ABSTRACT
BACKGROUND: Although uterine serous carcinoma (USC) represents a small proportion of all uterine cancer cases, patients with this aggressive subtype typically have high rates of chemotherapy resistance and disease recurrence that collectively result in a disproportionately high death rate. The goal of this study was to provide a deeper view of the tumor microenvironment of this poorly characterized uterine cancer variant through multi-region microsampling and quantitative proteomics. METHODS: Tumor epithelium, tumor-involved stroma, and whole "bulk" tissue were harvested by laser microdissection (LMD) from spatially resolved levels from nine USC patient tumor specimens and underwent proteomic analysis by mass spectrometry and reverse phase protein arrays, as well as transcriptomic analysis by RNA-sequencing for one patient's tumor. RESULTS: LMD enriched cell subpopulations demonstrated varying degrees of relatedness, indicating substantial intratumor heterogeneity emphasizing the necessity for enrichment of cellular subpopulations prior to molecular analysis. Known prognostic biomarkers were quantified with stable levels in both LMD enriched tumor and stroma, which were shown to be highly variable in bulk tissue. These USC data were further used in a comparative analysis with a data generated from another serous gynecologic malignancy, high grade serous ovarian carcinoma, and have been added to our publicly available data analysis tool, the Heterogeneity Analysis Portal ( https://lmdomics.org/ ). CONCLUSIONS: Here we identified extensive three-dimensional heterogeneity within the USC tumor microenvironment, with disease-relevant biomarkers present in both the tumor and the stroma. These data underscore the critical need for upfront enrichment of cellular subpopulations from tissue specimens for spatial proteogenomic analysis.
ABSTRACT
Enriched tumor epithelium, tumor-associated stroma, and whole tissue were collected by laser microdissection from thin sections across spatially separated levels of ten high-grade serous ovarian carcinomas (HGSOCs) and analyzed by mass spectrometry, reverse phase protein arrays, and RNA sequencing. Unsupervised analyses of protein abundance data revealed independent clustering of an enriched stroma and enriched tumor epithelium, with whole tumor tissue clustering driven by overall tumor "purity." Comparing these data to previously defined prognostic HGSOC molecular subtypes revealed protein and transcript expression from tumor epithelium correlated with the differentiated subtype, whereas stromal proteins (and transcripts) correlated with the mesenchymal subtype. Protein and transcript abundance in the tumor epithelium and stroma exhibited decreased correlation in samples collected just hundreds of microns apart. These data reveal substantial tumor microenvironment protein heterogeneity that directly bears on prognostic signatures, biomarker discovery, and cancer pathophysiology and underscore the need to enrich cellular subpopulations for expression profiling.
ABSTRACT
Melanoma is an aggressive malignancy arising from melanocytes in the skin and rarely in extracutaneous sites. The understanding of pathology of melanoma has evolved over the years, with the initial classifications based on the clinical and microscopic features to the current use of immunohistochemistry and genetic sequencing. The depth of invasion and lymph node metastasis are still the most important prognostic features of melanoma. Other important prognostic features include ulceration, lymphovascular invasion, mitosis, and tumor-infiltrating lymphocytes. This article reviews the pathology of melanoma and its precursor lesions, along with the recent advances in pathologic diagnosis of melanoma.
