Pure Spindle Cell Morphology Research Articles

Unclassified sex cord / gonadal stromal testis tumour with a pure spindle cell component

Incompletely differentiated sex cord / gonadal stromal tumours of the testis (SCST) of pure spindle cell morphology are extremely rare with only four reported cases in the literature.1 We report a case of a 73-year-old man who presented with acute on chronic renal failure and noted to have an enlarged tender left testicle. Ultrasound examination revealed an enlarged testis (40 cc) with diffuse heterogeneity of the testicular parenchyma. A radical orchiectomy procedure was performed. The histological examination revealed a well circumscribed tumour (55 mm in maximum diameter) comprised purely of fascicles of spindle cells with elongated to ovoid nuclei. Immunohistochemical stains demonstrated positive staining for Vimentin, S100, SMA, Inhibin, Calretinin and CD99. EMA, Cam 5.2, AE1&3, Desmin, CD34, Melan-A, HMB-45, Sox10, CD117 and PLAP stains were negative. The overall features were consistent with the diagnosis of unclassified SCSTs of pure spindle cells morphology. Due to the rarity, SCST of spindle cell morphology are under studied. They are of unknown clinical behaviour. However, they should be considered in the differential diagnosis of spindle cell lesions of the testis.

Clinic-pathological aspect of gastro-intestinal stromal tumors at tertiary care Hospital India

BackgroundThis study defines the disease profile in south Indian population and determine the clinic-pathological aspects of Gastro-Intestinal Stromal Tumors. MethodIn this prospective study patients diagnosed of gastrointestinal stromal tumors were taken thorough clinical examination and a database of Anthropometric details and clinical details were analyzed. Pathological data included tumor size, presence or absence necrosis, mitotic counts, immunohistochemistry for CD-117, CD-34. ResultsThere were 44 patients with confirmed diagnosis of gastro-intestinal stromal tumor. The highest incidence was found in the 6th decade. The most common symptoms were abdominal pain and gastrointestinal bleed. Stomach was most frequent site for gastro-intestinal stromal tumors. Immunochemistry for CD-117 was positive in 93.18% cases. Majority of tumors (79.5%) had pure spindle cell morphology and mitotic activity showed that 34% of the GISTs were of the high risk group. Forty two patients were suggestive of surgery as the primary treatment after presentation. ConclusionAbdominal pain was the most common presenting complaint. Majority of the tumors aroused from the stomach. The majority of the tumors had pure spindle cell morphology and 93% of the tumors were CD-117 positive. A significant relationship between tumor size, tumor necrosis and mitotic activity with large tumors having necrosis and high mitotic rate having high risk of malignancy, was observed. Surgical resection is considered mainstay of treatment of gastro-intestinal stromal tumor. Imatinib therapy should be given to patients in moderate to severe risk categories.

MYOD1-mutant spindle cell and sclerosing rhabdomyosarcoma: an aggressive subtype irrespective of age. A reappraisal for molecular classification and risk stratification

Sclerosing and spindle cell rhabdomyosarcoma is a rare histologic subtype, designated in the latest WHO classification as a stand-alone pathologic entity. Three genomic groups have been defined: an infantile subset of spindle cell rhabdomyosarcoma harboring VGLL2-related gene fusions, a MYOD1-mutant subset commonly associated with sclerosing morphology, and a subset lacking recurrent genetic abnormalities. In this study, we focus on MYOD1-mutant rhabdomyosarcoma to further define their clinicopathologic characteristics and behavior in a larger patient cohort. We investigated 30 cases of MYOD1-mutant rhabdomyosarcoma (12 previously reported and 18 newly diagnosed) with an age range of 2–94 years, including 15 children. All cases showed morphology within the spectrum of spindle cell/sclerosing rhabdomyosarcoma (8 cases showing pure sclerosing morphology, 8 cases showing pure spindle cell morphology and 14 cases showing a hybrid phenotype of spindle, sclerosing and primitive undifferentiated areas). All tumors harbored either homozygous or heterozygous MYOD1 (p.L122R) exon 1 mutations. In 10 (33%) cases, a co-existent PIK3CA mutation was identified. Hot-spot mutations in NRAS and HRAS were each identified in a single case, respectively. Follow-up was available on 22 (73%) patients with a median duration of 28 months. Local recurrence was seen in 12 (55%) and distant recurrence in 12 (55%) cases, despite multimodality chemoradiation therapy. At last follow-up, 15 (68%) patients died of the disease, one patient was alive with disease and five had no evidence of disease. The prognosis was equally poor in pediatric and adult patients. In conclusion, MYOD1 mutation defines an aggressive rhabdomyosarcoma subset, with poor outcome and response to therapy, irrespective of age. Given that this distinct molecular subtype is characterized by an aggressive biologic behavior compared to other genetic subtypes of spindle and sclerosing rhabdomyosarcoma, the MYOD1 genotype should be used as a molecular marker in both subclassification and prognostication of rhabdomyosarcoma.

