ABSTRACT
Wilms tumour (WT) is the most common renal tumour in children, and studies of immune checkpoint inhibitors (ICIs) treatment and markers are limited in number. In this study we investigated the ICIs' related immune landscape by examining the expression of PD-L1, PD-1, CD8 and DNA mismatch repair (MMR) proteins by immunohistochemistry (IHC), tumour mutation burden (TMB), and correlations with histology and clinical outcome. Positive PD-L1 (SP263) expression was defined as modified combined positive score (CPS) ≥1. A total of 59 WTs (from 2000 to 2017), including eight (14.0%) with anaplasia, from 46 patients were analysed (45 primary and 14 metastatic). Thirteen WTs (13/59, 22%) were positive for PD-L1 (8 primary, 5 metastatic; CPS 1.11-3.42). Positive PD-L1 expression was associated with diffuse anaplasia (p<0.05) and significantly shorter progression-free survival (p<0.05) among WTs with favourable histology (n=39). CD8+ lymphocytes were present in all analysed WTs. A subset of CD8+ cells co-expressed PD-1, which was associated with favourable histology and treatment. MMR IHC stains identified two (2/18, 11%) WTs with isolated PMS2 loss. All six WTs analysed for TMB showed low mutation burden. We found CD8+ lymphocytes in all analysed WTs and identified a fraction of WT (17.8% of primary and 35.8% of metastatic) with positive PD-L1 CPS, suggesting potential response to ICIs in some patients.
ABSTRACT
BACKGROUND: Anaplastic sarcoma of the kidney (ASK) is a DICER1-related neoplasm first identified as a distinctive tumor type through the evaluation of unusual cases of putative anaplastic Wilms tumors. Subsequent case reports identified the presence of biallelic DICER1 variants as well as progression from cystic nephroma, a benign DICER1-related neoplasm. Despite increasing recognition of ASK as a distinct entity, the optimal treatment remains unclear. METHODS: Individuals with known or suspected DICER1-related tumors including ASK were enrolled in the International Pleuropulmonary Blastoma/DICER1 Registry. Additionally, a comprehensive review of reported cases of ASK was undertaken, and data were aggregated for analysis with the aim to identify prognostic factors and clinical characteristics to guide decisions regarding genetic testing, treatment, and surveillance. RESULTS: Ten cases of ASK were identified in the Registry along with 37 previously published cases. Staging data, per Children's Oncology Group guidelines, was available for 40 patients: 13 were stage I, 12 were stage II, 10 were stage III, and five were stage IV. Outcome data were available for 37 patients. Most (38 of 46) patients received upfront chemotherapy and 14 patients received upfront radiation. Two-year event-free survival (EFS) for stage I-II ASK was 81.8% (95% confidence interval [CI]: 67.2%-99.6%), compared with 46.6% EFS (95% CI: 24.7%-87.8%) for stage III-IV (p = .07). Two-year overall survival (OS) for stage I-II ASK was 88.9% (95% CI: 75.5%-100.0%), compared with 70.0% (95% CI: 46.7%-100.0%) for stage III-IV (p = .20). Chemotherapy was associated with improved EFS and OS with hazard ratios of 0.09 (95% CI: 0.02-0.31) and 0.08 (95% CI: 0.02-0.42), respectively. CONCLUSION: ASK is a rare DICER1-related renal neoplasm. In the current report, we identify clinical and treatment-related factors associated with outcome including the importance of chemotherapy in treating ASK. Ongoing data collection and genomic analysis are indicated to optimize outcomes for children and adults with these rare tumors.