Subject(s)
Carcinoma in Situ/pathology , Melanoma/pathology , Nevus/pathology , Skin Neoplasms/pathology , Biopsy , Humans , Lymphatic Metastasis , Neoplasm Staging , Sentinel Lymph Node BiopsyABSTRACT
PURPOSE: Phase III adjuvant trials have reported significant benefits in both relapse-free survival (RFS) and overall survival (OS) for high-dose interferon alfa (HDI) and ipilimumab at 10 mg/kg (ipi10). E1609 evaluated the safety and efficacy of ipilimumab at 3 mg/kg (ipi3) and ipi10 versus HDI. PATIENTS AND METHODS: E1609 was a phase III trial in patients with resected cutaneous melanoma (American Joint Committee on Cancer 7th edition stage IIIB, IIIC, M1a, or M1b). It had 2 coprimary end points: OS and RFS. A 2-step hierarchic approach first evaluated ipi3 versus HDI followed by ipi10 versus HDI. RESULTS: Between May 2011 and August 2014, 1,670 adult patients were centrally randomly assigned (1:1:1) to ipi3 (n = 523), HDI (n = 636), or ipi10 (n = 511). Treatment-related adverse events grade ≥ 3 occurred in 37% of patients receiving ipi3, 79% receiving HDI, and 58% receiving ipi10, with adverse events leading to treatment discontinuation in 35%, 20%, and 54%, respectively. Comparison of ipi3 versus HDI used an intent-to-treat analysis of concurrently randomly assigned patient cases (n = 1,051) and showed significant OS difference in favor of ipi3 (hazard ratio [HR], 0.78; 95.6% repeated CI, 0.61 to 0.99; P = .044; RFS: HR, 0.85; 99.4% CI, 0.66 to 1.09; P = .065). In the second step, for ipi10 versus HDI (n = 989), trends in favor of ipi10 did not achieve statistical significance. Salvage patterns after melanoma relapse showed significantly higher rates of ipilimumab and ipilimumab/anti-programmed death 1 use in the HDI arm versus ipi3 and ipi10 (P ≤ .001). CONCLUSION: Adjuvant therapy with ipi3 benefits survival versus HDI; for the first time to our knowledge in melanoma adjuvant therapy, E1609 has demonstrated a significant improvement in OS against an active control regimen. The currently approved adjuvant ipilimumab dose (ipi10) was more toxic and not superior in efficacy to HDI.
Subject(s)
Antineoplastic Agents, Immunological/administration & dosage , Ipilimumab/administration & dosage , Melanoma/drug therapy , Skin Neoplasms/drug therapy , Adolescent , Adult , Aged , Aged, 80 and over , Antineoplastic Agents, Immunological/adverse effects , Chemotherapy, Adjuvant/methods , Disease-Free Survival , Dose-Response Relationship, Drug , Female , Humans , Interferon alpha-2/therapeutic use , Ipilimumab/adverse effects , Male , Melanoma/mortality , Middle Aged , Skin Neoplasms/mortality , Young Adult , Melanoma, Cutaneous MalignantABSTRACT
Uterine leiomyosarcoma in a prior myomectomy site is a rare phenomenon. We report an unusual case of a leiomyosarcoma arising six months post myomectomy in a 16-year old female.
ABSTRACT
Dermatofibrosarcoma protuberans with fibrosarcomatous transformation (DFSP-FS) is a higher grade tumor arising from dermatofibrosarcoma protuberans (DFSP). Recent literature highlights its impact on recurrence rates, metastatic rates, and survival. In this article, we aim to describe our experience with 13 cases of DFSP-FS in terms of pathologic findings, molecular alterations, clinical outcomes, management, and also perform a short recent literature review.
Subject(s)
Cell Transformation, Neoplastic/genetics , Dermatofibrosarcoma/therapy , Neoplasm Recurrence, Local/epidemiology , Skin Neoplasms/therapy , Skin/pathology , Adolescent , Adult , Aged , Cell Transformation, Neoplastic/pathology , Chemotherapy, Adjuvant , Chromosomes, Human, Pair 22/genetics , DNA Copy Number Variations , Dermatofibrosarcoma/genetics , Dermatofibrosarcoma/mortality , Disease-Free Survival , Female , Follow-Up Studies , Gene Rearrangement , Humans , Male , Middle Aged , Mohs Surgery , Neoplasm Recurrence, Local/pathology , Proto-Oncogene Proteins c-sis/genetics , Radiotherapy, Adjuvant , Registries/statistics & numerical data , Skin Neoplasms/genetics , Skin Neoplasms/mortality , Young AdultABSTRACT
Ovarian ependymomas are rare glial neoplasms that typically occur in women on their third to fourth decades of life. They are histologically similar to ependymomas of the central nervous system but may have a broader immunophenotype. We describe a 27-year-old woman who presented to the emergency department with a 3-week history of cough and shortness of breath. Further workup disclosed a left pelvic mass and extensive intra-abdominal metastases. Pathology revealed sheets of monomorphic cells within a fibrillary stroma, papillary projections, true ependymal rosettes, and pseudorosettes consistent with an ependymoma of ovarian origin. Next-generation sequencing showed ATRX and NF2 copy number losses. Fluorescence in situ hybridization for EWSR1 demonstrated monosomy of 22q in greater than 90% of cells. These molecular alterations have not been previously reported in ovarian or extra-central nervous system ependymomas.
