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1.
Lab Invest ; 99(1): 85-92, 2019 01.
Article in English | MEDLINE | ID: mdl-30353131

ABSTRACT

Distinct populations of effector memory T cells use different homing receptors to traffic to the skin and gut. Whether tissue-selective T cells are needed for early rejection of a neoplasm growing in these tissues remains an open question. We chose to study an allogeneic tumor model because growth of such a fully mismatched tumor would signify a profound immune deficit. We implanted allogeneic tumor cells in the skin or gut of mice deficient in either α(1,3) fucosyltransferases IV and VII, enzymes critical for generating E-selectin ligands on skin-homing T cells, or ß7 integrin, a component of the α4ß7 integrin ligand for the mucosal adressin MAdCAM. During the first 9 days after tumor implantation, FucTVII-/- mice showed a profoundly impaired capacity to reject tumors growing in the skin, but readily rejected tumors implanted in the gut. Rejection of tumors in the skin was even more impaired in mice deficient in both FucTIV and FucTVII. This impairment was corrected by infusion of T cells from normal mice. By contrast, ß7 integrin-/- mice showed profoundly impaired rejection of tumors in the gut, but no defect in the skin tumor rejection. These differences were unrelated to antigen recognition or effector function of T cells, since all strains of mice were capable of generating tumor-specific CTLs in vitro against the tumor cell line used in vivo. These results demonstrate that T-cell homing defects in vivo impair immune surveillance of peripheral epithelial tissues in a specific and selective fashion.


Subject(s)
Neoplasms/immunology , T-Lymphocytes/physiology , Allografts , Animals , Cell Line, Tumor , Fucosyltransferases/metabolism , Integrin beta Chains/metabolism , Mice, Inbred BALB C , Mice, Knockout , Neoplasm Transplantation
2.
J Neurosurg ; 129(3): 805-814, 2018 09.
Article in English | MEDLINE | ID: mdl-28885122

ABSTRACT

OBJECTIVE While sporadic peripheral schwannomas (SPSs) are generally well treated with surgery, their biology is not well understood. Consequently, treatment options are limited. The aim of this study was to provide a comprehensive description of SPS. The authors describe clinicopathological features and treatment outcomes of patients harboring these tumors, and they assess expression of biomarkers using a clinically annotated tissue microarray. Together, these data give new insight into the biology and management of SPS. METHODS Patients presenting with a primary SPS between 1993 and 2011 (n = 291) were selected from an institutional registry to construct a clinical database. All patients underwent follow-up, and short- and long-term outcomes were assessed. Expression of relevant biomarkers was assessed using a new tissue microarray (n = 121). RESULTS SPSs were generally large (mean 5.5 cm) and frequently painful at presentation (55%). Most patients were treated with surgery (80%), the majority of whom experienced complete resolution (52%) or improvement (18%) of their symptoms. Tumors that were completely resected (85%) did not recur. Some patients experienced short-term (16%) and long-term (4%) complications postoperatively. Schwannomas expressed higher levels of platelet-derived growth factor receptor-ß (2.1) than malignant peripheral nerve sheath tumors (MPNSTs) (1.5, p = 0.004) and neurofibromas (1.33, p = 0.007). Expression of human epidermal growth factor receptor-2 was greater in SPSs (0.91) than in MPNSTs (0.33, p = 0.002) and neurofibromas (0.33, p = 0.026). Epidermal growth factor receptor was expressed in far fewer SPS cells (10%) than in MPNSTs (58%, p < 0.0001) or neurofibromas (37%, p = 0.007). SPSs more frequently expressed cytoplasmic survivin (66% of tumor cells) than normal nerve (46% of cells), but SPS expressed nuclear survivin in fewer tumor cells than in MPNSTs (24% and 50%, respectively; p = 0.018). CONCLUSIONS Complete resection is curative for SPS. Left untreated, however, these tumors can cause significant morbidity, and not all patients are candidates for resection. SPSs express a pattern of biomarkers consistent with the dysregulation of the tumor suppressor merlin observed in neurofibromatosis Type 2-associated schwannomas, suggesting a shared etiology. This SPS pattern is distinct from that of other tumors of the peripheral nerve sheath.


Subject(s)
Biomarkers, Tumor/analysis , Neurilemmoma/pathology , Peripheral Nervous System Neoplasms/pathology , Diagnosis, Differential , ErbB Receptors/analysis , Follow-Up Studies , Humans , Neurilemmoma/diagnosis , Neurilemmoma/surgery , Neurofibroma/diagnosis , Neurofibroma/pathology , Neurofibroma/surgery , Neurofibrosarcoma/diagnosis , Neurofibrosarcoma/pathology , Neurofibrosarcoma/surgery , Peripheral Nervous System Neoplasms/diagnosis , Peripheral Nervous System Neoplasms/surgery , Postoperative Complications/etiology , Receptor, Platelet-Derived Growth Factor beta/analysis , Registries , Survivin/analysis
3.
Cancer ; 121(22): 4088-96, 2015 Nov 15.
Article in English | MEDLINE | ID: mdl-26349011