Subject(s)
DEAD-box RNA Helicases , Kidney Neoplasms , Pulmonary Blastoma , Registries , Ribonuclease III , Sarcoma , Humans , DEAD-box RNA Helicases/genetics , Ribonuclease III/genetics , Pulmonary Blastoma/pathology , Pulmonary Blastoma/therapy , Pulmonary Blastoma/genetics , Pulmonary Blastoma/mortality , Male , Female , Kidney Neoplasms/pathology , Kidney Neoplasms/genetics , Kidney Neoplasms/therapy , Kidney Neoplasms/mortality , Child, Preschool , Child , Infant , Sarcoma/genetics , Sarcoma/pathology , Sarcoma/therapy , Survival Rate , Prognosis , Adolescent , Follow-Up StudiesABSTRACT
OBJECTIVE: Sertoli-Leydig cell tumors (SLCTs) are rare sex cord-stromal tumors, representing <0.5% of all ovarian tumors. We sought to describe prognostic factors, treatment and outcomes for individuals with ovarian SLCT. METHODS: Individuals with SLCT were enrolled in the International Pleuropulmonary Blastoma/DICER1 Registry and/or the International Ovarian and Testicular Stromal Tumor Registry. Medical records were systematically abstracted, and pathology was centrally reviewed when available. RESULTS: In total, 191 participants with ovarian SLCT enrolled, with most (92%, 175/191) presenting with FIGO stage I disease. Germline DICER1 results were available for 156 patients; of these 58% had a pathogenic or likely pathogenic germline variant. Somatic (tumor) DICER1 testing showed RNase IIIb hotspot variants in 97% (88/91) of intermediately and poorly differentiated tumors. Adjuvant chemotherapy was administered in 40% (77/191) of cases, and among these, nearly all patients received platinum-based regimens (95%, 73/77), and 30% (23/77) received regimens that included an alkylating agent. Three-year recurrence-free survival for patients with stage IA tumors was 93.6% (95% CI: 88.2-99.3%) compared to 67.1% (95% CI: 55.2-81.6%) for all stage IC and 60.6% (95% CI: 40.3-91.0%) for stage II-IV (p < .001) tumors. Among patients with FIGO stage I tumors, those with mesenchymal heterologous elements treated with surgery alone were at higher risk for recurrence (HR: 74.18, 95% CI: 17.99-305.85). CONCLUSION: Most individuals with SLCT fare well, though specific risk factors such as mesenchymal heterologous elements are associated with poor prognosis. We also highlight the role of DICER1 surveillance in early detection of SLCT, facilitating stage IA resection.
Subject(s)
DEAD-box RNA Helicases , Ovarian Neoplasms , Pulmonary Blastoma , Registries , Ribonuclease III , Sertoli-Leydig Cell Tumor , Humans , Sertoli-Leydig Cell Tumor/pathology , Sertoli-Leydig Cell Tumor/surgery , Female , Ovarian Neoplasms/pathology , Ovarian Neoplasms/surgery , DEAD-box RNA Helicases/genetics , Pulmonary Blastoma/pathology , Adult , Ribonuclease III/genetics , Middle Aged , Young Adult , Aged , Male , Adolescent , Chemotherapy, Adjuvant , Sex Cord-Gonadal Stromal Tumors/pathology , Sex Cord-Gonadal Stromal Tumors/surgery , Sex Cord-Gonadal Stromal Tumors/diagnosis , Testicular Neoplasms/pathology , Testicular Neoplasms/surgery , Lung Neoplasms/pathology , Lung Neoplasms/surgeryABSTRACT
BACKGROUND: Pleuropulmonary blastoma (PPB), the hallmark tumour associated with DICER1-related tumour predisposition, is characterised by an age-related progression from a cystic lesion (type I) to a high-grade sarcoma with mixed cystic and solid features (type II) or purely solid lesion (type III). Not all cystic PPBs progress; type Ir (regressed), hypothesised to represent regressed or non-progressed type I PPB, is an air-filled, cystic lesion lacking a primitive sarcomatous component. This study aims to evaluate the prevalence of non-progressed lung cysts detected by CT scan in adolescents and adults with germline DICER1 pathogenic/likely pathogenic (P/LP) variants. METHODS: Individuals were enrolled in the National Cancer Institute Natural History of DICER1 Syndrome study, the International PPB/DICER1 Registry and/or the International Ovarian and Testicular Stromal Tumor Registry. Individuals with a germline DICER1 P/LP variant with first chest CT at 12 years of age or older were selected for this analysis. RESULTS: In the combined databases, 110 individuals with a germline DICER1 P/LP variant who underwent first chest CT at or after the age of 12 were identified. Cystic lung lesions were identified in 38% (42/110) with a total of 72 cystic lesions detected. No demographic differences were noted between those with lung cysts and those without lung cysts. Five cysts were resected with four centrally reviewed as type Ir PPB. CONCLUSION: Lung cysts are common in adolescents and adults with germline DICER1 variation. Further study is needed to understand the mechanism of non-progression or regression of lung cysts in childhood to guide judicious intervention.