Subject(s)
Ependymoma/genetics , Neurofibromin 2/genetics , Ovarian Neoplasms/genetics , X-linked Nuclear Protein/genetics , Adult , Ependymoma/pathology , Female , Gene Dosage , Humans , Ovarian Neoplasms/pathologyABSTRACT
PURPOSE: Interferon-α favors a Th1 shift in immunity, and combining with ipilimumab (ipi) at 3 or 10 mg/kg may downregulate CTLA4-mediated suppressive effects, leading to more durable antitumor immune responses. A study of tremelimumab and high-dose interferon-α (HDI) showed promising efficacy, supporting this hypothesis. PATIENTS AND METHODS: E3611 followed a 2-by-2 factorial design (A: ipi10+HDI; B: ipi10; C: ipi3+HDI; D: ipi3) to evaluate (i) no HDI versus HDI (across ipilimumab doses) and (ii) ipi3 versus ipi10 (across HDI status). We hypothesized that median progression-free survival (PFS) would improve from 3 to 6 months with HDI versus no HDI and with ipi10 versus ipi3. RESULTS: For eligible and treated patients (N = 81) at a median follow-up time of 29.8 months, median PFS was 4.4 months [95% confidence interval (CI), 2.7-8.2] when ipilimumab was used alone and 7.5 months (95% CI, 5.1-11.0) when HDI was added. Median PFS was 3.8 months (95% CI, 2.6-7.5) with 3 mg/kg ipilimumab and 6.5 months (95% CI, 5.1-13.5) with 10 mg/kg. By study arm, median PFS was 8.0 months (95% CI, 2.8-20.2) in arm A, 6.2 months (95% CI, 2.7-25.7) in B, 5.7 months (95% CI, 1.5-11.1) in C, and 2.8 months (95% CI, 2.6-5.7) in D. The differences in PFS and overall survival (OS) did not reach statistical significance. Adverse events were consistent with the known profiles of ipilimumab and HDI and significantly higher with HDI and ipi10. CONCLUSIONS: Although PFS was increased, the differences resulting from adding interferon-α or a higher dose of ipilimumab did not reach statistical significance and do not outweigh the added toxicity risks.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Melanoma/drug therapy , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Female , Humans , Interferon alpha-2 , Interferon-alpha/administration & dosage , Ipilimumab/administration & dosage , Kaplan-Meier Estimate , Male , Melanoma/etiology , Melanoma/mortality , Melanoma/pathology , Middle Aged , Neoplasm Metastasis , Neoplasm Staging , Treatment Outcome , Young AdultABSTRACT
BACKGROUND: Neoadjuvant immunotherapy utilizing novel combinations has the potential to transform the standard of care for locally/regionally advanced melanoma. We hypothesized that neoadjuvant ipilimumab in combination with high dose IFNα2b (HDI) is safe and associated with durable pathologic complete responses (pCR). METHODS: Patients with locally/regionally advanced melanoma were randomized to ipilimumab 3 or 10 mg/kg × 4 doses bracketing definitive surgery, then every 12 weeks × 4. HDI was given concurrently. We evaluated the safety and efficacy of the combination with ipilimumab 3 or 10 mg/kg. The impact on T-cell fraction and clonality were investigated in tumor and blood. RESULTS: Thirty patients (age 37-76), 15 each at 3 and 10 mg/kg, 18 male and 12 female were treated. Considering immune related adverse events (irAEs) of interest, more grade 3/4 irAEs were seen with ipilimumab 10 mg/kg versus 3 mg/kg (p = 0.042). Among 28 evaluable patients, 11 relapsed, of whom 5 died. Median follow-up for 17 patients who have not relapsed was 32 months. The radiologic preoperative response rate was 36% (95% CI, 21-54); 4 patients at ipilimumab 3 mg/kg and 6 at 10 mg/kg and 2 (at 10 mg/kg) later relapsed. The pCR was 32% (95% CI, 18-51); 5 patients at ipilimumab 3 mg/kg and 4 at 10 mg/kg and one (at 3 mg/kg) had a late relapse. In patients with pCR, T-cell fraction was significantly higher when measured in primary melanoma tumors (p = 0.033). Higher tumor T-cell clonality in primary tumor and more so following neoadjuvant therapy was significantly associated with improved relapse free survival. CONCLUSIONS: Neoadjuvant ipilimumab-HDI was relatively safe and exhibited promising tumor response rates with an associated measurable impact on T-cell fraction and clonality. Most pCRs were durable supporting the value of pCR as a primary endpoint in neoadjuvant immunotherapy trials. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01608594 . Registered 31 May 2012.