Spindle Cell Atypical Fibroxanthoma: Myofibroblastic Differentiation Represents a Diagnostic Pitfall in This Variant of AFX.

Atypical fibroxanthoma (AFX) is a low-grade, dermal, mesenchymal neoplasm, which lacks a specific lineage of differentiation. The classical histologic appearance of AFX is that of a pleomorphic and spindle cell neoplasm with marked nuclear pleomorphism, mitotic figures, and often prominent storiform pattern that superficially resembles a pleomorphic high-grade sarcoma ("malignant fibrous histiocytoma"). Many histologic variants have been described. We have reviewed 15 cases of AFX characterized by a pure spindle cell morphology that could be easily mistaken for other spindle cell dermal neoplasms. All of our cases were stained with CD68, CD163, CD10, S-100p, p63, wide-spectrum keratin, CD31, CD34, smooth muscle actin (SMA), desmin, calponin, and h-caldesmon. All 15 cases showed an immunoprofile consistent with AFX. In 9 cases, SMA was also strongly expressed; this finding, coupled with the malignant spindle cell histomorphology, can lead to an erroneous diagnosis of cutaneous leiomyosarcoma with potential clinical consequences. Awareness of this pattern of immunoreactivity in this unusual variant of AFX is of importance for avoiding diagnostic misinterpretation. This study intends to characterize the nature and frequency of SMA immunoreactivity in AFX and to discuss the potential diagnostic pitfalls of immunohistochemical markers in distinguishing this entity from other malignant spindle cell neoplasms.

P-0140 - Experience of Managing Patients with Metastatic Gastrointestinal Stromal Tumour with Imatinib Mesylate at an Indian Centre

Background: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. Most commonly originate in the stomach and small intestine. Historically, these lesions were classified as leiomyomas or leiomyosarcomas. They are submucosal lesions, which grow endophytically in parallel with the lumen. One third of high risk, malignant GIST have poor prognosis after surgery. Imatinib mesylate is a KIT tyrosine kinase inhibitor with effect on metastatic GIST. About 80% of patients with GIST would experience tumor recurrence or metastasis after radical resection. The most common site of the metastasis is the liver. We report our long term follow up in patients with metastatic GIST receiving Imatinib. Methods: Retrospective analysis of patients diagnosed with metastatic GIST from 2004 to 2012 at our centre, who received Imatinib mesylate at an dose of 400 mg per day over 6 months. Patients profile, tumor response, side effects, time to progression and survival were evaluated. Results: Ten C-Kit or CD 117 positive GIST patients were enrolled at our centre, there were 8 (80%) male and 2 (20%) female. Median age of patients was 64 years (range 38 to 86 years). Five GISTs originated from stomach, 3 from rectum, 1 each from jejunum & ileum. Most common symptoms were anaemia and pain abdomen. Liver metastasis in 6, lung in 3 and breast in 1. Five patients underwent surgical treatment. Majority of them (80%) were of the high-risk malignant category. All of them started on Imatinib, all had palliative benefit, half had significant shrinkage of tumour mass. Most common side effects were periorbital oedema, muscle cramps, and diarrhea. Histologically, the majority had a pure spindle cell morphology. Follow-up of 5 cases, treated with adjuvant Imatinib for 6 months after surgical resection showed stable disease for periods from 5 to 8 years. However, 3 cases treated with Imatinib for longer than 6 months had problems due to recurrent, metastatic, or inoperable disease. The long-term Imatinib mesylate treatment was safe and well tolerated. At a median follow-up of 48 months (range 15 to 112 months), the 5 year survival rate was 88%. Conclusion: Adjuvant therapy Imatinib should be used for patients with high-risk advanced GISTs. The Imatinib mesylate treatment can prolong the survival of the patients who have metastatic GIST before or after radical surgery without toxicity of chemotherapy.