Subject(s)
Cysts , DEAD-box RNA Helicases , Germ-Line Mutation , Pulmonary Blastoma , Registries , Ribonuclease III , Adolescent , Adult , Child , Female , Humans , Male , Middle Aged , Young Adult , Cysts/genetics , Cysts/pathology , Cysts/diagnostic imaging , DEAD-box RNA Helicases/genetics , Lung Diseases/genetics , Lung Diseases/pathology , Lung Diseases/diagnostic imaging , Lung Diseases/epidemiology , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Lung Neoplasms/diagnostic imaging , Prevalence , Pulmonary Blastoma/genetics , Pulmonary Blastoma/pathology , Ribonuclease III/genetics , Tomography, X-Ray Computed , United States/epidemiology , AgedABSTRACT
Background: Placental examination is important for its diagnostic immediacy to correlate with maternal and/or fetal complications and parturitional difficulties. In a broader context, clinicopathologic studies of the placenta have addressed a range of pathogenetic questions that have led to conclusive and inconclusive results and interpretations. Methods: Recent standardized morphologic criteria and terminology of placental lesions have facilitated the ability to compare findings from studies that have focused on complications and outcomes of pregnancy. This review is an evaluation of recent studies on placental lesions associated with hypoxic-ischemic encephalopathy (HIE). Conclusion: No apparent consensus exists on whether it is fetal inflammation with the release of cytokines or chronic maternal and/or fetal vascular malperfusion is responsible for HIE with a lowering of the threshold for hypoxic ischemia. The counter argument is that HIE occurs solely as an intrapartum event. Additional investigation is necessary.
Subject(s)
Hypoxia-Ischemia, Brain , Infant, Newborn, Diseases , Infant, Newborn , Pregnancy , Humans , Female , Placenta/pathology , Hypoxia-Ischemia, Brain/complications , Hypoxia-Ischemia, Brain/diagnosis , Case-Control Studies , Prenatal Care , Infant, Newborn, Diseases/pathology , Retrospective StudiesABSTRACT
BACKGROUND: Pleuropulmonary blastoma (PPB) is the most common primary lung neoplasm of infancy and early childhood. Given the rarity of PPB, the role of positron emission tomography (PET) and bone scintigraphy (bone scans) in diagnostic evaluation and surveillance has not been documented to date. Available PET and bone scan data are presented in this study. PROCEDURES: Patients with PPB enrolled in the International PPB/DICER1 Registry and available PET imaging and/or bone scan reports were retrospectively abstracted. RESULTS: On retrospective analysis, 133 patients with type II and III (advanced) PPB were identified with available report(s) (PET scan only = 34, bone scan only = 83, and both bone scan and PET = 16). All advanced primary PPB (n = 11) and recurrent (n = 8) tumors prior to treatment presented with 18 F-fluorodeoxyglucose (FDG)-avid lesions, with median maximum standardized uptake values of 7.4 and 6.7, respectively. False positive FDG uptake in the thorax was noted during surveillance (specificity: 59%). Bone metastases were FDG-avid prior to treatment. Central nervous system metastases were not discernable on PET imaging. Sensitivity and specificity of bone scans for metastatic bone disease were 89% and 92%, respectively. Bone scans had a negative predictive value of 99%, although positive predictive value was 53%. Four patients with distant bone metastases had concordant true positive bone scan and PET. CONCLUSION: Primary, recurrent, and/or extracranial metastatic PPB presents with an FDG-avid lesion on PET imaging. Additional prospective studies are needed to fully assess the utility of nuclear medicine imaging in surveillance for patients with advanced PPB.