Subject(s)
Antineoplastic Agents, Immunological/therapeutic use , Interferon-alpha/therapeutic use , Ipilimumab/therapeutic use , Melanoma/drug therapy , Neoadjuvant Therapy/methods , Skin Neoplasms/drug therapy , Adult , Aged , Antineoplastic Agents, Immunological/pharmacology , Female , Humans , Interferon alpha-2 , Interferon-alpha/pharmacology , Ipilimumab/pharmacology , Male , Melanoma/pathology , Middle Aged , Skin Neoplasms/pathologyABSTRACT
Mediator is a multiprotein complex that acts as a versatile transcription coactivator in eukaryotes. CDK8 kinase complex is a 4-protein subunit of the mediator complex that can act as a transcriptional repressor or coactivator, depending on the specific pathways involved. Although the role of MED12 exon 2 mutations is documented in the pathogenesis of uterine leiomyomas, its role in extrauterine smooth muscle tumorigenesis is less clear. Similarly, there is a paucity of data on the role of CDK8 in extrauterine smooth muscle tumorigenesis and progression. Our study correlates immunohistochemical expression of CDK8 and MED12 with clinical and pathologic parameters in extrauterine leiomyosarcomas. Immunohistochemical expression of CDK8 and MED12 in leiomyosarcomas was correlated with the tumor grade, stage, and the presence of local recurrence or metastasis. MED12 was expressed in the majority of leiomyosarcomas regardless of their stage or grade. CDK8 expression was lost in 1 of 6 pT1 tumors, compared with 9 of 10 pT2 tumors (P=0.0076). When the second group was expanded to include those tumors that did not have a recorded pathologic stage but had local recurrence and distant metastases, the difference in CDK8 expression was also statistically significant. Loss of CDK8 expression by immunohistochemistry is more prevalent in somatic leiomyosarcomas presenting at a higher histopathologic stage, as well as with local and distant recurrence, and can be used to enhance the current predictive parameters.
Subject(s)
Cyclin-Dependent Kinase 8/metabolism , Leiomyosarcoma/physiopathology , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor , Female , Humans , Immunohistochemistry , Leiomyoma/physiopathology , Male , Mediator Complex/metabolism , Middle Aged , Neoplasm Recurrence, Local , Neoplasm StagingABSTRACT
Pseudomyogenic hemangioendothelioma (PHE) is an uncommon neoplasm with propensity for local recurrence. The tumor mimics epithelioid hemangioendothelioma and epithelioid sarcoma, representing a possible diagnostic pitfall. We investigated the clinicopathological, immunohistochemical, and fluorescence in situ hybridization features of PHEs. Eight cases of PHE were retrieved from our pathology archives. The clinical and outcome information was available in 6 patients. In 6 cases, the tumors were located in the lower limb, whereas the upper limb was involved in 2 cases. Three patients had exclusively bone involvement, and 2 patients had cutaneous tumor only. The tumor was multifocal in 5 cases, of which 2 patients had simultaneous bone and soft tissue involvement. Immunohistochemical stains revealed all tumors to be positive for AE1/AE3 (8/8), ERG (7/7), and FLI-1 (7/7) with preserved INI1 (7/7) expression. Most of the tumors were variably positive for CD31 (7/8), CAM5.2 (2/3), and SMA (4/6). t(7;19)(q22;q13) fusion pattern was detected in 3 cases (5 tumors) with cutaneous and multifocal PHE. In 3 cases, a translocation pattern was detected in a few nuclei but did not meet our laboratory cutoff value. MYC amplification was not detected in any of the 5 cases examined, aiding in ruling out the possibility of angiosarcoma. Four patients underwent excision, and 2 with multifocal tumor required below-knee amputation. Six patients with outcome information were alive and free of disease after a median follow-up of 35 months. We conclude that ancillary techniques can be helpful in differentiating this unusual indolent tumor from potentially aggressive epithelioid hemangioendothelioma, epithelioid sarcoma, and epithelioid angiosarcoma. Long-term follow-up is warranted.