ABSTRACT

BACKGROUND: Desmoid tumors (DTs) are rare mesenchymal lesions that can recur repeatedly. When it is feasible, DTs are surgically resected; however, this often results in high recurrence rates. Recently, treatment with PF-03084014, a potent γ-secretase inhibitor, has been shown to have antitumor activity in several tumor types by affecting the WNT/ß-catenin pathway. Consequently, Notch pathway inhibition by PF-03084014 might be a promising approach for DT treatment. METHODS: The expression of Notch pathway components was analyzed in DT tissues and cell strains with immunohistochemistry and Western blotting, respectively. A panel of DT cell strains was exposed to PF-03084014 and evaluated for cell proliferation. Antitumor effects were assessed via cell cycle, apoptosis, and migration and invasion analysis. Cells treated with PF-03084014 were characterized with a gene array analysis combined with Ingenuity Pathway Analysis. RESULTS: The results showed that Notch pathway components were expressed at different levels in DTs. Hes1 (Hes Family BHLH Transcription Factor 1) was overexpressed in DT tumors versus dermal scar tissue, and PF-03084014 caused significant decreases in Notch intracellular domain and Hes1 expression in DT cell strains. PF-03084014 decreased DT cell migration and invasion and also caused cell growth inhibition in DT cell strains, most likely through cell cycle arrest. Gene array analysis combined with Ingenuity Pathway Analysis showed that Wnt1-inducible signaling pathway protein 2 possibly regulated Notch and WNT pathways after treatment with PF-03084014 through integrin. CONCLUSION: Our findings suggest that the Notch pathway is an important DT therapeutic target. Furthermore, PF-03084014 has significant antitumor activity against DTs, and it may be an alternative strategy for DT treatment.


Subject(s)
Fibromatosis, Aggressive/drug therapy , Receptors, Notch/antagonists & inhibitors , Signal Transduction/physiology , CCN Intercellular Signaling Proteins/physiology , Cell Cycle Checkpoints/drug effects , Cell Movement/drug effects , Cell Proliferation/drug effects , Fibromatosis, Aggressive/etiology , Fibromatosis, Aggressive/pathology , Humans , Neoplasm Invasiveness , Receptors, Notch/physiology , Repressor Proteins/physiology , Tetrahydronaphthalenes/pharmacology , Valine/analogs & derivatives , Valine/pharmacology
4.
Eur J Cancer ; 50(3): 593-601, 2014 Feb.
Article in English | MEDLINE | ID: mdl-24291235

ABSTRACT

Mesenchymal to epithelial transition (MET) in carcinomas has been proposed to promote the growth of epithelial tumour cells at distant sites during metastasis. MET has also been suggested as an important biological and clinical process in mesenchymal tumors, sarcomas. Here we review studies on MET in sarcomas, including molecular markers, signalling mechanisms, regulation by micro RNAs and therapeutic implications. Accumulating evidences suggest that deeper investigation and understanding of MET in sarcomas would shed light on the pathogenesis of sarcomas and might lead to identification of potential clinical biomarkers for prognosis and targets for sarcoma therapeutics.


Subject(s)
Epithelial-Mesenchymal Transition , MicroRNAs/metabolism , Sarcoma/pathology , Animals , Biomarkers, Tumor/metabolism , Cell Differentiation/physiology , Humans , MicroRNAs/genetics , Sarcoma/genetics , Sarcoma/metabolism
5.
PLoS One ; 8(6): e67306, 2013.
Article in English | MEDLINE | ID: mdl-23825651

ABSTRACT

Fixed, paraffin-embedded (FPE) tissues are a potentially rich resource for studying the role of NOTCH1 in cancer and other pathologies, but tests that reliably detect activated NOTCH1 (NICD1) in FPE samples have been lacking. Here, we bridge this gap by developing an immunohistochemical (IHC) stain that detects a neoepitope created by the proteolytic cleavage event that activates NOTCH1. Following validation using xenografted cancers and normal tissues with known patterns of NOTCH1 activation, we applied this test to tumors linked to dysregulated Notch signaling by mutational studies. As expected, frequent NICD1 staining was observed in T lymphoblastic leukemia/lymphoma, a tumor in which activating NOTCH1 mutations are common. However, when IHC was used to gauge NOTCH1 activation in other human cancers, several unexpected findings emerged. Among B cell tumors, NICD1 staining was much more frequent in chronic lymphocytic leukemia than would be predicted based on the frequency of NOTCH1 mutations, while mantle cell lymphoma and diffuse large B cell lymphoma showed no evidence of NOTCH1 activation. NICD1 was also detected in 38% of peripheral T cell lymphomas. Of interest, NICD1 staining in chronic lymphocytic leukemia cells and in angioimmunoblastic lymphoma was consistently more pronounced in lymph nodes than in surrounding soft tissues, implicating factors in the nodal microenvironment in NOTCH1 activation in these diseases. Among carcinomas, diffuse strong NICD1 staining was observed in 3.8% of cases of triple negative breast cancer (3 of 78 tumors), but was absent from 151 non-small cell lung carcinomas and 147 ovarian carcinomas. Frequent staining of normal endothelium was also observed; in line with this observation, strong NICD1 staining was also seen in 77% of angiosarcomas. These findings complement insights from genomic sequencing studies and suggest that IHC staining is a valuable experimental tool that may be useful in selection of patients for clinical trials.


Subject(s)
Receptor, Notch1/metabolism , Animals , Cell Line, Tumor , Heterografts , Humans , Immunohistochemistry , Mice , Mutation , Receptor, Notch1/genetics
6.
Am J Surg Pathol ; 36(10): 1444-51, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22982887