Subject(s)
Bone Neoplasms , Fluorodeoxyglucose F18 , Humans , Child, Preschool , Retrospective Studies , Positron-Emission Tomography , Radionuclide Imaging , Sensitivity and Specificity , Bone Neoplasms/diagnostic imaging , Bone Neoplasms/secondary , Registries , Radiopharmaceuticals , Ribonuclease III , DEAD-box RNA HelicasesABSTRACT
Congenital cystic pulmonary lesions (CCPLs) are represented by the following entities: congenital pulmonary airway malformation (CPAM), formerly congenital cystic adenomatoid malformation, extra- and intralobar sequestration (EIS), congenital lobar emphysema (overexpansion), and bronchogenic cyst. The developmental model of CPAM histogenesis by Stocker proposed perturbations designated as CPAM type 0 to type 4 without known or specific pathogenetic mechanisms along the airway from the bronchus to the alveolus. This review highlights mutational events either at the somatic level in KRAS (CPAM types 1 and possibly 3) or germline variants in congenital acinar dysplasia, formerly CPAM type 0, and pleuropulmonary blastoma (PPB), type I, formerly CPAM type 4. The potential for overt malignant progression exists in the case of PPB type I and CPAM type 1 in some cases to well-differentiated mucinous adenocarcinoma. On the other hand, CPAM type 2 is an acquired lesion resulting from interruption in lung development secondary to bronchial atresia. The latter is also regarded as the etiology of EIS whose pathologic features are similar, if not identical, to CPAM type 2. These observations have provided important insights into the pathogenetic mechanisms in the development of the CPAMs since the Stocker classification.
Subject(s)
Bronchopulmonary Sequestration , Cystic Adenomatoid Malformation of Lung, Congenital , Lung Neoplasms , Pulmonary Blastoma , Respiratory System Abnormalities , Humans , Cystic Adenomatoid Malformation of Lung, Congenital/diagnosis , Cystic Adenomatoid Malformation of Lung, Congenital/genetics , Lung/pathology , Pulmonary Blastoma/diagnosis , Pulmonary Blastoma/genetics , Lung Neoplasms/congenital , Respiratory System Abnormalities/diagnosis , Respiratory System Abnormalities/genetics , Bronchopulmonary Sequestration/pathologyABSTRACT
Sertoli-Leydig cell tumors (SLCTs) are uncommon ovarian sex cord-stromal neoplasms which are currently classified into well, moderately, and poorly differentiated and retiform types. Well-differentiated SLCT is the least common and typically occurs in pure form, whereas moderately and poorly differentiated and retiform types often comprise a morphologic spectrum with an admixture of all 3. DICER1 pathogenic variants are very common in SLCTs but, as far as we are aware, have not been reported in well-differentiated neoplasms, although the number of cases studied is small due to the rarity of this neoplasm. We undertook DICER1 molecular testing in a cohort of 18 well-differentiated SLCTs and show all these to be DICER1 wild-type. None of the cases harbored the p. FOXL2 C134W hotspot mutation. Based upon the DICER1 molecular results, together with morphologic observations, we propose that well-differentiated SLCT is an unrelated neoplasm to the more common moderately/poorly differentiated and retiform SLCTs and is a fundamentally distinct and unrelated tumor type within the ovarian sex cord-stromal tumor family. The implications for tumor nomenclature and recommendations for future tumor classification are discussed within the context of tumors collectively known as SLCTs.
