ABSTRACT
Wilms tumors are highly curable in up to 90% of cases with a combination of surgery and radio-chemotherapy, but treatment-resistant types such as diffuse anaplastic Wilms tumors pose significant therapeutic challenges. Our multi-omics profiling unveils a distinct desert-like diffuse anaplastic Wilms tumor subtype marked by immune/stromal cell depletion, TP53 alterations, and cGAS-STING pathway downregulation, accounting for one-third of all diffuse anaplastic cases. This subtype, also characterized by reduced CD8 and CD3 infiltration and active oncogenic pathways involving histone deacetylase and DNA repair, correlates with poor clinical outcomes. These oncogenic pathways are found to be conserved in anaplastic Wilms tumor cell models. We identify histone deacetylase and/or WEE1 inhibitors as potential therapeutic vulnerabilities in these tumors, which might also restore tumor immunogenicity and potentially enhance the effects of immunotherapy. These insights offer a foundation for predicting outcomes and personalizing treatment strategies for aggressive pediatric Wilms tumors, tailored to individual immunological landscapes.
Subject(s)
Kidney Neoplasms , Wilms Tumor , Child , Humans , Kidney Neoplasms/genetics , Kidney Neoplasms/therapy , Kidney Neoplasms/metabolism , Wilms Tumor/genetics , Wilms Tumor/therapy , Histone DeacetylasesABSTRACT
AIM: To evaluate the efficacy and safety of the modified FOLFIRI3-aflibercept as second-line therapy in patients with metastatic colorectal cancer. METHODS: This is a retrospective multicenter cohort, evaluating the efficacy and safety of the association of aflibercept with FOLFIRI3 (day 1: aflibercept 4 mg/kg, folinic acid 400 mg/m2, irinotecan 90 mg/m2, 5-fluorouracil infusion 2400 mg/m2 per 46 h; day 3: irinotecan 90 mg/m2) in patients with previously treated metastatic colorectal cancer. The primary endpoint was overall response rate (ORR). Secondary endpoints were disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Among 74 patients treated in four French centers, nine were excluded due to prior use of aflibercept (n = 3), more than one prior treatment line in irinotecan-naïve patients (n = 3), and inadequate liver function (n = 3). In the "irinotecan-naïve" patients (n = 30), ORR was 43.3% and DCR was 76.7%. Median PFS and OS were 11.3 mo (95%CI: 6.1-29.0) and 17.0 mo (95%CI: 13.0-17.3), respectively. The most common (> 5%) grade 3-4 adverse events were diarrhea (37.9%), neutropenia (14.3%), stomatitis and anemia (10.4%), and hypertension (6.7%). In the "pre-exposed irinotecan" patients (n = 35), 20 (57.1%) received ≥ 2 prior lines of treatment. ORR was 34.3% and DCR was 60.0%. Median PFS and OS were 5.7 mo (95%CI: 3.9-10.4) and 14.3 mo (95%CI: 12.8-19.5), respectively. CONCLUSION: Minimally modified FOLFIRI has improvement dramatically the FOLFIRI3-aflibercept efficacy, whatever prior use of irinotecan. A prospective randomized trial is warranted to compare FOLFIRI-aflibercept to FOLFIRI3-aflibercept.
ABSTRACT
Mendelian susceptibility to mycobacterial disease is a rare syndrome characterized by severe clinical infections usually caused by weakly virulent mycobacterial species such as Bacillus Calmette-Guérin vaccines and environmental nontuberculous mycobacteria or more virulent mycobacteria as mycobacterium tuberculosis. Since 1996, 9 genes including 7 autosomal ( STAT1, IFNGR1, IFNGR2, IL12B, IL12RB1, ISG15, and IRF8) and 2 X-linked genes ( NEMO and CYBB) have been identified. Allelic heterogeneity leaded to recognize about 18 genetic diseases with variable clinical phenotypes, but sharing a same physiological mechanism represented by a defect in human IL-12-dependant-INF-γ-mediated immunity. We report here a case of multifocal Bacillus Calmette-Guérin osteomyelitis in a context Mendelian susceptibility to mycobacterial disease mimicking a metastatic neuroblastoma in a child presenting with delayed growth. The investigation of her twin sister showed the same disease. A heterozygous mutation in exon 22 of STAT1 gene was found in both sisters, another sister and the father being healthy and heterozygous for the same mutation.