ABSTRACT

Sclerosing epithelioid fibrosarcoma (SEF) is a rare aggressive fibroblastic neoplasm composed of cords of epithelioid cells embedded in a dense collagenous stroma. The reported immunophenotype of SEF is nonspecific. Some SEF cases show morphologic and molecular overlap with low-grade fibromyxoid sarcoma (LGFMS), suggesting a relationship between these tumor types. MUC4 has recently been identified as a sensitive and specific marker for LGFMS; MUC4 expression was also observed in 2 tumors with hybrid features of SEF and LGFMS. We investigated MUC4 expression in SEF and other epithelioid soft tissue tumors to determine (1) the potential diagnostic utility of MUC4 for SEF and (2) the association between MUC4 expression and FUS rearrangement in SEF. Whole sections of 180 tumors were evaluated: 41 cases of SEF (including 29 "pure" SEF and 12 hybrid LGFMS-SEF), 20 epithelioid sarcomas, 11 clear cell sarcomas, 11 metastatic melanomas, 10 perivascular epithelioid cell tumors, 10 alveolar soft part sarcomas, 10 epithelioid angiosarcomas, 10 epithelioid hemangioendotheliomas, 10 epithelioid gastrointestinal stromal tumors, 10 myoepithelial carcinomas, 17 ossifying fibromyxoid tumors, 10 leiomyosarcomas, and 10 biphasic synovial sarcomas. Immunohistochemical analysis was performed after antigen retrieval using a mouse anti-MUC4 monoclonal antibody. Fluorescence in situ hybridization (FISH) was performed on 33 SEF cases using FUS break-apart probes. A subset of cases was also evaluated for EWSR1 and CREB3L2/L1 rearrangements by FISH. Strong diffuse cytoplasmic staining for MUC4 was observed in 32 of 41 (78%) cases of SEF, including all 12 hybrid tumors. FUS rearrangement was detected in 8 of 21 (38%) MUC4-positive cases of SEF with successful FISH studies. The prevalence of FUS rearrangement was similar in hybrid LGFMS-SEF (2 of 6; 33%) and SEF without an LGFMS component (6 of 15; 40%). FUS rearrangement was not detected in any cases of MUC4-negative SEF. Two hybrid tumors had both EWSR1 and CREB3L1 rearrangements. MUC4 expression was also seen in 9 of 10 (90%) biphasic synovial sarcomas, predominantly in the glandular component. All other tumor types were negative for MUC4, apart from focal reactivity in 5 ossifying fibromyxoid tumors, 2 epithelioid gastrointestinal stromal tumors, and 1 myoepithelial carcinoma. MUC4 is a sensitive and relatively specific marker for SEF among epithelioid soft tissue tumors. MUC4 expression occurs more frequently than FUS rearrangement in SEF. The finding of EWSR1 and CREB3L1 rearrangements in 2 cases of hybrid LGFMS-SEF suggests that SEFs are genetically heterogenous. MUC4-positive SEFs with FUS rearrangement are likely closely related to LGFMS. MUC4-positive SEFs that lack FUS rearrangement may be related to LGFMS but could have alternate fusion partners, including EWSR1. SEF without MUC4 expression may represent a distinct group of tumors. MUC4 expression correlates with glandular epithelial differentiation in biphasic synovial sarcoma and is very limited in other epithelioid soft tissue tumors.


Subject(s)
Biomarkers, Tumor/metabolism , Fibrosarcoma/metabolism , Gene Rearrangement , Mucin-4/metabolism , RNA-Binding Protein FUS/genetics , Sclerosis/pathology , Soft Tissue Neoplasms/metabolism , Adolescent , Adult , Aged , Child , Diagnosis, Differential , Epithelioid Cells/metabolism , Epithelioid Cells/pathology , Female , Fibrosarcoma/diagnosis , Fibrosarcoma/genetics , Humans , Immunohistochemistry , In Situ Hybridization, Fluorescence , Male , Middle Aged , Neoplasms, Multiple Primary , RNA-Binding Protein FUS/metabolism , Sarcoma, Synovial/diagnosis , Sarcoma, Synovial/genetics , Sarcoma, Synovial/metabolism , Sclerosis/genetics , Sclerosis/metabolism , Soft Tissue Neoplasms/diagnosis , Soft Tissue Neoplasms/genetics , Young Adult
7.
J Pathol ; 227(2): 223-33, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22294416

ABSTRACT

Soft-tissue sarcomas are a group of malignant tumours whose clinical management is complicated by morphological heterogeneity, inadequate molecular markers and limited therapeutic options. Receptor tyrosine kinases (RTKs) have been shown to play important roles in cancer, both as therapeutic targets and as prognostic biomarkers. An initial screen of gene expression data for 48 RTKs in 148 sarcomas showed that ROR2 was expressed in a subset of leiomyosarcoma (LMS), gastrointestinal stromal tumour (GIST) and desmoid-type fibromatosis (DTF). This was further confirmed by immunohistochemistry (IHC) on 573 tissue samples from 59 sarcoma tumour types. Here we provide evidence that ROR2 expression plays a role in the invasive abilities of LMS and GIST cells in vitro. We also show that knockdown of ROR2 significantly reduces tumour mass in vivo using a xenotransplantation model of LMS. Lastly, we show that ROR2 expression, as measured by IHC, predicts poor clinical outcome in patients with LMS and GIST, although it was not independent of other clinico-pathological features in a multivariate analysis, and that ROR2 expression is maintained between primary tumours and their metastases. Together, these results show that ROR2 is a useful prognostic indicator in the clinical management of these soft-tissue sarcomas and may represent a novel therapeutic target.


Subject(s)
Biomarkers, Tumor/metabolism , Gastrointestinal Stromal Tumors/enzymology , Leiomyosarcoma/enzymology , Receptor Tyrosine Kinase-like Orphan Receptors/metabolism , Uterine Neoplasms/enzymology , Animals , Biomarkers, Tumor/genetics , Cell Line, Tumor , Cell Movement , Disease-Free Survival , Female , Gastrointestinal Stromal Tumors/genetics , Gastrointestinal Stromal Tumors/mortality , Gastrointestinal Stromal Tumors/pathology , Gastrointestinal Stromal Tumors/therapy , Gene Expression Profiling/methods , Genetic Therapy , Humans , Immunohistochemistry , Kaplan-Meier Estimate , Leiomyosarcoma/genetics , Leiomyosarcoma/mortality , Leiomyosarcoma/pathology , Leiomyosarcoma/therapy , Male , Mice , Mice, Inbred NOD , Mice, SCID , Multivariate Analysis , Neoplasm Invasiveness , Oligonucleotide Array Sequence Analysis , Prognosis , Proportional Hazards Models , RNA Interference , RNA, Messenger/metabolism , Receptor Tyrosine Kinase-like Orphan Receptors/genetics , Time Factors , Transfection , Tumor Burden , Uterine Neoplasms/genetics , Uterine Neoplasms/mortality , Uterine Neoplasms/pathology , Uterine Neoplasms/therapy , Xenograft Model Antitumor Assays
8.
J Cutan Pathol ; 39(3): 356-60, 2012 Mar.
Article in English | MEDLINE | ID: mdl-22335595