Subject(s)
Ovarian Neoplasms , Sertoli-Leydig Cell Tumor , Sex Cord-Gonadal Stromal Tumors , Male , Female , Humans , Sertoli-Leydig Cell Tumor/genetics , Sertoli-Leydig Cell Tumor/pathology , Sex Cord-Gonadal Stromal Tumors/genetics , Sex Cord-Gonadal Stromal Tumors/pathology , Ovarian Neoplasms/genetics , Ovarian Neoplasms/pathology , Mutation , Molecular Diagnostic Techniques , Ribonuclease III/genetics , DEAD-box RNA Helicases/geneticsABSTRACT
PURPOSE: Pleuropulmonary blastoma (PPB) is the most common lung cancer of infancy and early childhood and is associated with germline DICER1 variants. Type I and Ir PPB are cystic lesions treated surgically, with a subset of children with type I receiving chemotherapy. Type II and III are more aggressive lesions, treated with surgery, intensive chemotherapy and potentially radiation. We sought to assess health-related quality of life (HRQoL) in children with PPB and known germline DICER1 variants. METHODS: Children with a diagnosis of PPB or germline DICER1 pathogenic variant without history of PPB or other DICER1-related neoplasm (DICER1+ only) were enrolled in the International PPB/DICER1 Registry. Parent reports for participants aged 2-17 years for the PedsQL v.4 and PedsQL Multidimensional Fatigue Scale v.3 were collected. Fatigue, physical, and psychosocial function scores were compared. RESULTS: Analysis included 84 participants (PPB type Ir = 20, type I = 15, type II/III = 27, DICER1+ only = 22). Total fatigue scores of participants with type I and II/III PPB were lower compared to DICER1+ only, with effect size larger in type II/III (-0.82 vs. -0.40). Total psychosocial and physical functioning scores were lower in participants with type I and type II/III PPB compared to DICER1+ only, with larger effects noted in type II/III. Female sex was suggestive of worse HRQoL for both type I/Ir and type II/III cohorts. CONCLUSIONS: These data demonstrate the importance of regular HRQoL assessment in patients with a history of PPB as well as the importance and feasibility of studying HRQoL in children with rare tumors.
Subject(s)
Lung Neoplasms , Pulmonary Blastoma , Child , Humans , Child, Preschool , Female , Adolescent , Quality of Life , Pulmonary Blastoma/pathology , Lung Neoplasms/pathology , Ribonuclease III , Registries , DEAD-box RNA HelicasesABSTRACT
BACKGROUND: Pleuropulmonary blastoma (PPB) is the most common lung cancer of infancy and early childhood. Type I PPB is a purely cystic lesion that has a microscopic population of primitive small cells with or without rhabdomyoblastic features and may progress to type II or III PPB, whereas type Ir lacks primitive small cells. METHODS: Children with suspected PPB were enrolled in the International PPB/DICER1 Registry. Pathology was centrally reviewed, and follow-up was ascertained annually. RESULTS: Between 2006 and 2022, 205 children had centrally reviewed type I or Ir PPB; 39% of children with type I and 5% of children with type Ir PPB received chemotherapy. Outcomes were favorable, although 11 children (nine with type I and two with type Ir PPB) experienced progression to type II/III (n = 8) or regrowth of type I PPB at the surgical site (n = 3), none of whom received chemotherapy before progression. Age and cyst size in combination were more suitable than either factor alone in predicting whether a particular lesion was type I or Ir PPB. CONCLUSIONS: For young children with type I PPB, outcomes are favorable, but complete resection is indicated because of the risk for progression. Chemotherapy may be useful in a subset of children at increased risk for recurrence/progression. Efforts to risk stratify children with type I PPB to optimize outcomes while reducing treatment-related side effects are underway.