Subject(s)
Diseases in Twins/genetics , Genetic Diseases, Inborn/diagnosis , Mycobacterium Infections/genetics , Mycobacterium bovis/isolation & purification , Osteomyelitis/genetics , STAT1 Transcription Factor/genetics , Diseases in Twins/diagnosis , Female , Genetic Diseases, Inborn/complications , Genetic Diseases, Inborn/genetics , Genetic Markers , Genetic Predisposition to Disease , Heterozygote , Humans , Infant , Mutation , Mycobacterium Infections/diagnosis , Osteomyelitis/diagnosis , STAT1 Transcription Factor/deficiencyABSTRACT
Cherubism is a rare genetic disease characterized by bilateral giant cell reparative granuloma of the jaws consisting of a fibrotic stroma with giant multinucleated cells (GMCs) and osteoclastic features. Cherubism severity is highly variable, and recurrence after surgery is the most important risk. Currently, there are no prognostic indicators. The aims of this study were to evaluate the osteoclastogenesis phenotype by histologic examination of nuclear factor of activated T cells 1 (NFATc1) localization and tartrate-resistant acid phosphatase (TRAP) activity and to correlate the results to disease aggressiveness to define prognostic indicators. Based on cherubism evolution 1 year after surgery, 3 classes of cherubism aggressiveness were identified: mild (group A), moderate (group B), and severe (group C). Histologically, in grade A and B cherubism lesions, GMCs were negative for both TRAP activity and NFATc1 nuclear localization. In contrast, in grade C cherubism lesions, GMCs were all positive for TRAP activity and NFATc1 nuclear localization and displayed osteoclast-like features. Other histopathologic findings were not different among the 3 groups. Our results establish that TRAP activity and NFTAc1 nuclear localization are associated with aggressive cherubism and therefore could be added to routine pathologic examination to aid in prognosis and management of the disease. The finding of NFATc1 nuclear localization in aggressive tumors supports the addition of anticalcineurin treatment to the therapeutic arsenal for cherubism.
Subject(s)
Cell Nucleus/chemistry , Cherubism/diagnosis , Giant Cells/chemistry , Jaw/chemistry , NFATC Transcription Factors/analysis , Osteoclasts/chemistry , Adaptor Proteins, Signal Transducing/genetics , Adolescent , Biomarkers/analysis , Cell Nucleus/pathology , Cherubism/metabolism , Cherubism/pathology , Cherubism/surgery , Child , Female , Genetic Predisposition to Disease , Giant Cells/pathology , Humans , Immunohistochemistry , Jaw/pathology , Male , Mutation , Orthognathic Surgical Procedures , Osteoclasts/pathology , Phenotype , Predictive Value of Tests , Prospective Studies , Severity of Illness Index , Tartrate-Resistant Acid Phosphatase/analysis , Time Factors , Treatment OutcomeABSTRACT
Collecting duct carcinoma (CDC) is a kidney cancer subtype that is thought to arise from principal cells in distal parts of the collecting ducts. Some studies suggested an overlap of CDC with upper tract urothelial carcinoma (UTUC), making the pathological diagnosis challenging. Herein, we performed for the first time transcriptome sequencing of CDC and compared them to UTUC and renal cell carcinoma subtypes. We discovered that CDC displays a unique transcriptomic signature among kidney cancer subtypes, with a putative cell of origin in the distal convoluted tubules. Hierarchical unsupervised clustering reveals that the CDC signature is closer to that of other RCC subtypes than to UTUC, which is similar to that of bladder carcinoma. CDC is characterized by a metabolic shift, with impairment of oxidoreductase activity, pyruvate metabolism and the tricarboxlyic acid cycle, as well as an immunogenic response consistent with increased tumor infiltrating lymphocytes, particularly within metastatic cases. In addition, pathways differentially altered between CDC and UTUC point to a basal-like phenotype of CDC in contrast to the luminal-like signature of UTUC. We conclude that CDC harbors a pathognomonic transcriptomic signature characterized by immunogenic and a metabolic aberrations, indicating that targeting these processes might provide therapeutic options for patients.
