, and leiomyosarcomas in the duodenum: a clinicopathologic, immunohistochemical, and molecular genetic study of 167 cases. 1271 47

The myocardium responds to chronic pressure or volume overload by activation and proliferation of cardiac fibroblasts and their differentiation into myofibroblasts. Because alpha-smooth muscle actin (SMA) expression is the classical marker for myofibroblast differentiation, we examined force-induced SMA expression and regulation by specific MAPK pathways. Rat cardiac fibroblasts were separated from myocytes and smooth muscle cells, cultured, and phenotyped by using the presence of SMA, vimentin, and ED-A fibronectin and the absence of desmin as myofibroblast markers. Static tensile forces (0.65 pN/microm2) were applied to fibroblasts via collagen-coated magnetite beads. In neonatal cardiac fibroblasts cultured for 1 day, immunostaining and Western and Northern blotting showed very low basal levels of SMA. After the application of force, there were 1.5- to 2-fold increases of SMA protein and mRNA within 4 h. Force-induced SMA expression was dependent on ERK phosphorylation and on intact actin filaments. In contrast to cells cultured for 1 day, cells grown for 3 days on rigid substrates showed prominent stress fibers and high basal levels of SMA, which were reduced by 32% within 4 h after force application. ERK was not activated by force, but p38 phosphorylation was required for force-induced inhibition of SMA expression. These results indicate that mechanical force-induced regulation of SMA content is dependent on myofibroblast differentiation and by selective activation of MAPKs.
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PMID:Mechanical force regulation of myofibroblast differentiation in cardiac fibroblasts. 1284 14

We report a case of an intraocular inflammatory myofibroblastic tumor nearly filling the vitreous cavity of the eye of a 50-year-old man. The tumor was composed of a mixture of spindle cells and mixed inflammatory elements, including numerous plasma cells. The differential diagnosis included inflammatory pseudotumor and neoplastic mimics of this condition. Further investigation with immunohistochemistry revealed the mass to be composed of myofibroblasts, positive for smooth muscle actin stains and with weak anaplastic lymphoma kinase (ALK) expression in some tumor cells. Evaluation by fluorescence in situ hybridization revealed the tumor cells to have multiple copies of chromosome 2 and ALK but no rearrangement of the ALK gene. The authors propose that multiple copies of the ALK gene may be involved in inflammatory myofibroblastic tumor tumorigenesis, in addition to ALK gene rearrangements.
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PMID:Intraocular inflammatory myofibroblastic tumor with ALK overexpression. 1469 30

Inflammatory fibroid polyps (IFPs) are rare mesenchymal tumors of the gastrointestinal tract that consist of spindle-shaped stromal cells and an inflammatory infiltrate rich in eosinophils. Their etiology and histogenesis remain unknown. Based on previous reports of their immunoreactivity for CD34 and c-kit biomarkers, IFPs have been thought to be related to gastrointestinal stromal tumors (GISTs). After reviewing the current literature and examining IFPs at the light microscopic level, we evaluated a series of IFPs using an extensive panel of immunohistochemical and in situ hybridization markers in an effort to gain insight into their etiology and histogenesis and to determine their true relationship to GISTs. Sixteen routinely processed IFP specimens (14 gastric, 1 ileal, and 1 rectal) were immunohistochemically stained for antibodies to CD34, HMB-45, desmin, smooth muscle actin, calponin, h-caldesmon, anaplastic lymphoma kinase, S-100 protein, epithelial membrane antigen, c-kit (CD117), stem cell factor (SCF/N19 or kit ligand), p53, bcl-2, cyclin D1, and human herpesvirus-8 (HHV8). In situ hybridization for Epstein-Barr virus-encoded RNA (EBER) was also performed. Ten cases were further evaluated for the dendritic cell markers fascin, CD21, CD23, and CD35. Stromal cells were diffusely positive for CD34 and fascin in all (100%) cases, and these stromal cells were, in addition, immunoreactive for calponin and smooth muscle actin in 88% and 25% of cases, respectively. CD35 was also found to be focally reactive in the stromal cells. Cyclin-D1 was overexpressed in all (100%) IFPs. All other immunohistochemical markers and EBER were negative in the stromal cells. These findings suggest that the proliferating stromal cells in IFPs are of dendritic cell origin, with some cases also exhibiting myofibroblastic features. Absence of c-kit, SCF, and h-caldesmon immunoreactivity fails to support a relationship to GISTs. We also conclude that Epstein Barr virus and HHV8 are unlikely etiologic agents of IFPs. Overexpression of cyclin D1 in all cases suggests that a defect in cell-cycle regulation may be involved in the growth of IFPs.
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PMID:Inflammatory fibroid polyps of the gastrointestinal tract: evidence for a dendritic cell origin. 1470 72

Inflammatory myofibroblastic tumours (IMFT) may arise at any anatomical site, including lung, soft tissues, retroperitoneum and bladder. Although morphologically similar, these lesions encompass a spectrum of entities with differing aetiology, ranging from reactive/regenerative proliferations to low-grade neoplasms with a risk of local recurrence, but no significant metastatic potential. Vesical IMFT usually presents as a polypoid mass with a pale firm cut surface and can be of considerable size, mimicking a malignant tumour clinically and radiologically. Its good outcome, however, warrants conservative surgical excision, emphasising the importance of identification and distinction from malignant tumours of the bladder that may require more radical surgery and/or adjuvant therapy. We conducted a preliminary retrospective, comparative immunocytochemical study of 20 bladder tumours, including nine IMFTs, five spindle cell (sarcomatoid) carcinomas, two rhabdomyosarcomas, two leiomyosarcomas and two neurofibromas. The results confirmed IMFT positivity for smooth muscle actin, desmin and cytokeratin in 78-89% cases, resulting in potential confusion with sarcomatoid carcinoma or leiomyosarcoma. In contrast, cytoplasmic anaplastic lymphoma kinase (ALK 1) staining was present in eight IMFT (89%), but was not seen in any other lesion examined. The ALK 1 staining was confirmed by fluorescence in situ hybridisation, with translocation of the ALK gene present in 15-60% tumour cells in four of six IMFT examined, but not in four cases of sarcomatoid carcinoma or three of leiomyosarcoma. In conclusion, ALK 1 staining may be of value in the distinction of vesical IMFT from morphologically similar entities, and often reflects ALK gene translocations in these lesions.
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PMID:Anaplastic lymphoma kinase (ALK 1) staining and molecular analysis in inflammatory myofibroblastic tumours of the bladder: a preliminary clinicopathological study of nine cases and review of the literature. 1510 7


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