Subject(s)
Drug-Related Side Effects and Adverse Reactions , Lung Neoplasms , Pulmonary Blastoma , Child , Humans , Child, Preschool , Pulmonary Blastoma/drug therapy , Lung Neoplasms/drug therapy , Registries , Ribonuclease III , DEAD-box RNA HelicasesABSTRACT
PURPOSE: Pleuropulmonary blastoma (PPB) is the most common primary lung neoplasm of infancy and early childhood. Type II and type III PPB have historically been associated with a poor prognosis. METHODS: Patients with known or suspected PPB were enrolled in the International PPB/DICER1 Registry. Medical records were abstracted with follow-up ascertained annually. All PPB diagnoses were confirmed by central pathology review. Beginning in 2007, the IVADo regimen (ifosfamide, vincristine, actinomycin-D, and doxorubicin) was recommended as a potential treatment regimen for children with type II and type III PPB. This regimen was compared with a historical control cohort. RESULTS: From 1987 to 2021, 314 children with centrally confirmed type II and type III PPB who received upfront chemotherapy were enrolled; 132 children (75 with type II and 57 with type III) received IVADo chemotherapy. Adjusted analyses suggest improved overall survival for children treated with IVADo in comparison with historical controls with an estimated hazard ratio of 0.65 (95% CI, 0.39 to 1.08). Compared with localized disease, distant metastasis at diagnosis was associated with worse PPB event-free survival and overall survival with hazard ratio of 4.23 (95% CI, 2.42 to 7.38) and 4.69 (95% CI, 2.50 to 8.80), respectively. CONCLUSION: The use of IVADo in children with type II and type III PPB resulted in similar-to-improved outcomes compared with historical controls. Inferior outcomes with metastatic disease suggest the need for novel therapies. This large cohort of uniformly treated children with advanced PPB serves as a benchmark for future multicenter therapeutic studies for this rare pediatric tumor.
Subject(s)
Lung Neoplasms , Pulmonary Blastoma , Child , Humans , DEAD-box RNA Helicases , Doxorubicin/therapeutic use , Lung Neoplasms/pathology , Pulmonary Blastoma/drug therapy , Registries , Ribonuclease IIIABSTRACT
INTRODUCTION: The absence of submucosal ganglion cells does not reliably distinguish Hirschsprung disease from non Hirschsprung disease in anorectal line biopsies. Calretinin staining might be helpful in these biopsies. To determine its value, we analyzed calretinin positive mucosal neurites in anorectal line biopsies. METHODS: Two pediatric pathologists, without access to patient data, evaluated calretinin positive mucosal neurites in anorectal line junctional mucosa in archival rectal biopsies contributed by 17 institutions. A separate investigator compiled patient information and sent data for statistical analysis. RESULTS: Biopsies with anorectal junctional mucosa from 115 patients were evaluated for calretinin positive mucosal neurites. 20/20 Hirschsprung disease biopsies were negative. 87/88 non Hirschsprung disease biopsies and 7/7 post pullthrough Hirschsprung disease neorectal biopsies were positive. Statistical analysis of the 108 non pullthrough biopsies yielded an accuracy of 99.1% (sensitivity 100%, specificity 98.9%). Age range was preterm to 16 years. Biopsy size was less than 1 mm to over 1 cm. CONCLUSIONS: Absence of calretinin positive mucosal neurites at the anorectal line was highly accurate in distinguishing Hirschsprung disease from non Hirschsprung disease cases in this blinded retrospective study. Calretinin staining is useful for interpreting biopsies from the physiologic hypoganglionic zone up to the anorectal line.
Subject(s)
Hirschsprung Disease , Infant, Newborn , Child , Humans , Infant , Adolescent , Retrospective Studies , Immunohistochemistry , Calbindin 2 , Hirschsprung Disease/diagnosis , Hirschsprung Disease/pathology , Biopsy , Rectum/pathologyABSTRACT
Homer-Wright-like rosettes are a common finding in neural tumors but seldom seen in melanocytic nevi and melanoma. We report a case of a 23-year-old male with a compound melanocytic nevus with such rosette-like structures and summarize the current literature on this histopathological feature in melanocytic neoplasms. A symmetric, well-circumscribed, compound nevus consisting of aggregations of epithelioid melanocytes with eccentric nuclei and central eosinophilic cytoplasm, resembling Homer-Wright rosettes, was present on biopsy. Immunohistochemical stains strongly supported a melanocytic entity and were negative for NTRK1/2/3, a fusion protein potentially associated with rosette-like structures. We found 17 other cases of benign melanocytic nevi, including 9 atypical Spitz tumors and 6 Spitz nevi, and 11 malignant melanomas, including 3 Spitz melanomas and 4 metastases. We observed remarkable diversity among lesion morphologies containing rosettes, as well as level of prominence and cytology of the rosettes themselves. This case illustrates the morphologic malleability of neural-crest-derived lesions to share microscopic and phenotypic attributes.