Subject(s)
Biomarkers, Tumor/genetics , Carcinoma, Renal Cell/genetics , Kidney Neoplasms/genetics , Urologic Neoplasms/genetics , Adolescent , Adult , Aged , Carcinoma, Renal Cell/pathology , Female , Humans , Kidney Neoplasms/pathology , Male , Middle Aged , Transcriptome , Urologic Neoplasms/pathology , Young AdultABSTRACT
PURPOSE: Wilms tumor (WT) is the most common pediatric renal tumor. Treatment planning under International Society of Paediatric Oncology (SIOP) protocols is based on staging and histologic assessment of response to preoperative chemotherapy. Despite high overall survival (OS), many relapses occur in patients without specific risk factors, and many successfully treated patients are exposed to treatments with significant risks of late effects. To investigate whether molecular biomarkers could improve risk stratification, we assessed 1q status and other potential copy number biomarkers in a large WT series. MATERIALS AND METHODS: WT nephrectomy samples from 586 SIOP WT 2001 patients were analyzed using a multiplex ligation-dependent probe amplification (MLPA) assay that measured the copy number of 1q and other regions of interest. RESULTS: One hundred sixty-seven (28%) of 586 WTs had 1q gain. Five-year event-free survival (EFS) was 75.0% in patients with 1q gain (95% CI, 68.5% to 82.0%) and 88.2% in patients without gain (95% CI, 85.0% to 91.4%). OS was 88.4% with gain (95% CI, 83.5% to 93.6%) and 94.4% without gain (95% CI, 92.1% to 96.7%). In univariable analysis, 1q gain was associated with poorer EFS (P < .001; hazard ratio, 2.33) and OS (P = .01; hazard ratio, 2.16). The association of 1q gain with poorer EFS retained significance in multivariable analysis adjusted for 1p and 16q loss, sex, stage, age, and histologic risk group. Gain of 1q remained associated with poorer EFS in tumor subsets limited to either intermediate-risk localized disease or nonanaplastic localized disease. Other notable aberrations associated with poorer EFS included MYCN gain and TP53 loss. CONCLUSION: Gain of 1q is a potentially valuable prognostic biomarker in WT, in addition to histologic response to preoperative chemotherapy and tumor stage.
Subject(s)
Biomarkers, Tumor/genetics , Chromosome Aberrations , Chromosomes, Human, Pair 1 , DNA Copy Number Variations , Neoadjuvant Therapy , Nephrectomy , Wilms Tumor/therapy , Chemotherapy, Adjuvant , Disease-Free Survival , Female , Genetic Predisposition to Disease , Humans , Kaplan-Meier Estimate , Logistic Models , Male , Multivariate Analysis , Neoadjuvant Therapy/adverse effects , Neoadjuvant Therapy/mortality , Neoplasm Staging , Nephrectomy/adverse effects , Nephrectomy/mortality , Phenotype , Proportional Hazards Models , Prospective Studies , Risk Factors , Time Factors , Treatment Outcome , Wilms Tumor/genetics , Wilms Tumor/mortality , Wilms Tumor/pathologyABSTRACT
BACKGROUND: Patients with Beckwith-Wiedemann syndrome (BWS) or isolated hemihypertrophy (HH) treated for a Wilms tumor (WT) carry an increased risk of developing metachronous lesion. There are no guidelines on precise indications for nephron sparing surgery (NSS) in unilateral WT (UWT). The objective of this retrospective study was to delineate the indications of NSS in patients with BWS/HH treated for WT and to evaluate their outcome. PROCEDURE: All cases of BWS/HH treated for a WT according to SIOP protocols from 1980 to 2013 were reviewed. Patients were divided into two groups (G): isolated UWT (G1) and bilateral lesions (G2) with two subgroups: bilateral tumors suspected of malignancy (G2a), and unilateral tumor suspected of malignancy with contralateral nephroblastomatosis (G2b). RESULTS: Forty-six patients were included (34 G1, three G2a, and nine G2b). Nine NSS and 25 total nephrectomies (TN) were performed in G1, two bilateral NSS and one NSS with contralateral TN in G2a, and eight NSS and one TN in G2b. The 3-year event-free survival was 92.3% (95% CI [77.9-97.5%]). One death occurred after a local relapse following a TN for a stage III stromal WT (G1) and another after a combined local and distant relapse following a NSS for a stage I diffuse anaplastic WT (G2b). There were two metachronous WT (4%), 3 years after a TN (G1) and 12 years after a NSS (G2b). CONCLUSIONS: NSS is recommended in bilateral WT and may be an option in selected UWT patients with BWS/HH because it was not associated with an increased risk of local relapse.