Subject(s)
Biomarkers, Tumor/analysis , Bone Neoplasms/diagnosis , Hemangioendothelioma/diagnosis , Skin Neoplasms/diagnosis , Soft Tissue Neoplasms/diagnosis , Adolescent , Adult , Bone Neoplasms/genetics , Bone Neoplasms/pathology , Child , Female , Hemangioendothelioma/genetics , Hemangioendothelioma/pathology , Humans , Immunohistochemistry , In Situ Hybridization, Fluorescence , Male , Middle Aged , Skin Neoplasms/genetics , Skin Neoplasms/pathology , Soft Tissue Neoplasms/genetics , Soft Tissue Neoplasms/pathology , Young AdultABSTRACT
The purpose of this study was to learn whether molecular characterization through gene expression profiling of node-positive and node-negative sentinel lymph nodes (SLNs) in patients with clinical stage I and II melanoma may improve the understanding of mechanisms of metastasis and identify gene signatures for SLNs/SLNs that correlate with diagnosis or clinical outcome. Gene expression profiling was performed on SLN biopsies of 48 (24 SLN and 24 SLN) patients (T3a/b-T4a/b) who underwent staging of SLNs using transcriptome profiling analysis on 5 µm sections of fresh SLNs. U133A 2.0 Affymetrix gene chips were used. Significance analysis of microarrays was used to test the association between gene expression level and SLN status. Genes with fold change more than 1.5 and q value less than 0.05 were considered differentially expressed. Pathway analysis was performed using Ingenuity Pathway Analysis. The Benjamini and Hochberg method was used to adjust for multiple testing in pathway analysis. We identified 89 probe sets that were significantly differentially expressed (1.5-27-fold; q<0.05). Upon performing the pathway analysis, it was found that 25 genes were common among the most significant and biologically relevant canonical pathways. The molecules and pathways that achieved differential expression of highest statistical significance were notably related to melanoma and its microenvironment and to signaling pathways implicated in immunosuppression and development of cancer. A 25-gene signature is significantly differentially expressed between SLN and SLN and is related to melanoma oncogenesis and immunosuppression. The identified expression profile provides a signature of melanoma nodal involvement. These findings warrant further investigation into the mechanisms of metastasis, melanoma metastasis diagnosis, and prediction of outcome.
Subject(s)
Melanoma/genetics , Sentinel Lymph Node/pathology , Skin Neoplasms/genetics , Adolescent , Adult , Aged , Female , Humans , Male , Melanoma/pathology , Middle Aged , Skin Neoplasms/pathology , Transcriptome , Young AdultABSTRACT
Glomus coccygeum is a prominent or hyperplastic glomus structure that is located at the ventral tip of the coccyx, which frequently causes concern to pathologists that are unfamiliar with this entity.
Subject(s)
Arteriovenous Anastomosis , Coccyx , Aged , HumansABSTRACT
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft-tissue tumors. They can occur in patients with neurofibromatosis type-1 (NF-1) or as sporadic tumors. Only 10% of MPNSTs are radiation induced. Divergent differentiation in MPNSTs can occur in 15% of cases and may include cartilage, bone, skeletal muscle, blood vessels, and very rarely well-formed glands, the latter typically described in NF-1-associated MPNSTs. We report an exceedingly rare case of radiation induced glandular MPNST arising in a neurofibroma of the femoral nerve in a patient previously irradiated for endometrial carcinoma.