P-0133 Long Term Follow up of Managing Patients with Metastatic Gastrointestinal Stromal Tumour with Imatinib Mesylate at an Indian Centre

ABSTRACT Introduction Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. Most commonly originate in the stomach and small intestine. One third of high risk, malignant GIST have poor prognosis after surgery. The most common site of the metastasis is the liver. Imatinib mesylate is a KIT tyrosine kinase inhibitor with effect on metastatic GIST. We report our long term follow up in patients with metastatic GIST receiving Imatinib. Methods Retrospective analysis of patients diagnosed with metastatic GIST from 2004 to 2011 at our centre, who received Imatinib mesylate at a dose of 400 mg per day over 6 months. Patients' profile, tumor response, side effects, time to progression and survival were evaluated. Results Eight C-Kit or CD 117 positive GIST patients were enrolled at our centre, there were 6 (75%) male and 2 (25%) female. Median age of patients was 64 years (range 38 to 86 years). Four GISTs originated from stomach, 2 from Rectum, 1 each from jejunum & ileum. Most common symptoms were anaemia and pain abdomen. Liver metastasis in 5, lung in 2 and breast in 1. Four patients underwent surgical treatment. Majority of them (75%) were of the high-risk malignant category. Histologically, the majority had a pure spindle cell morphology. All of them started on Imatinib, all had palliative benefit, half had significant shrinkage of tumour mass. Most common side effects were periorbital oedema, muscle cramps, and diarrhea. Follow-up of 4 cases, treated with adjuvant Imatinib for 6 months after surgical resection showed stable disease for periods from 5 to 8 years. However, 2 cases treated with Imatinib for longer than 6 months had problems due to recurrent, metastatic, or inoperable disease. The long-term Imatinib mesylate treatment was safe and well tolerated. At a median follow-up of 38 months (range 13 to 96 months), the 5 year survival rate was 88%. Conclusion Adjuvant therapy Imatinib should be used for patients with high-risk advanced GISTs. The Imatinib mesylate treatment can prolong the survival of the patients who have metastatic GIST before or after radical surgery without toxicity of chemotherapy.

The CIC-DUX4 fusion transcript is present in a subgroup of pediatric primitive round cell sarcomas

Pediatric undifferentiated soft tissue sarcomas are a group of diagnostically challenging tumors. Recent studies have identified a subgroup of undifferentiated soft tissue sarcomas with primitive round to plump spindle cell morphology and a t(4;19)(q35;q13.1) translocation resulting in the expression of a CIC-DUX4 fusion transcript, including 2 tumors previously reported by our laboratory (Cancer Genet Cytogenet 2009;195:1). In the present study, reverse transcriptase polymerase chain reaction assays developed for both frozen and paraffin-based tissues were applied to a series of 19 pediatric undifferentiated soft tissue sarcomas using a combination of primer sets covering the CIC-DUX4 fusion transcript. Of the 19 undifferentiated soft tissue sarcomas, 16 had primitive round to plump spindle cell morphology, and 3 had pure spindle cell morphology. Three of the 16 undifferentiated soft tissue sarcomas with primitive round cell morphology were found to harbor the CIC-DUX4 fusion transcript by reverse transcriptase polymerase chain reaction. Automated DNA sequencing of the polymerase chain reaction products identified 2 distinct transcript variants. One CIC-DUX4-positive tumor showed membranous CD99 positivity, 2 showed focal S100 positivity, and 1 showed focal CD57 positivity. With the 2 previously reported cases, the total number of CIC-DUX4-positive primitive round cell sarcomas identified at our institution has been brought to 5 (28%) of 18. Given the consistent involvement of the CIC-DUX4 fusion in a subset of primitive round cell undifferentiated soft tissue sarcomas, these findings suggest a central role for the fusion transcript in such tumors. The current findings further define a novel genetic subset of pediatric primitive round cell sarcomas and provide an additional diagnostic tool for their characterization and diagnosis.