Subject(s)
Beckwith-Wiedemann Syndrome/surgery , Hyperplasia/surgery , Kidney Neoplasms/surgery , Nephrons/surgery , Wilms Tumor/surgery , Child , Child, Preschool , Female , Humans , Infant , Male , Retrospective StudiesABSTRACT
A 29-year-old primigravida presented with a spontaneous miscarriage at 8 weeks of gestation. There was no consanguinity in the family. Aspiration was performed. Pathological examination showed immature villi with numerous slightly yellow intracytoplasmic inclusions within the early implantation stage cytotrophoblastic cells. Inclusions were periodic acid-Schiff and Alcian blue positive and partially positive with periodic acid-Schiff with amylase. Diagnosis of Glycogen storage disease type IV (GSD IV) was made. Genetic analysis of glycogen branching enzyme 1 gene (GBE1) was performed in parents and showed a novel deletion of 1 nucleotide, c.1937delT, affecting the mother and a mutation affecting a consensus splice site, c.691+2T>C, in the father. At time of subsequent pregnancy, genetic counseling with GBE1 gene analysis was performed on throphoblastic biopsy and showed a mutated allele, c.1937delT, inherited from the mother. The mother gave birth to a healthy, unaffected female newborn. Our findings demonstrate that GSD IV may affect early pregnancies, leading to trophoblastic damage and early fetal loss. Diagnosis can accurately be made on pathological examination and should be further documented by genetic analysis.
Subject(s)
Glycogen Debranching Enzyme System/genetics , Glycogen Storage Disease Type IV/genetics , Mutation , Pregnancy Complications/genetics , Trophoblasts/pathology , Abortion, Spontaneous , Adult , Female , Glycogen Storage Disease Type IV/complications , Humans , Polymerase Chain Reaction , Pregnancy , Pregnancy Complications/pathology , Pregnancy Trimester, FirstABSTRACT
BACKGROUND: Image-guided percutaneous core needle biopsy is a common procedure for diagnosis of both solid tumors and hematological malignancies in children. Despite recent improvements, a certain rate of non-diagnostic biopsies persists. OBJECTIVE: To assess the factors influencing the diagnostic yield and accuracy of percutaneous core needle biopsies of pediatric tumors. MATERIALS AND METHODS: We conducted a single-center retrospective study of a 26-year experience with image-guided biopsies in children and young adults. Using uni- and multivariate analysis, we evaluated the association of diagnostic yield and accuracy with technical factors (image-guided procedure, pathological technique) and clinical factors (complication rate, histological type and anatomical location). RESULTS: We retrieved data relating to 396 biopsies were performed in 363 children and young adults (mean age: 7.4 years). Overall, percutaneous core needle biopsy showed a diagnostic yield of 89.4% (95% confidence interval [CI] 85.9-92.2) and an accuracy of 90.9% (CI 87.6-93.6) with a complication rate of 2.5% (CI 1.2-4.6).The diagnostic yield increased with the use of advanced tissue assessment techniques (95.7% with immunohistochemistry versus 82.3% without immunohistochemistry; P < 0.0001) and an increased number of passes (mean: 3.96 for diagnostic biopsies versus 3.62 for non-diagnostic biopsies; P = 0.044). CONCLUSION: The use of advanced pathological techniques and an increased number of passes are the two main factors influencing the diagnostic success of biopsies in pediatric tumors.