Subject(s)
Endometrial Neoplasms/therapy , Neoplasms, Radiation-Induced/pathology , Nerve Sheath Neoplasms/pathology , Neurilemmoma/pathology , Female , Femur/innervation , Femur/surgery , Humans , Hysterectomy , Magnetic Resonance Imaging , Middle Aged , Neoplasms, Radiation-Induced/diagnosis , Neoplasms, Radiation-Induced/etiology , Neoplasms, Radiation-Induced/surgery , Nerve Sheath Neoplasms/diagnosis , Nerve Sheath Neoplasms/etiology , Nerve Sheath Neoplasms/surgery , Neurilemmoma/diagnosis , Neurilemmoma/etiology , Neurilemmoma/surgery , Radiotherapy, Adjuvant/adverse effects , Radiotherapy, Adjuvant/methods , Salpingo-oophorectomyABSTRACT
In this study the histologic grade of dedifferentiated liposarcomas was correlated with outcome in surgically resected specimens in 55 patients over a 19-year period at the University of Pittsburgh Medical Center. The tumors were located in the retroperitoneum (N=35); the extremities and thigh (N=16), and the remainder involved the spermatic cord and head and neck. Most tumors were large (mean=21 cm.) Follow-up was available in all 55 patients (median=36 months). Forty-one tumors classified as high-grade dedifferentiated liposarcoma (HG-DDLPS) had mitotically active pleomorphic and spindle cells and foci of necrosis. They included tumors with foci of smooth muscle differentiation (N=12), osteosarcoma (N=4), and myxoid areas (N=9). Fourteen tumors classified as low-grade dedifferentiated liposarcoma (LG-DDLPS) displayed a predominantly bland, monomorphic, spindle cell population with few mitoses and scant necrosis. The Kaplan-Meier method and log-rank test were used for statistical analysis. All tumors had unequivocal foci of well-differentiated liposarcoma (WDLPS). Fluorescence in situ hybridization (FISH) detected amplification of MDM2 in 29 cases. Twenty of 41 patients (49%) with HG-DDLPS died of tumor, and two patients died with LG-DDLPS (14%). The overall survival of patients with LG-DDLPS was significantly longer (P=.02). The median survival was 113 months for the LG-DDLPS and 48 months for the HG-DDLPS. Metastases (N=4) occurred only in the high-grade tumors and were independent of the type of heterologous differentiation. Patients with HG-DDLPS were at a greater risk of earlier death. Distinction between the two groups is important for patient selection for possible adjuvant therapy.
Subject(s)
Cell Dedifferentiation , Liposarcoma/pathology , Liposarcoma/surgery , Academic Medical Centers , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/genetics , Biopsy , Female , Gene Amplification , Humans , In Situ Hybridization, Fluorescence , Kaplan-Meier Estimate , Liposarcoma/genetics , Liposarcoma/mortality , Male , Middle Aged , Mitosis , Necrosis , Neoplasm Grading , Neoplasm Metastasis , Pennsylvania , Predictive Value of Tests , Proto-Oncogene Proteins c-mdm2/genetics , Risk Factors , Time Factors , Treatment Outcome , Tumor BurdenABSTRACT
INTRODUCTION: Sarcomas are heterogeneous, and their treatment and prognosis are driven by the morphologic subtype and the clinical stage. Classic cytogenetics and fluorescence in situ hybridization (FISH) analysis play an important role in their diagnostic work up. MATERIALS AND METHODS: Forty-six cases of soft-tissue sarcoma were reviewed that underwent karyotyping and simultaneous FISH analysis at initial diagnosis. They included 10 dedifferentiated liposarcomas, 10 myxoid liposarcomas, and 14 synovial sarcomas. Six tumors were investigated for EWSR1 rearrangement. Six high-grade miscellaneous sarcomas were also examined. RESULTS: The dedifferentiated liposarcoma had complex karyotypes and MDM2 amplification by FISH, and of these, 5 tumors with myxoid changes also had complex signals for DDIT3. All but 4 myxoid liposarcomas had complex karyotypes, in addition to the characteristic translocation. FISH analysis displayed DD1T3 rearrangement. All synovial sarcomas except 1 recurrence had a t(X;18) translocation by karyotyping and FISH. The EWSR1 rearrangement was present in all extraskeletal myxoid chondrosarcomas, angiomatoid fibrous histiocytoma, atypical Ewing sarcoma, and a clear-cell sarcoma, all of which had characteristic karyotypes. Seven high-grade sarcomas had no specific karyotype or rearrangements for DDIT3, SS18, and EWSR1 by FISH. CONCLUSIONS: There is good correlation between karyotyping and FISH. Complex FISH signals found in dedifferentiated liposarcomas may be related to an increased chromosome 12 copy number and ploidy. Karyotyping is an important baseline standard for the quality assurance of newly developed FISH probes. It also provides a global view of chromosomal changes and the opportunity to investigate the role of other genetic alterations and potential therapeutic targets.