ABSTRACT

We report two unique cases of dermatofibrosarcoma protuberans (DFSP) that included a pseudocystic component. Molecular analysis of one of the cases showed a characteristic COL1A1-PDGFB rearrangement in both the main tumor and also in the cells lining the pseudocystic portion of the tumor, confirming the diagnosis and indicating that the lining represented a component of the proliferation. It is important to raise awareness of this rare variant within the varied spectrum of DFSP. Shvartsbeyn M, Lazar AJF, Lopez-Terrada D, Meehan SA. Pseudocystic dermatofibrosarcoma protuberans: report of two cases and demonstration of COL1A1-PDGFB rearrangement.


Subject(s)
Collagen Type I/genetics , Cysts , Dermatofibrosarcoma , Gene Rearrangement , Oncogene Proteins, Fusion/genetics , Proto-Oncogene Proteins c-sis/genetics , Skin Neoplasms , Adult , Cell Proliferation , Collagen Type I, alpha 1 Chain , Cysts/genetics , Cysts/pathology , Dermatofibrosarcoma/genetics , Dermatofibrosarcoma/pathology , Female , Humans , Male , Skin Neoplasms/genetics , Skin Neoplasms/pathology
9.
Am J Dermatopathol ; 33(4): 354-60, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21478726

ABSTRACT

Dermatofibrosarcoma protuberans (DFSP) is a superficial sarcoma of intermediate malignancy usually composed of monotonous short spindle cells with storiform architecture. The tumor cells are diffusely reactive for CD34 and characterized by a translocation involving chromosomes 17 and 22 or a supernumerary ring chromosome that results in the fusion of exon 2 of platelet-derived growth factor beta (PDGFß; 22q13) to various exons of collagen type 1 alpha 1 (COL1A1; 17q22). In some tumors, fibrosarcomatous transformation can occur and is characterized by a monotonous spindle cell proliferation arranged in fascicles or a herringbone-type pattern. We report 4 DFSPs with unusual and pleomorphic sarcomatous transformation. They occurred on the back, scalp, shoulder, and forehead of women (ages 31,48, 48, and 27 year). In addition to areas of conventional DFSP that strongly expressed CD34, 2 cases showed pleomorphic areas mimicking undifferentiated pleomorphic sarcoma/malignant fibrous histiocytoma: 1 case had a patternless area and 1 case had combined round/spindled cells with myxoid areas. Reverse transcription--polymerase chain reaction was performed in 1 case, confirming the presence of a COL1A1-PDGFß fusion transcript. The remaining three cases were found to be positive for a PDGFß gene rearrangement by fluorescence in situ hybridization. This series illustrates that sarcomatous transformation in DFSP may occasionally display areas, which can mimic undifferentiated pleomorphic or unclassified sarcoma. Ancillary diagnostic testing may be helpful to confirm the diagnosis, especially in small biopsies.


Subject(s)
Cell Transformation, Neoplastic/pathology , Dermatofibrosarcoma/pathology , Skin Neoplasms/pathology , Adult , Antigens, CD34/metabolism , Biomarkers, Tumor/metabolism , Cell Transformation, Neoplastic/genetics , DNA, Neoplasm/analysis , Dermatofibrosarcoma/genetics , Dermatofibrosarcoma/metabolism , Female , Humans , In Situ Hybridization, Fluorescence , Middle Aged , Oncogene Proteins, Fusion/genetics , Oncogene Proteins, Fusion/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Sequence Analysis, DNA , Skin Neoplasms/genetics , Skin Neoplasms/metabolism , Translocation, Genetic
10.
J Cutan Pathol ; 38(6): 475-82, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21352259

ABSTRACT

BACKGROUND: We describe a series of previously unreported, distinctive, polypoid solitary T-cell-rich cutaneous pseudolymphomas. METHODS: The clinicopathologic features were examined in 17 cases. RESULTS: Patient ages ranged from 16 to 71 years (mean = 38.5) with a female predominance (female : male = 14 : 3). All lesions, clinically diagnosed most often as pyogenic granuloma, presented as a solitary, polypoid, erythematous, papule ranging in size from 2.5 to 7.5 mm (mean = 5.8). Most occurred on the head and neck (7) and trunk (6) with other sites including the thigh (1), shoulder (1) and knee (1). A dense dermal infiltrate composed of mildly atypical lymphocytes with variable numbers of admixed plasma cells and histiocytes was prototypical. Commonly, there was an associated epidermal collarette (16/17), Grenz zone (11/17) or admixed eosinophils (8/17). Prominent vessels lined by plump endothelial cells, reminiscent of high endothelial venules of lymph nodes, were universal and some degree of telangiectasia was also common (12/17). CD3-positive T-cells consisted of an admixture of CD4-positive and CD8-positive forms (15/16). Multiple studies suggested polyclonality (seven cases). No recurrences after lesional excision were noted in the 17 patients with a follow-up range from 24 to 120 months (mean = 46.6). CONCLUSION: Although these lesions share histopathologic features of the so-called acral pseudolymphomatous angiokeratoma of children (APACHE), they occur in a completely different clinical setting, present in solitary and polypoid fashion and are T-cell rich. We propose the diagnostic label T-cell-rich angiomatoid polypoid pseudolymphoma for this distinctive but presumably reactive lesion.