Subject(s)
Image-Guided Biopsy/statistics & numerical data , Image-Guided Biopsy/trends , Medical Audit , Neoplasms/epidemiology , Neoplasms/pathology , Child , Female , France/epidemiology , Humans , Male , Neoplasms/diagnostic imaging , Prevalence , Reproducibility of Results , Sensitivity and Specificity , Utilization ReviewABSTRACT
Soft tissue tumors arising in association with genetic or malformation syndromes have been increasingly reported. Malignant rhabdoid tumor (MRT) is a highly aggressive neoplasm of infancy and young childhood, characterized by typical morphology and biallelic inactivation of the SMARCB1 (INI1/hSNF5/BAF47) gene on chromosome 22q.2 which encodes a subunit of the SWI/SNF ATP-dependent chromatin remodeling complex. Congenital infantile disseminated MRT represents a unique clinicopathologic presentation of this tumor. We report a case occurring in a female neonate who presented at birth a voluminous left thigh mass. Surgical biopsy performed at day 9 showed morphology and immunoprofile of MRT. Staging evaluation identified hypercalcemia and distant nodules. The mass showed rapid growth. Despite chemotherapy, the tumor progressed with exteriorization through the biopsy scar. Chemotherapy was discontinued and treatment limited to palliative care and the child died on day 51. The tumor was homozygous for the SMARCB1 deletion with apparent de novo heterozygous germ line deletion in the infant, not identified in the parents.
Subject(s)
Rhabdoid Tumor/congenital , Rhabdoid Tumor/pathology , Soft Tissue Neoplasms/congenital , Soft Tissue Neoplasms/pathology , Chromosomal Proteins, Non-Histone/genetics , DNA-Binding Proteins/genetics , Fatal Outcome , Female , Humans , Infant, Newborn , Rhabdoid Tumor/genetics , SMARCB1 Protein , Soft Tissue Neoplasms/genetics , Thigh/pathology , Transcription Factors/geneticsABSTRACT
Precursor B-cell lymphoblastic lymphoma (B-LBL) is an uncommon high-grade neoplasm. Primary cutaneous B-LBL is uncommon and clinical diagnosis is difficult. We report two cases of primary cutaneous B-LBL that had initially been diagnosed as an infected dermoid cyst and lipoma, respectively, and referred for excision. The cases demonstrate the importance of biopsy and histopathologic examination of subcutaneous tumors to guide appropriate therapy.
Subject(s)
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/diagnosis , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/pathology , Subcutaneous Tissue/pathology , Adolescent , Child, Preschool , Dermoid Cyst/diagnosis , Diagnosis, Differential , Female , Humans , Lipoma/diagnosis , MaleABSTRACT
Cherubism is a rare genetic disorder characterized by extensive growth of a bilateral granuloma of the jaws, resulting in facial disfigurement. Cherubism is caused by gain-of-function mutations in the SH3BP2 gene, leading to overactivation of nuclear factor of activated T cells, cytoplasmic 1 (NFATc1)-dependent osteoclastogenesis. Recent findings in human and mouse cherubism have suggested that calcineurin inhibitors might be drug candidates in cherubism medical treatment. A 4-year-old boy with aggressive cherubism was treated with the calcineurin inhibitor tacrolimus for 1 year, and clinical, radiological, and molecular data were obtained. Immunohistologic analysis was performed to compare preoperative and postoperative NFATc1 staining and tartrate resistant acid phosphatase (TRAP) activity. Real-time PCR was performed to analyze the relative expression levels of OPG and RANKL. After tacrolimus therapy, the patient showed significant clinical improvement, including stabilization of jaw size and intraosseous osteogenesis. Immunohistologic analyses on granuloma showed that tacrolimus caused a significant reduction in the number of TRAP-positive osteoclasts and NFATc1 nuclear staining in multinucleated giant cells. Molecular analysis showed that tacrolimus treatment also resulted in increased OPG expression. We present the first case of effective medical therapy in cherubism. Tacrolimus enhanced bone formation by stimulating osteogenesis and inhibiting osteoclastogenesis.