Gastrointestinal stromal tumors: A 7-year experience from a tertiary care hospital

Gastrointestinal stromal tumor (GIST), now the most common mesenchymal tumor of the gastrointestinal tract (GIT), has been frequently studied, especially with regard to its successful targeted therapy using imatinib mesylate. Our aim was to describe the clinicopathological features of a large number of cases from a tertiary care hospital in India and report on the follow-up after treatment of some of the cases, comparing them with series described in the west. This is a retrospective study of cases encountered over a 7-year period (1999-2005). Ninety-two cases of GIST were studied, which made up the largest group (52.8%) of mesenchymal tumors of the GIT, with smooth muscle tumors comprising 38.1%, the next large group. GISTs were almost equally prevalent in the stomach and the small intestine, unlike in most studies where stomach is the most common site. GIST may be considered as a cause of bleeding when upper and lower GI endoscopy is normal. Ninety-five percent of the GISTs were positive for CD117 (KIT), as is known. A majority of them (70.4%) were of the high-risk malignant category, unlike most studies where high-risk tumors make up 30-45%. Histologically, the majority had a pure spindle cell morphology and skenoid fibers were rare. Follow-up of 11 cases, the majority with high-risk tumor, treated with adjuvant imatinib for 6 months after surgical resection showed stable disease for periods from 2 to 5 years. However, 11 cases treated with imatinib for longer than 6 months had a poorer outcome due to recurrent, metastatic, or inoperable disease. In our study of a large number of GISTs, which were equally prevalent in the stomach and small intestine, the majority were of the high-risk malignant category and of pure spindle cell morphology. Limited numbers had follow-up after imatinib therapy, which showed in one group treated for 6 months, after resection of high-risk GIST, stable disease for periods ranging from 2 to 5 years. Molecular studies and larger numbers are required for meaningful conclusions to be drawn.

Spindle cell myoepithelial carcinoma of the oral cavity—A report of two cases

Myoepithelial carcinomas are not as rare as is generally believed, but they are simply not well recognized. Those arising in the oral cavity and exhibiting pure spindle cell morphology are often difficult to diagnose primarily and are likely to be misinterpreted as other more common spindle cell lesions of the oral cavity. Use of ancillary studies like Electron microscopy (EM) and immunohistochemistry (IHC) is very much essential for confirmation of diagnosis. Here we present two such cases of spindle cell myoepithelial carcinoma, which were initially misinterpreted as nerve sheath tumours after IHC and later presented with multiple recurrences and lymph node metastasis.

Gastrointestinal Stromal Tumors Metastatic to the Ovary

Five cases of gastrointestinal stromal tumor metastatic to the ovary are reported. The average patient age was 59 years (range, 44-81 years). The primary tumor was in the small bowel or its mesentery (4 cases) or stomach (1 case). The primary and metastatic tumors were discovered synchronously in 3 cases. In the other 2 cases, the ovarian tumors were discovered 18 months before a gastric tumor was identified and 27 years after a small bowel tumor had been resected. The ovarian tumors (three of which were bilateral) were usually solid, tan, and lobulated. Microscopically, three tumors had a pure spindle cell morphology, and two both spindle and epithelioid cell components. The diagnosis in all 5 cases was confirmed with positive c-kit (CD117) and negative desmin immunostaining. Variably positive immunoreactivity for either or both h-caldesmon and smooth muscle actin was seen in all 5 cases, and 3 cases were CD34-positive. Four patients died between 1 and 6.5 years (mean, 2.8 years) from the time of ovarian tumor diagnosis. The main differential diagnostic consideration was leiomyosarcoma; the most important features to help exclude this diagnosis were an absence of tumor in the uterus, low histologic grade, and a desmin-negative, c-kit-positive immunophenotype. Other differential considerations, including endometrial stromal sarcoma and fibrosarcoma, are discussed. Most of the ovarian tumors in this series were initially diagnosed as tumors of other types, a misdiagnosis with significant therapeutic and prognostic implications because of the specific therapy now available for gastrointestinal stromal tumors.