Subject(s)
Pseudolymphoma/classification , Pseudolymphoma/pathology , Skin Diseases/classification , Skin Diseases/pathology , T-Lymphocytes/pathology , Adult , Aged , Antigens, CD/biosynthesis , Biomarkers/analysis , Female , Humans , Immunophenotyping , Male , Middle Aged , Polymerase Chain Reaction , Young Adult
11.
Cancer ; 117(2): 380-9, 2011 Jan 15.
Article in English | MEDLINE | ID: mdl-20818650

ABSTRACT

BACKGROUND: Gastrointestinal stromal tumors (GISTs) historically were grouped with leiomyosarcomas (LMSs) based on their morphologic similarities; however, recently, GIST was established unequivocally as a distinct type of sarcoma based on its molecular features and response to imatinib treatment. METHODS: To gain further insight into the genomic differences between GISTs and LMSs, the authors mapped gene copy number aberrations (CNAs) in 42 GISTs and 30 LMSs and integrated the results with gene expression profiles. RESULTS: Distinct patterns of CNAs were revealed between GISTs and LMSs. Losses in 1p, 14q, 15q, and 22q were significantly more frequent in GISTs than in LMSs (P < .001); whereas losses in chromosomes 10 and 16 and gains in 1q, 14q, and 15q (P < .001) were more common in LMSs. By integrating CNAs with gene expression data and clinical information, the authors identified several clinically relevant CNAs that were prognostic of survival in patients with GIST. Furthermore, GISTs were categorized into 4 groups according to an accumulating pattern of genetic alterations. Many key cellular pathways were expressed differently in the 4 groups, and the patients in each group had increasingly worse prognoses as the extent of genomic alterations increased. CONCLUSIONS: Based on the current findings, the authors proposed a new tumor-progression genetic staging system termed genomic instability stage to complement the current prognostic predictive system based on tumor size, mitotic index, and v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) mutation.


Subject(s)
DNA Copy Number Variations , Gastrointestinal Stromal Tumors/genetics , Leiomyosarcoma/genetics , Comparative Genomic Hybridization , Female , Gastrointestinal Stromal Tumors/mortality , Gene Expression Profiling , Genomic Instability , Humans , Leiomyosarcoma/mortality , Male , Middle Aged , Prognosis , Signal Transduction
12.
Am J Surg Pathol ; 35(1): 135-44, 2011 Jan.
Article in English | MEDLINE | ID: mdl-21164297

ABSTRACT

Inflammatory myofibroblastic tumor (IMT) is a mesenchymal neoplasm of intermediate biological potential, which may recur and rarely metastasize. Pathologic features do not correlate well with behavior. Approximately 50% of conventional IMTs harbor ALK gene rearrangement and overexpress ALK, most showing diffuse cytoplasmic staining. Rare IMTs with a distinct nuclear membrane or perinuclear pattern of ALK staining and epithelioid or round cell morphology have been reported. These cases pursued an aggressive clinical course, suggesting that such patterns may predict malignant behavior. We describe 11 cases of IMT with epithelioid morphology and a nuclear membrane or perinuclear pattern of immunostaining for ALK. Ten patients were male and 1 was female, ranging from 7 months to 63 years in age (median, 39 y). All tumors were intra-abdominal; most arose in the mesentery or omentum, measuring 8 to 26 cm (median, 15 cm). Six tumors were multifocal at presentation. The tumors were composed predominantly of sheets of round-to-epithelioid cells with vesicular nuclei, large nucleoli, and amphophilic-to-eosinophilic cytoplasm. In all cases, a minor spindle cell component was present. Nine tumors had abundant myxoid stroma. In 7 cases neutrophils were prominent and in 3 cases lymphocytes were prominent. Plasma cells were often absent. Median mitotic rate was 4/10 HPF; 6 tumors had necrosis. By immunohistochemistry, all tumors were positive for ALK, 9 tumors showing a nuclear membrane staining pattern and 2 tumors showing a cytoplasmic pattern with perinuclear accentuation. Other positive markers were desmin (10 of 11), focal smooth muscle actin (4 of 8), and CD30 (8 of 8). All tumors were negative for MYF4, caldesmon, keratins, EMA, and S-100. Fluorescence in situ hybridization was positive for ALK gene rearrangement in 9 cases, and in 3 cases tested, a RANBP2-ALK fusion was detected by reverse transcription polymerase chain reaction. Ten patients underwent surgical resection; 1 patient was inoperable. Follow-up was available for 8 patients and ranged from 3 to 40 months (median, 13 mo). All patients experienced rapid local recurrences; 4 patients had multiple recurrences. Eight patients were treated with postoperative chemotherapy; 2 patients received additional radiotherapy. Two patients also developed metastases (both patients developed metastases to the liver; 1 patient developed metastases to the lung and lymph nodes as well). Thus far, 5 patients died of disease, 2 patients are alive with disease, and 1 patient, treated with an experimental ALK inhibitor, has no evidence of disease. In summary, the epithelioid variant of IMT with nuclear membrane or perinuclear ALK is a distinctive intra-abdominal sarcoma with a predilection for male patients. Unlike conventional IMT, abundant myxoid stroma and prominent neutrophils are common. These tumors pursue an aggressive course with rapid local recurrences and are frequently fatal. We propose the designation "epithelioid inflammatory myofibroblastic sarcoma" to convey both the malignant behavior of these tumors and their close relationship with IMT.