Subject(s)
Melanoma , Nevus, Epithelioid and Spindle Cell , Nevus, Pigmented , Skin Neoplasms , Adult , Diagnosis, Differential , Humans , Male , Melanoma/pathology , Nevus, Pigmented/pathology , Skin Neoplasms/pathology , Young AdultABSTRACT
BACKGROUND: Juvenile xanthogranuloma (JXG) is the most common type of non-Langerhans cell histiocytosis whose cell of origin, etiology and pathogenesis are not fully understood. We aimed to provide an update on histopathologic and immunophenotypic profile of this well-characterized entity whose relationship to the other histiocytoses has received renewed attention in light of recent molecular genetic studies. MATERIALS AND METHODS: A retrospective review of all the cases with the pathologic diagnosis of "xanthogranuloma" was performed on our archives from 1989 to 2019. RESULTS: A total of 525 patients with 547 lesions diagnosed as JXG were identified with the median age of 4.5 years, a male predominance (M:F ratio 1.3:1) and a predilection for the head and neck region (40.8%). Cutaneous lesions comprised 76.8% cases and another 15.7% presented within soft tissues. The most common non-soft tissue, extracutaneous lesions included the brain (2.6%), and lungs (1.8%). Three basic histopathologic patterns were identified: early classic (EJXG) (14.2%), classic (CJXG) (45.3%), and transitional JXG (TJXG) (40.5%). Multinucleated giant cells, either Touton or non-Touton, were most frequently present in CJXG followed by TJXG. Mitosis was rare (<1/10 high-power field) among different patterns. There was an association among the patterns and lymphocytic infiltrates (P = 0.036), and presence of Touton or non-Touton giant cells (P < 0.001 for both) but not for mitotic count (P = 0.105) or eosinophilic infiltrates (P = 0.465). Additionally, there was a correlation between age groups and presence of non-Touton giant cells (P = 0.012) but not for Touton cells (P = 0.127). We have demonstrated that immunophenotypic expression of the lesion was not associated with age at diagnosis nor morphologic pattern: factor XIIIa 192/204 (94.1%), CD11c 75/77 (97.4%), CD4 82/84 (97.6%), CD68 200/201 (99.5%), CD163 15/15 (100%), CD1a 1/110 (0.9%), S-100 48/152 (31.6%), CD31 15/21 (71.4%), and vimentin 104/105 (99.0%). CONCLUSION: We have documented in a substantial series of cases of JXG that there is a correlation between one of the three basic histopathologic patterns with age at diagnosis, but with a consistent immunophenotype among the three patterns. Considering sensitivity and specificity rates, we suggest that a combination of CD11c, CD4, CD1a and either CD163 (preferred) or CD68 stains provides more specific diagnostic yield in the differentiation of JXG from other histiocytic disorders. JXG is also discussed in terms of its relationship and distinction from other similar histiocytic disorders in the context of MAPK/ERK pathway mutations.
Subject(s)
Hematologic Neoplasms , Skin Neoplasms , Xanthogranuloma, Juvenile , Adult , Child, Preschool , Female , Histiocytes/pathology , Humans , Male , Retrospective Studies , S100 Proteins , Xanthogranuloma, Juvenile/complications , Xanthogranuloma, Juvenile/diagnosis , Xanthogranuloma, Juvenile/pathologyABSTRACT
ABSTRACT: Juvenile xanthogranuloma is a group C and L non-Langerhans cell histiocytosis, and its cell of origin is still debatable. The expression of CD11c, a more recently described macrophage marker, and CD4 have not been studied comprehensively. This study aimed to expand immunophenotypic profile and hence our understanding of the origin of these lesions. The surgical pathology archive was searched for the cases with the pathologic diagnosis of "xanthogranuloma" from 1995 to 2019. Immunohistochemical (IHC) stains were performed for factor XIIIa, CD11c, and CD4. Morphologically, each lesion was classified into early classic, classic, or transitional subtypes. Seventy-seven cases were included with the median age of 7.8 years (male:female 1.3:1). Uniform positivity was noticed for CD4 (n = 77), CD68 (n = 37), CD163 (n = 5), and vimentin (n = 4) stains. Other stains included CD11c 75/77 (97.4%), factor XIIIa 71/76 (93.4%), S-100 protein 4/23 (17.4%), and CD1a 0/18 (0%). Despite insignificant association between morphologic subtype and main studied IHC stains, factor XIIIa reactivity was highest in transitional lesions and CD11c showed higher reactivity in early classic lesions. CD11c and CD4 are sensitive markers and showed promising results in the diagnosis of juvenile xanthogranuloma compared with factor XIIIa. Despite different reactivity of factor XIIIa and CD11c in various morphologic subtypes, such association was statistically insignificant.