Subject(s)
Calcineurin Inhibitors/therapeutic use , Cherubism/drug therapy , Tacrolimus/therapeutic use , Acid Phosphatase/metabolism , Calcineurin Inhibitors/pharmacology , Cell Count , Cherubism/diagnostic imaging , Child, Preschool , Humans , Isoenzymes/metabolism , Male , Models, Biological , NFATC Transcription Factors/metabolism , Osteoclasts/drug effects , Osteoclasts/pathology , Osteogenesis/drug effects , Osteoprotegerin/metabolism , RANK Ligand/metabolism , Radiography , Tacrolimus/pharmacology , Tartrate-Resistant Acid PhosphataseABSTRACT
Juvenile recurrent respiratory papillomatosis is the most common benign neoplastic disease of the larynx in children, characterized by numerous squamous papillomas caused by Human Papilloma Virus type 6 and 11. HPV is thought to be acquired at the time of vaginal delivery from maternal genital condylomas. Juvenile recurrent respiratory papillomatosis can be protracted by surgical interventions performed to avoid airway obstruction and extend below the vocal cords as far as the main stem bronchi. Lung involvement in Juvenile recurrent respiratory papillomatosis seems to be more prevalent than non-systematic reviews have reported until now and progression to cancer occurs in a significant proportion of these cases at a younger age than previously reported. This would suggest that closer attention should be paid to these children. We report a case of malignant transformation in a 12 year-old boy followed-up since the birth for an invasive juvenile recurrent respiratory papillomatosis with pulmonary involvement. The presence of HPV 6/11 was demonstrated by PCR analysis performed on material obtained from a metastatic vertebral lesion.
Subject(s)
Carcinoma, Squamous Cell/pathology , Cell Transformation, Neoplastic/pathology , Lung Neoplasms/pathology , Papillomavirus Infections/pathology , Respiratory Tract Infections/pathology , Child , Humans , MaleABSTRACT
BACKGROUND: A 45-year old woman of Cambodian ethnic background presented with fatal respiratory failure due to a severe diaphragmatic dysfunction. Two years before, she had developed early onset of urinary symptoms. METHODS AND RESULTS: Neuroimaging showed atrophy of the spine and medulla as well as a leukodystrophy affecting both supra- and infra-tentorial regions. At autopsy, polyglucosan bodies (PB) were seen in several peripheral tissues, including the diaphragm, and nervous tissues such as peripheral nerves, cerebral white matter, basal ganglia, hippocampus, brainstem and cerebellum. Immunohistochemistry and electron microscopy of the brain revealed an exclusive astrocytic localization of the PB. The diagnosis of adult polyglucosan body disease (APBD) was confirmed by enzymatic and molecular studies. CONCLUSION: Storage of abnormal glycogen in astrocytes is sufficient to cause the leukodystrophy of APBD. Since brain glycogen is almost exclusively metabolized in astrocytes, this observation sheds light on the pathophysiology of APBD. In addition, this is the first report of an APBD patient presenting with a subacute diaphragmatic failure.
Subject(s)
Astrocytes/metabolism , Glycogen Storage Disease/diagnosis , Nervous System Diseases/diagnosis , Brain/pathology , DNA Mutational Analysis , Fatal Outcome , Female , Glucans/metabolism , Glycogen/metabolism , Glycogen Debranching Enzyme System/genetics , Glycogen Storage Disease/genetics , Glycogen Storage Disease/pathology , Humans , Middle Aged , Mutation , Nervous System Diseases/genetics , Nervous System Diseases/pathologyABSTRACT
PURPOSE: To develop a tumor growth inhibition model for adult diffuse low-grade gliomas (LGG) able to describe tumor size evolution in patients treated with chemotherapy or radiotherapy. EXPERIMENTAL DESIGN: Using longitudinal mean tumor diameter (MTD) data from 21 patients treated with first-line procarbazine, 1-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea, and vincristine (PCV) chemotherapy, we formulated a model consisting of a system of differential equations, incorporating tumor-specific and treatment-related parameters that reflect the response of proliferative and quiescent tumor tissue to treatment. The model was then applied to the analysis of longitudinal tumor size data in 24 patients treated with first-line temozolomide (TMZ) chemotherapy and in 25 patients treated with first-line radiotherapy. RESULTS: The model successfully described the MTD dynamics of LGG before, during, and after PCV chemotherapy. Using the same model structure, we were also able to successfully describe the MTD dynamics in LGG patients treated with TMZ chemotherapy or radiotherapy. Tumor-specific parameters were found to be consistent across the three treatment modalities. The model is robust to sensitivity analysis, and preliminary results suggest that it can predict treatment response on the basis of pretreatment tumor size data. CONCLUSIONS: Using MTD data, we propose a tumor growth inhibition model able to describe LGG tumor size evolution in patients treated with chemotherapy or radiotherapy. In the future, this model might be used to predict treatment efficacy in LGG patients and could constitute a rational tool to conceive more effective chemotherapy schedules.