Subject(s)
Neoplasms, Adipose Tissue/pathology , Sarcoma, Synovial/pathology , Sarcoma/genetics , Humans , In Situ Hybridization, Fluorescence , Neoplasms, Adipose Tissue/genetics , Retrospective Studies , Sarcoma/pathology , Sarcoma, Synovial/geneticsABSTRACT
Ossifying fibromyxoid tumors (OFMT) of soft parts are rare, slow-growing tumors that have potential for local recurrence and may metastasize. While OFMT originally was considered benign, several cases of malignant OFMT have been documented. There is no universally accepted risk stratification, although this study emphasizes the importance of utilizing histology, immunohistochemistry and FISH in establishing the diagnosis. Herein, we describe six cases of atypical and malignant OFMT with differences in morphologic features, 5 of which display the proposed morphological criteria for malignancy. The patients were mostly male (M=5, F=1) with an age range of 33-69 years. The tumors arose from the extremities (3 cases), the shoulder (1 case), the head and neck area (1 case), and the paraspinal area (1 case). One tumor had high grade and overtly sarcomatous changes, while another invaded the underlying clavicle. Two cases showed cytological atypia and necrosis. Fluorescence in situ hybridization (FISH) detected rearrangement of the PHF1 gene in 5 cases. All cases were positive for EAAT4 and actin by immunohistochemistry, while negative for desmin. Three tumors were immunoreactive for S100 protein. INI-1 immunohistochemical staining was conserved in all but 2 cases in which a mosaic loss of expression was noted. All but two patients are currently alive and free of disease.
Subject(s)
Bone Neoplasms/pathology , Fibroma, Ossifying/pathology , Actins/analysis , Adult , Aged , Biomarkers, Tumor/analysis , Biomarkers, Tumor/genetics , Biopsy , Bone Neoplasms/chemistry , Bone Neoplasms/genetics , Bone Neoplasms/therapy , DNA-Binding Proteins/genetics , Disease-Free Survival , Excitatory Amino Acid Transporter 4/analysis , Female , Fibroma, Ossifying/chemistry , Fibroma, Ossifying/genetics , Fibroma, Ossifying/therapy , Gene Rearrangement , Humans , Immunohistochemistry , In Situ Hybridization, Fluorescence , Male , Middle Aged , Necrosis , Polycomb-Group Proteins/genetics , S100 Proteins/analysis , SMARCB1 Protein/analysis , Time Factors , Treatment OutcomeABSTRACT
BACKGROUND: Characterization of PD-L1 expression within clinically/radiologically negative but microscopically tumor positive sentinel lymph nodes (SLN) is important to our understanding of the relevance of this immune checkpoint pathway for adjuvant therapy. METHODS: Patients included had primary cutaneous melanoma, Breslow thickness of 2.01-4.0 or >4 mm with or without tumor ulceration (T3a, T3b, T4a, T4b). All patients had microscopically tumor positive SLN. Hematoxylin and eosin (H&E) staining was performed, followed by PD-L1 immunohistochemical (IHC) staining using a preliminary IHC assay with anti-PD-L1 antibody clone 22C3. The slides were separately evaluated by two pathologists (JY and CG). Samples containing metastatic melanoma lesions were scored separately for PD-L1 expression in intratumoral and peritumoral locations, by utilizing two scoring methods. RESULTS: Twenty-four patients where metastatic melanoma presence in the SLN was confirmed by H&E review of the cut sections were included in the final analysis of PD-L1 expression. SLN tumor size ranged from 1 to 2 mm. For three patients, the melanin content was too high to confidently assign a PD-L1 score. For the remaining 21 patients, all had some evidence of either intratumoral or peritumoral PD-L1 expression. The frequency of intratumoral tumor-associated PD-L1 expression was: 0 % of tumor cells (3 pts, 14 %); <1 % (5 pts, 24 %); 1-10 % (6 pts, 29 %) and >10 % (7 pts, 33 %). CONCLUSIONS: Tumor-associated PD-L1 expression is readily detectable within melanoma micrometastases in the SLN of the majority of patients. These results support the testing of a therapeutic role for PD1/PD-L1 inhibition in the adjuvant setting, targeting melanoma micrometastases.