Subject(s)
Histiocytosis, Non-Langerhans-Cell , Xanthogranuloma, Juvenile , Biomarkers , Child , Factor XIIIa/metabolism , Female , Humans , Male , S100 Proteins , Xanthogranuloma, Juvenile/pathologyABSTRACT
BACKGROUND: Regardless of age at presentation, many soft tissue neoplasms have overlapping histopathologic and immunophenotypic features to serve as a diagnostic challenge. CASE REPORT: We reported a case of a spindle cell neoplasm in an infant, which was initially considered a vascular anomaly clinically and an eventual biopsy revealed marked inflammation with a spindle cell component that was resolved as an infantile fibrosarcoma with an ETV6 break-apart. CONCLUSION: The context of this case lead to a further consideration of various other spindle cell neoplasms arising predominantly in the soft tissues during the infancy period as defined by the first two years of age. Though sharing similar morphologic features, these tumors can be categorized into several molecular genetic groups, which have provided both diagnostic and pathogenetic insights as well as treatment options in some cases.
Subject(s)
Fibrosarcoma , Soft Tissue Neoplasms , Infant , Humans , Immunohistochemistry , Diagnosis, Differential , Fibrosarcoma/diagnosis , Fibrosarcoma/genetics , Fibrosarcoma/pathology , Soft Tissue Neoplasms/diagnosis , Soft Tissue Neoplasms/genetics , Soft Tissue Neoplasms/pathologyABSTRACT
Extrapulmonary DICER1-associated sarcomas (DS) can harbor morphological features overlapping with pleuropulmonary blastoma. We report three children with intracranial and genital tract sarcomas, suspected to have DS based on a heterogeneous yet defining combination of spindle-cell sarcomatous and blastemal morphology, with rhabdomyomatous differentiation. Foci of immature cartilage at diagnosis (n = 2/3) and increased neuroepithelial differentiation at recurrence (n = 1) were noted. Morphological suspicion prompted somatic testing at reference centers, confirming likely biallelic, loss-of-function, and "hotspot" missense DICER1 variants in all three tumors. This can serve as a model for this diagnosis in resource-limited settings and has implications for germline testing, surveillance, and tumor management.
Subject(s)
Pulmonary Blastoma , Sarcoma , Soft Tissue Neoplasms , Child , DEAD-box RNA Helicases/genetics , Developing Countries , Germ-Line Mutation , Humans , Pulmonary Blastoma/diagnosis , Pulmonary Blastoma/genetics , Pulmonary Blastoma/pathology , Ribonuclease III/genetics , Sarcoma/diagnosis , Sarcoma/genetics , Sarcoma/pathologyABSTRACT
This report documents a unique multicystic neoplasm of the liver in an 8-month-old boy with a heterozygous germline pathogenic DICER1 variant. This neoplasm, initially considered most likely a mesenchymal hamartoma based on imaging, demonstrated the characteristic histologic pattern of embryonal rhabdomyosarcoma residing in the subepithelial or cambium layer-like zone of the epithelial-lined cysts. Thus, although the differential diagnosis includes mesenchymal hamartoma, a young child with a multicystic mass lesion in the liver, lung, or kidney should both raise the possibility of a germline pathogenic DICER1 variant and also not be mistaken for one of the other hepatic neoplasms of childhood.