Subject(s)
Abdominal Neoplasms/enzymology , Epithelioid Cells/enzymology , Inflammation/enzymology , Myofibroblasts/enzymology , Nuclear Envelope/enzymology , Protein-Tyrosine Kinases/analysis , Sarcoma/enzymology , Abdominal Neoplasms/classification , Abdominal Neoplasms/genetics , Abdominal Neoplasms/mortality , Abdominal Neoplasms/pathology , Abdominal Neoplasms/therapy , Adult , Anaplastic Lymphoma Kinase , Biomarkers, Tumor/analysis , Child , Cytogenetic Analysis , Epithelioid Cells/pathology , Female , Gene Expression Regulation, Enzymologic , Gene Expression Regulation, Neoplastic , Humans , Immunohistochemistry , In Situ Hybridization, Fluorescence , Infant , Inflammation/genetics , Inflammation/pathology , Male , Middle Aged , Myofibroblasts/pathology , Neoplasm Invasiveness , Neoplasm Recurrence, Local , Protein-Tyrosine Kinases/genetics , Receptor Protein-Tyrosine Kinases , Reverse Transcriptase Polymerase Chain Reaction , Sarcoma/classification , Sarcoma/genetics , Sarcoma/mortality , Sarcoma/pathology , Sarcoma/therapy , Terminology as Topic , Time Factors , Treatment Outcome
13.
Proc Natl Acad Sci U S A ; 107(32): 14333-8, 2010 Aug 10.
Article in English | MEDLINE | ID: mdl-20660757

ABSTRACT

Although gastrointestinal stromal tumors (GISTs) harboring activating KIT or platelet-derived growth factor receptor A (PDGFRA) mutations respond to treatment with targeted KIT/PDGFRA inhibitors such as imatinib mesylate, these treatments are rarely curative. Most often, a sizeable tumor cell subpopulation survives and remains quiescent for years, eventually resulting in acquired resistance and treatment failure. Here, we report that imatinib induces autophagy as a survival pathway in quiescent GIST cells. Inhibiting autophagy, using RNAi-mediated silencing of autophagy regulators (ATGs) or antimalarial lysosomotrophic agents, promotes the death of GIST cells both in vitro and in vivo. Thus, combining imatinib with autophagy inhibition represents a potentially valuable strategy to promote GIST cytotoxicity and to diminish both cellular quiescence and acquired resistance in GIST patients.


Subject(s)
Antimalarials/pharmacology , Autophagy/drug effects , Gastrointestinal Stromal Tumors/drug therapy , Benzamides , Cell Death/drug effects , Cell Survival/drug effects , Drug Resistance, Neoplasm/drug effects , Drug Therapy, Combination , Gastrointestinal Stromal Tumors/pathology , Humans , Imatinib Mesylate , Piperazines/pharmacology , Pyrimidines/pharmacology
14.
Mol Cell Proteomics ; 9(11): 2405-13, 2010 Nov.
Article in English | MEDLINE | ID: mdl-20651304

ABSTRACT

Leiomyosarcoma is one of the most common mesenchymal tumors. Proteomics profiling analysis by reverse-phase protein lysate array surprisingly revealed that expression of the epithelial marker E-cadherin (encoded by CDH1) was significantly elevated in a subset of leiomyosarcomas. In contrast, E-cadherin was rarely expressed in the gastrointestinal stromal tumors, another major mesenchymal tumor type. We further sought to 1) validate this finding, 2) determine whether there is a mesenchymal to epithelial reverting transition (MErT) in leiomyosarcoma, and if so 3) elucidate the regulatory mechanism responsible for this MErT. Our data showed that the epithelial cell markers E-cadherin, epithelial membrane antigen, cytokeratin AE1/AE3, and pan-cytokeratin were often detected immunohistochemically in leiomyosarcoma tumor cells on tissue microarray. Interestingly, the E-cadherin protein expression was correlated with better survival in leiomyosarcoma patients. Whole genome microarray was used for transcriptomics analysis, and the epithelial gene expression signature was also associated with better survival. Bioinformatics analysis of transcriptome data showed an inverse correlation between E-cadherin and E-cadherin repressor Slug (SNAI2) expression in leiomyosarcoma, and this inverse correlation was validated on tissue microarray by immunohistochemical staining of E-cadherin and Slug. Knockdown of Slug expression in SK-LMS-1 leiomyosarcoma cells by siRNA significantly increased E-cadherin; decreased the mesenchymal markers vimentin and N-cadherin (encoded by CDH2); and significantly decreased cell proliferation, invasion, and migration. An increase in Slug expression by pCMV6-XL5-Slug transfection decreased E-cadherin and increased vimentin and N-cadherin. Thus, MErT, which is mediated through regulation of Slug, is a clinically significant phenotype in leiomyosarcoma.


Subject(s)
Epithelial-Mesenchymal Transition , Genomics/methods , Leiomyosarcoma , Proteomics/methods , Transcription Factors/metabolism , Biomarkers , Cadherins/genetics , Cadherins/metabolism , Cell Movement , Cell Proliferation , Gastrointestinal Stromal Tumors/genetics , Gastrointestinal Stromal Tumors/metabolism , Gastrointestinal Stromal Tumors/pathology , Gene Expression Regulation, Neoplastic , Humans , Leiomyosarcoma/genetics , Leiomyosarcoma/metabolism , Leiomyosarcoma/pathology , Microarray Analysis , Snail Family Transcription Factors , Survival Rate , Transcription Factors/genetics , Vimentin/metabolism
15.
Mod Pathol ; 23(10): 1301-6, 2010 Oct.
Article in English | MEDLINE | ID: mdl-20495536