Subject(s)
B7-H1 Antigen/metabolism , Lymphatic Metastasis/diagnosis , Melanoma/metabolism , Sentinel Lymph Node Biopsy , Skin Neoplasms/metabolism , Adolescent , Adult , Aged , Chemotherapy, Adjuvant , Female , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Humans , Immune System , Immunohistochemistry , Lymphatic Metastasis/pathology , Male , Melanoma/therapy , Middle Aged , Neoplasm Metastasis , Neoplasm Micrometastasis , Programmed Cell Death 1 Receptor/metabolism , Skin Neoplasms/therapy , Young Adult , Melanoma, Cutaneous MalignantABSTRACT
Meningeal melanocytomas are rare melanin-producing tumors that are often found to be benign. However, a small subset of these tumors can present as intermediate-grade melanocytomas (IGMs) that have histopathological features that are between those of benign melanocytomas and malignant melanomas. IGMs have the potential to recur and metastasize or progress to a more histologically high grade melanoma. Melanocytomas appear to differ from primary and metastatic melanoma by their prolonged clinical course and they appear to have different driver mutations (i.e. mutation of GNAQ gene). The association of a meningeal melanocytoma with nevus of Ota is extremely rare. To our knowledge, there have been only 10 reported cases of synchronous occurrence and only one of the cases involved an IGM. We report the second case of intermediate-grade meningeal melanocytoma that is associated with congenital nevus of Ota. Histopathological work-up confirmed the intermediate grade of the lesion and a driver GNAQ mutation was identified consistent with previous reports.
Subject(s)
GTP-Binding Protein alpha Subunits/genetics , Melanocytes/pathology , Melanoma/genetics , Meningeal Neoplasms/genetics , Nevus of Ota/genetics , Adolescent , Adult , Aged , Female , GTP-Binding Protein alpha Subunits, Gq-G11 , Humans , Male , Melanins/biosynthesis , Melanoma/complications , Melanoma/therapy , Meningeal Neoplasms/complications , Meningeal Neoplasms/therapy , Middle Aged , Nevus of Ota/pathology , Young AdultABSTRACT
Oncolytic viral therapy utilizes a tumor-selective replicating virus which preferentially infects and destroys cancer cells and triggers antitumor immunity. The Western Reserve strain of vaccinia virus (VV) is the most virulent strain of VV in animal models and has been engineered for tumor selectivity through two targeted gene deletions (vvDD). We performed the first-in-human phase 1, intratumoral dose escalation clinical trial of vvDD in 16 patients with advanced solid tumors. In addition to safety, we evaluated signs of vvDD replication and spread to distant tumors, pharmacokinetics and pharmacodynamics, clinical and immune responses to vvDD. Dose escalation proceeded without dose-limiting toxicities to a maximum feasible dose of 3 × 10(9) pfu. vvDD replication in tumors was reproducible. vvDD genomes and/or infectious particles were recovered from injected (n = 5 patients) and noninjected (n = 2 patients) tumors. At the two highest doses, vvDD genomes were detected acutely in blood in all patients while delayed re-emergence of vvDD genomes in blood was detected in two patients. Fifteen of 16 patients exhibited late symptoms, consistent with ongoing vvDD replication. In summary, intratumoral injection of the oncolytic vaccinia vvDD was well-tolerated in patients and resulted in selective infection of injected and noninjected tumors and antitumor activity.