Gastrointestinal stromal tumours (GISTs): a clinicopathological and molecular study of 66 cases

Predicting the clinical behaviour of gastrointestinal stromal tumours (GISTs) is difficult and criteria delineating benign from malignant cases are not firmly established. The aims of this study were to define the clinicopathological and molecular features of 66 GISTs, and to determine whether any specific parameters were associated with patient outcome. Archival cases of GIST from two major teaching hospitals in Western Australia were studied. Inclusion criteria for the study were: (1) appropriate morphology, (2) CD117 positivity, (3) adequacy of pathological material for study, and (4) exclusion of other tumour types on the basis of immunophenotypic and/or ultrastructural features. Expression of CD117, CD34, S100 protein, keratin (using broad spectrum MNF116), alpha-smooth muscle actin (SMA) was determined by immunohistochemistry. PCR and single strand conformation polymorphism (PCR-SSCP) analysis were used to screen for mutations in exons 11 and 9 of c-kit. There were equal numbers of males and females with a mean age at diagnosis of 60 years, followed up for a mean of 54 months. Thirteen patients (21%) had died of GIST by the end of the study. Tumours were mostly located in the stomach (67%) and small intestine (SI; 25%). The cell types were pure spindle (68%), pure epithelioid (12%) and mixed epithelioid/spindle (20%). c-kit mutations were found in 69% of GISTs, with the large majority (91%) occurring in exon 11. Size > or = 10 cm, tumour necrosis and pure epithelioid cell morphology each were the only factors significantly associated with adverse survival (p=0.038, and p=0.047 and p=0.028, respectively). Mitotic activity > or = 5/50 HPF showed a definite trend association with adverse survival, but unlike some other studies, did not achieve statistical significance (p=0.067). c-kit mutations were more frequent in small intestinal GISTs (p=0.05) and in those with pure spindle cell morphology (p=0.023) but were not associated with patient outcome. In this study, size > or = 10cm, necrosis and/or pure epithelioid cell morphology correlated significantly with adverse survival. Mitotic activity showed a strong association with survival but this did not reach statistical significance. c-kit mutations occurred mainly in GISTs of the SI, and in purely spindle cell tumours. While the mutation status did not associate with patient outcome in this series, this remains a controversial issue, and further studies are needed to assess whether the type of mutation affects response to tyrosine kinase inhibitor therapy in metastatic GISTs. CD117 staining of any mesenchymal lesion of the gastrointestinal tract should be mandatory for accurate classification. PCR-SSCP analysis is a fast, sensitive and relatively inexpensive method of analysing c-kit mutations, which may be important prognostically and also of therapeutic relevance in the assessment of new tyrosine kinase inhibitor therapies.

E-cadherin mutation and Snail overexpression as alternative mechanisms of E-cadherin inactivation in synovial sarcoma.

We have recently reported frequent E-cadherin gene mutations in synovial sarcoma (SS), suggesting mutational inactivation of E-cadherin as a potential mechanism of spindle cell morphology in SS, a spindle cell sarcoma that shows areas of glandular epithelial differentiaton in some cases (biphasic SS) and only pure spindle cell morphology in most cases (monophasic SS). However, the mechanism of downregulation of E-cadherin in SS remains unknown. To further address this issue, we analysed the mechanisms of E-cadherin silencing in 40 SS. Genetic and epigenetic changes in the E-cadherin gene, and the expression level of its transcriptional repressor Snail were examined by polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP), methylation-specific PCR, and real-time quantitative PCR, respectively. Expression of E-cadherin was examined by RT-PCR and immunohistochemistry. We also examined ELF3, a transcription factor associated with epithelial differentiation in SS in a previous cDNA microarray, by RT-PCR. E-cadherin and ELF3 transcripts were detected, respectively, in 27/40 (67.5%) and in 25/40 (62.5%) of SS, and these epithelial-related genes were almost always coexpressed. Hypermethylation of the promoter of the E-cadherin gene was detected in five cases (12.5%) in SS; however, E-cadherin was silenced at mRNA level in only one of the five cases. E-cadherin missense mutations were observed in five cases (12.5%) of SS. In SS, all five cases with E-cadherin missense mutations had the SYT-SSX1 fusion and were monophasic tumors, suggesting a relationship between the SYT-SSX fusion type and E-cadherin missense mutation (P=0.07). E-cadherin mRNA expression in SS was associated with reduced Snail expression level (P=0.03). E-cadherin membranous expression was observed in 14/40 (35.0%) of SS, and was also correlated with SYT-SSX1 fusion type and biphasic histology. ELF3 was confirmed to be more highly expressed in biphasic than monophasic SS by real-time quantitative PCR. These results suggest that in SS the loss of E-cadherin expression occurs either by Snail trans-repression or by inactivating mutations. Thus, E-cadherin downregulation is associated with the loss or absence of glandular epithelial differentiation in certain SS.