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Glioma/therapy , Models, Biological , Adolescent , Algorithms , Child , Child, Preschool , Female , Glioma/drug therapy , Glioma/radiotherapy , Humans , Male , Neoplasm Staging , Reproducibility of Results , Tumor Burden , Young AdultABSTRACT
Primary squamous cell carcinoma of the thyroid gland (PSCCT) is rare and its aetiology is debated. A 67-year-old man presented with neck mass. Fine-needle-aspiration (FNA) cytology and through-cut biopsy were suggestive of poorly differentiated or anaplastic carcinoma. The patient was offered tracheostomy and palliative cure for unresectable tumor of the thyroid; he refused and decided for other opinion. Lobe-isthmusectomy was performed with diagnostic and debulking intent. Final pathology report was of mixed squamous cell and follicular carcinoma of the thyroid. The tumor was a PSCCT. The patient underwent adjuvant chemoradiotherapy. After 2 years, an iliac crest metastasis of follicular carcinoma was diagnosed. The patient is disease free, after surgery and radio-active-iodine treatment. The hypothesis of squamous cell carcinoma transformation from well differentiated thyroid cancer has to be considered in case of PSCCT. Primary squamous cell carcinoma of the thyroid gland (PSCCT) is rare [1-3]; different theories on its aetiology do exist [4-6]. Mixed squamous cell and follicular carcinoma is even more rare than pure squamous cell of the thyroid gland and only few cases are reported in literature [7]. Preoperative diagnosis can be very challenging and the differential diagnosis with secondary squamous cell carcinoma of the thyroid (SSCCT) is manadatory in order to plan a correct management of the disease. The presence of PSCCT with distant metastasis of follicular carcinoma supports the histogenesis of squamous cell carcinomas arising from follicular epithelial cells.
Subject(s)
Adenocarcinoma, Follicular/pathology , Carcinoma, Squamous Cell/pathology , Neoplasms, Second Primary/pathology , Thyroid Neoplasms/pathology , Aged , Biopsy, Fine-Needle , Cell Transformation, Neoplastic , Humans , MaleABSTRACT
Gastric neuroendocrine neoplasms differ considerably in histology, clinicopathologic background, stage, and patient outcome, implying a wide spectrum of therapeutic options, hence the need for improved diagnostic and prognostic criteria to select appropriate therapy. Here, we tested the European NeuroEndocrine Tumor Society and the novel World Health Organization 2010 grade and stage classifications together with additional clinicopathologic and histologic parameters in a series of 209 gastric neuroendocrine neoplasms with a median follow-up of 89 months. Fifty-one grade 3 neuroendocrine carcinomas and 15 mixed endocrine-exocrine carcinomas of poor outcome were separated from 143 neuroendocrine tumors, including 132 G1 or G2 enterochromaffin-like (ECL) cell neoplasms and 11 G1 gastrin-cell, somatostatin-cell, or serotonin-cell tumors. Most G1 cases had excellent prognosis, even when metastatic, whereas G2 and G3 neoplasms had worse or very severe prognosis, respectively. The European NeuroEndocrine Tumor Society-World Health Organization 2010 proliferative grading system well correlated with patient survival. Structural histologic parameters were equally predictive and when combined with the European NeuroEndocrine Tumor Society-World Health Organization 2010 grading system in a "global grade" improved tumor prognostic stratification. The European NeuroEndocrine Tumor Society-World Health Organization 2010 staging system proved effective. Introduction of novel T (T(1a) and T(1b) or deep submucosal) and N categories (N(1), <3 nodes metastases; N(2), ≥3) allowed a simplified, equally informative 3-stage TNM system. Such improved diagnostic and prognostic criteria for gastric neuroendocrine neoplasms are proposed and discussed.