ABSTRACT

Well-differentiated liposarcoma/atypical lipomatous tumor can be difficult to differentiate from benign lipomatous tumors, especially on limited biopsy material. Adjunctive tests for MDM2 (murine double minute 2) have proven useful in whole-tissue sections; however, their utility has not been determined within the increasingly popular core needle biopsy. Herein, we compare the ability of MDM2 immunohistochemistry and MDM2 fluorescence in situ hybridization (FISH) to discriminate benign lipomatous tumors from well-differentiated liposarcoma on core needle biopsies. Well-differentiated liposarcoma (n=17) and an assortment of benign lipomatous tumors (n=37), which had concurrent or previous core needle biopsies, and resection specimens were subjected to both MDM2 immunohistochemistry and MDM2 FISH on both whole-tissue sections and corresponding core needle biopsy sections. Percentage tumor cells positive for MDM2 by immunohistochemistry and an MDM2:CEP12 FISH ratio was calculated in each biopsy and resection specimen pair and the results were compared. MDM2 FISH had a higher sensitivity (100%) and specificity (100%) compared with MDM2 immunohistochemistry (65 and 89%) in core needle biopsies, respectively. In addition, MDM2 immunohistochemistry had a false-positive rate of 11%, compared to 0% with FISH. The average MDM2:CEP12 ratio was similar in the biopsy material compared with the whole-tissue sections in both well-differentiated liposarcoma and the benign lipomatous tumor group of neoplasms. Detection of MDM2 amplification by FISH is a more sensitive and specific adjunctive test than MDM2 immunohistochemistry to differentiate well-differentiated liposarcoma from various benign lipomatous tumors, especially on limited tissue samples.


Subject(s)
Biomarkers, Tumor/analysis , Biopsy, Needle , Liposarcoma/diagnosis , Proto-Oncogene Proteins c-mdm2/biosynthesis , Diagnosis, Differential , Humans , Immunohistochemistry , In Situ Hybridization, Fluorescence , Lipoma/diagnosis , Liposarcoma/metabolism , Sensitivity and Specificity
16.
Histopathology ; 56(1): 133-47, 2010 Jan.
Article in English | MEDLINE | ID: mdl-20055911

ABSTRACT

Sebaceous neoplasia comprises a spectrum ranging from benign to malignant. Proper histological identification is important for treatment, prognosis and potential association with the Muir-Torre syndrome (MTS). Our increased understanding of the significance and pathogenesis of these tumours has led to improved risk stratification, screening recommendations, and treatment of patients with an initial presentation of a sebaceous tumour. This review focuses on the diagnostic and histological features of sebaceous lesions, the MTS, and recent insights into the molecular pathogenesis of sebaceous tumours.


Subject(s)
Adenocarcinoma, Sebaceous/pathology , Adenoma/pathology , Muir-Torre Syndrome/pathology , Sebaceous Gland Neoplasms/pathology , Adenocarcinoma, Sebaceous/complications , Adenoma/complications , Humans , Muir-Torre Syndrome/complications , Sebaceous Gland Neoplasms/complications
17.
Am J Dermatopathol ; 32(2): 149-53, 2010 Apr.
Article in English | MEDLINE | ID: mdl-19940748

ABSTRACT

Indeterminate fibrohistiocytic lesions of the skin share histological and immunohistochemical features of both benign fibrous histiocytoma/dermatofibroma and dermatofibrosarcoma protuberans (DFSP). Unlike dermatofibroma, DFSP harbors recurrent genetic aberrations resulting in the fusion of COL1A1 on chromosome 17 and PDGFB on chromosome 22. Because indeterminate fibrohistiocytic lesions share some features with DFSP, they were evaluated for the possible presence of COL1A1-PDGFB chimeric transcripts. Twelve formalin-fixed paraffin-embedded cases were examined for COL1A1-PDGFB chimeric transcripts using a previously validated sensitive multiplex reverse transcriptase-polymerase chain reaction assay. The median patient age was 52.5 years (33-70 years) with 9 females and 3 males. The most common site was the extremities (n = 8) followed by the trunk (n = 2) and the head and neck region (n = 2). All demonstrated the expected reactivity for both CD34 and factor XIIIa, and the majority focally infiltrated into subcutaneous fat. Of the 6 patients with follow-up, 2 had residual tumor excised, but no patient developed a recurrence. None of the tumors harbored COL1A1-PDGFB fusion transcripts identified by reverse transcriptase-polymerase chain reaction. Although indeterminate fibrohistiocytic lesions share some features with DFSP, the lack of COL1A1-PDGFB chimeric transcripts suggests that they are distinct entities.


Subject(s)
Chimera/genetics , Collagen Type I/genetics , Dermatofibrosarcoma/genetics , Histiocytoma, Benign Fibrous/genetics , Proto-Oncogene Proteins c-sis/genetics , Skin Neoplasms/genetics , Adult , Aged , Biopsy , Chimera/metabolism , Collagen Type I/metabolism , Collagen Type I, alpha 1 Chain , Dermatofibrosarcoma/diagnosis , Dermatofibrosarcoma/metabolism , Diagnosis, Differential , Female , Gene Expression Regulation, Neoplastic , Histiocytes/metabolism , Histiocytes/pathology , Histiocytoma, Benign Fibrous/diagnosis , Histiocytoma, Benign Fibrous/metabolism , Humans , Immunohistochemistry , Male , Middle Aged , Prevalence , Proto-Oncogene Proteins c-sis/metabolism , Retrospective Studies , Skin/metabolism , Skin/pathology , Skin Neoplasms/metabolism , Skin Neoplasms/pathology
18.
J Cutan Pathol ; 37(2): 231-6, 2010 Feb.
Article in English | MEDLINE | ID: mdl-19614729

ABSTRACT

Sebaceous carcinoma has a predominant periocular origin but can also be extraocular. These two groups have distinct clinical courses. Insight into the molecular determinants of tumorigenesis and metastasis is limited. There is no effective treatment for metastatic sebaceous carcinoma. Epidermal growth factor receptor (EGFR) is implicated in tumorigenesis and can be a therapeutic target in certain settings. We evaluated EGFR levels by immunohistochemistry (IHC), comparing its expression between periocular and extraocular tumors and assessed EGFR mutation status. IHC was performed in 36 cases: 19 periocular and 17 extraocular (10 associated with Muir-Torre syndrome-MTS). EGFR IHC was scored for percentage of positive cells (< 5%, 5-25%, 26-50%, > 50%) and intensity (+1 = low , +2 = moderate , +3 = high ). Extraocular carcinomas showed markedly increased levels of EGFR when compared to periocular carcinoma cases, both in terms of distribution (88% were > 25% of tumor cells vs. 16%) and intensity (77% were 2+ or 3+ vs. 21%) (p < 0.001). Among extraocular cases, there was significantly lower EGFR expression in MTS-related cases (p < 0.05). No EGFR mutations were identified. Our results underscore the divergent mechanisms underlying the tumorigenesis of periocular and extraocular sebaceous carcinoma and suggest an association between aggressive behavior and increased EGFR expression in extraocular sebaceous carcinoma.