Subject(s)
Neuroendocrine Tumors/pathology , Stomach Neoplasms/pathology , Carcinoma, Neuroendocrine/diagnosis , Carcinoma, Neuroendocrine/pathology , Humans , Neoplasm Staging , Neoplasms, Complex and Mixed/diagnosis , Neoplasms, Complex and Mixed/pathology , Neuroendocrine Tumors/diagnosis , Prognosis , Stomach Neoplasms/diagnosisABSTRACT
Currently used histopathologic criteria for the diagnosis of pancreatic endocrine tumors are still under discussion as far as to their capacity to identify prognostically different tumor subsets, which are potentially helpful for patient management. A recently developed TNM staging system and a variety of proposed histologic and clinicopathologic parameters still need to be fully validated. One hundred fifty-five pancreatic endocrine tumors encompassing all the main histologic types and stages, operated with intention to cure and then followed up for a median 126 months, were carefully investigated histologically to identify prognostically informative parameters at univariable, bivariable, and multivariable analysis. Ki67 index, mitotic rate, neuroinvasion with or without vascular, peritumoral or stromal infiltrative patterns, as well as tumor size, and association with endocrine syndromes other than insulinoma proved effective in predicting recurrence and disease-specific death among well-differentiated tumors. Poorly differentiated histologic features, more than 10 mitoses/10 high power fields, and necrosis were helpful in the identification of high-grade cancers with an invariably poor prognosis. The TNM system proved to be highly predictive of patient outcome and easy to combine with histologic and clinicopathologic parameters to classify pancreatic endocrine tumors into groups of increasing malignant potential.
Subject(s)
Biomarkers, Tumor/metabolism , Pancreatic Neoplasms/diagnosis , Pancreatic Neoplasms/pathology , Adenoma, Islet Cell/diagnosis , Adenoma, Islet Cell/metabolism , Adenoma, Islet Cell/pathology , Carcinoma, Islet Cell/diagnosis , Carcinoma, Islet Cell/metabolism , Carcinoma, Islet Cell/pathology , Carcinoma, Pancreatic Ductal/diagnosis , Carcinoma, Pancreatic Ductal/metabolism , Carcinoma, Pancreatic Ductal/pathology , Humans , Insulinoma/diagnosis , Insulinoma/metabolism , Insulinoma/pathology , Ki-67 Antigen/analysis , Mitotic Index , Necrosis/pathology , Neoplasm Invasiveness , Neoplasm Recurrence, Local/pathology , Neoplasm Staging , Pancreatic Neoplasms/metabolism , Prognosis , Retrospective Studies , Survival Rate , Tumor BurdenABSTRACT
c-kit (CD117) is a tyrosine kinase receptor involved in the proliferation, differentiation, and secretory functions of various cells. In experimental animal models, c-kit has been detected in the pars intermedia of the normal pituitary gland and in alpha-melanocyte-stimulating-hormone-positive adenomas and it has been suggested that it plays a role in regulating adrenocorticotropic hormone (ACTH) secretion. To the best of our knowledge, the expression of c-kit in normal human pituitary cells and in pituitary adenomas has never been reported, so the possible biological role of this receptor in the control of pituitary hormone secretion remains unclear. The aim of this study was to evaluate the immunohistochemical expression of c-kit in normal human pituitary glands and in a series of 62 well-characterized pituitary adenomas. In normal adenohypophyses, several cells, mainly located in the central mucoid wedge, showed a c-kit immunoreactivity (IR). Double label immunostaining procedures showed that the c-kit-IR cells corresponded to ACTH cells. Out of 62 adenomas, 15 (24%) were c-kit-IR, including 7/16 (44%) ACTH cell, 3/7 (42%) null cell, 4/11 (36%) alpha-subunit cell, and 1/11 (10%) follicle-stimulating hormone-luteinizing hormone cell adenomas. By contrast, all ten prolactin cell and seven growth hormone cell adenomas were c-kit negative. These data suggest that, in normal conditions, c-kit may be involved in the pituitary-adrenal axis regulation.