Subject(s)
Adenocarcinoma, Sebaceous/metabolism , ErbB Receptors/metabolism , Sebaceous Gland Neoplasms/metabolism , Adenocarcinoma, Sebaceous/complications , Adenocarcinoma, Sebaceous/genetics , Adult , Aged , Aged, 80 and over , Chi-Square Distribution , ErbB Receptors/genetics , Female , Head and Neck Neoplasms/complications , Head and Neck Neoplasms/genetics , Head and Neck Neoplasms/metabolism , Humans , Immunohistochemistry , Male , Middle Aged , Muir-Torre Syndrome/complications , Muir-Torre Syndrome/genetics , Muir-Torre Syndrome/metabolism , Mutation , Polymerase Chain Reaction , Sebaceous Gland Neoplasms/complications , Sebaceous Gland Neoplasms/genetics
19.
Curr Opin Oncol ; 21(4): 352-9, 2009 Jul.
Article in English | MEDLINE | ID: mdl-19436199

ABSTRACT

PURPOSE OF REVIEW: Desmoid tumors are associated with a variable and unpredictable clinical course. Surgery is the therapeutic mainstay, but there has been much discussion of late regarding its proper application. Little is known regarding the molecular determinates of desmoid tumor behavior. Some recent work has focused on the role of beta-catenin in desmoid tumor biology. RECENT FINDINGS: Given the variable clinical course of desmoid tumors, the interpretation of factors classically associated with recurrence such as microscopic status of margins appears more nuanced that previously thought. The application of multidisciplinary assessment with multimodality treatment, including surgery, radiation and systemic therapies may underlie these changes and now form the basis of care for this tumor. The precise CTNNB1 mutation present appears to be strongly predictive of recurrence after initial resection in one large, retrospective, multivariate analysis. SUMMARY: Establishing the population benefiting most from various treatment modalities and combinations is critical for progress in this disease. Assessment and treatment of individual patients in a multidisciplinary setting is critical to achieve the most favorable outcome. Additional study of the molecular determinates of desmoid behavior is needed to guide therapeutic selection.


Subject(s)
Fibromatosis, Aggressive/therapy , Combined Modality Therapy , Fibromatosis, Aggressive/genetics , Fibromatosis, Aggressive/metabolism , Fibromatosis, Aggressive/pathology , Humans , Mesenchymoma/genetics , Mesenchymoma/metabolism , Mesenchymoma/pathology , Mesenchymoma/therapy , Wnt Proteins/metabolism , beta Catenin/genetics , beta Catenin/metabolism
20.
Am J Dermatopathol ; 31(3): 297-300, 2009 May.
Article in English | MEDLINE | ID: mdl-19384074

ABSTRACT

Gastrointestinal stromal tumors (GISTs) rarely metastasize to the skin. We describe 5 patients with GIST with subcutaneous and cutaneous metastases. The mean age at metastasis was 54 years (range 30-68 years) with a male predominance (4:1). Primary tumors occurred in the stomach (n = 3), small bowel (n = 1), and abdomen, not otherwise specified (n = 1). The average time from primary tumor resection to the resection of skin metastases was 59 months (range 11-155 months). The metastases occurred in the scalp (n = 2), cheek (n = 1), and abdomen (n = 2) with 3 patients presenting with solitary nodules and 2 patients with multiple nodules. The average size was 2 cm (range 0.6-4 cm). Histologically, 2 cases were spindled and 3 cases demonstrated mixed epithelioid and spindle cell morphology. All were confirmed to have CD117 reactivity. KIT genotyping was performed in 4 of 5 cases. Two cases harbored a mutation in exon 11, and the remaining 2 cases were wild type in exons 9, 11, 13, and 17. All 5 patients had multiple concurrent or subsequent abdominal and/or hepatic metastases. In 4 patients with an average follow-up of 32 months (range 6-75 months), after the resection of the metastases, 2 were alive with disease and 2 died of disease. Cutaneous metastases seem to be a late complication of GIST, but their presence does not necessarily herald a rapid demise of the patient.


Subject(s)
Gastrointestinal Stromal Tumors/pathology , Proto-Oncogene Proteins c-kit , Skin Neoplasms/secondary , Soft Tissue Neoplasms/secondary , Subcutaneous Tissue/pathology , Adult , Aged , DNA Mutational Analysis , Exons , Female , Gastrointestinal Stromal Tumors/genetics , Gastrointestinal Stromal Tumors/immunology , Gastrointestinal Stromal Tumors/mortality , Gastrointestinal Stromal Tumors/surgery , Gene Expression Regulation, Neoplastic , Humans , Immunohistochemistry , Male , Middle Aged , Mutation , Proto-Oncogene Proteins c-kit/analysis , Proto-Oncogene Proteins c-kit/genetics , Skin Neoplasms/genetics , Skin Neoplasms/immunology , Skin Neoplasms/mortality , Skin Neoplasms/surgery , Soft Tissue Neoplasms/genetics , Soft Tissue Neoplasms/immunology , Soft Tissue Neoplasms/mortality , Soft Tissue Neoplasms/surgery , Subcutaneous Tissue/immunology , Subcutaneous Tissue/surgery , Time Factors , Treatment Outcome
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