Interdigitating Dendritic Cell Sarcoma Research Articles

Difficult Diagnosis of Interdigitating Dendritic Cell Sarcoma of the Retroperitoneum: A Case Report and A Brief Review of the Literature.

Interdigitating dendritic cell sarcoma (IDCS) is a rare and aggressive neoplasm classified within the M-group of malignant histiocytoses. Its diagnosis poses a significant challenge. This article aims to describe a rare clinical case of IDCS and to illustrate the differential diagnostic process undertaken by the authors in establishing this diagnosis. A 60-year-old woman was admitted for the resection of a retroperitoneal mass discovered via CT scan. Morphological examination revealed a 7.5×5.5×5.0 cm tumor, encapsulated by a thin fibrous capsule. The tumor was composed of 90-95% inflammatory infiltrate with lymphocyte-like cells showing mature nuclear morphology (CD3+ and CD20+ cells) mixed with histiocytes and plasma cells, and 5-10% large polymorphic spindle-shaped cells expressing expression of CD45, CD68, CD1a, CD21, CD35, CD31, and CD34. An extensive immunohistochemical panel was performed to exclude various other tumors. Based on the morphology and immunophenotype, a diagnosis of IDCS was established. Further literature analysis indicated the nonspecificity of symptoms in patients with this tumor localization and variability in CD45 and CD68 staining in tumor cells, with consistent lack of expression of CD21, CD23, CD35, CD1a, and specific T- and B-cell antigens. IDCS is a rare and poorly understood tumor with a poor prognosis. The nonspecificity of clinical symptoms and the need for extensive morphological differential diagnosis render this entity a diagnosis of exclusion, requiring significant diligence from the pathologist.

Clinical characteristics, molecular aberrations, treatments, and outcomes of malignant histiocytosis.

Malignant histiocytosis (MH) is an extremely rare neoplasm of the macrophage-dendritic cell lineage. We report the clinical characteristics, molecular aberrations, treatments, and outcomes of patients with MH seen at two referral centers from January 2000 to May 2023. We identified 43 patients with MH, of which 26 had histiocytic sarcoma (MH-H), 9 interdigitating dendritic cell sarcoma (MH-IDC), and 8 Langerhans cell sarcoma (MH-LC). The median age at diagnosis was 61 years (range, 3-83). Thirty-three patients (77%) had multifocal disease, while 10 had unifocal involvement. Tumor specimens from 22 patients (51%) underwent targeted next generation sequencing, and 19 of 22 (86%) had at least one pathogenic mutation, including mutations in MAPK pathway genes (73%). The median overall survival (OS) among the entire cohort was 16 months (95% CI: 8-50). The outcomes of those with multifocal disease were significantly shorter than their unifocal counterpart: median OS of 10 months versus 50 months (p = .07). Patients with risk organ involvement (bone marrow, spleen, or liver) had significantly inferior outcomes. Chemotherapy and surgery were the most common first-line treatments for multifocal and unifocal disease, respectively. While the outcome for patients with multifocal disease was poor, there was a subset of patients who had durable responses to treatment. Our study highlights that MH has heterogeneous clinical presentation, frequent oncogenic mutations, and prognosis, which is strongly tied to disease extent and type of organ involvement.

Interdigitating Dendritic Cell Sarcoma and Indeterminate Dendritic Cell Tumor: Patient Characteristics, Prognostic Factors, and Survival Outcomes for Rare Dendritic Cell Neoplasms

Background Dendritic cells are nonlymphoid, nonphagocytic, antigen-presenting cells present in lymphoid and nonlymphoid tissue. There are 4 types of dendritic cells: follicular, interdigitating, Langerhans, and fibroblastic cells. The WHO 2022 classification system groups dendritic cell and histiocytic neoplasms into 3 categories: plasmacytoid dendritic cell neoplasms, Langerhans cell and other dendritic cell neoplasms, and histiocytic neoplasms. The 2nd category is subdivided into “Langerhans cells neoplasms” and “other dendritic cell neoplasms”, which contains indeterminate dendritic cell tumor (IDCT) and interdigitating dendritic cell sarcoma (IDCS). The 2022 classification eliminated follicular dendritic cell sarcoma (FDCS) as it is no longer thought to be of hematopoietic origin. A prior Surveillance, Epidemiology, and End Results (SEER) review published in 2013 by Perkins and Shinohara grouped FDCS and IDCS and included 20 cases of IDCS diagnosed between 2001 and 2008. To our knowledge, this is the first update of epidemiologic and survival data for non-Langerhans cell and non-plasmacytoid dendritic cell neoplasms since the WHO reclassification. Methods We used the SEER 22 database, which collects data from cancer registries covering approximately 47.9% of the U.S. population. We selected all patients with cancers falling in the “other dendritic cell neoplasms” category according to the WHO 2022 classification from 2000-2020 using International Classification of Diseases for Oncology edition 3 (ICD-O-3) code of 9757/3, which codes for IDCS but also includes IDCT. The Kaplan-Meier method was used to display the survival curves. The Cox proportional hazards model was used to determine p values. Results A total of 72 cases of IDCS/IDCT were identified. Median follow up was 19 months and median OS for the entire cohort was 24 months (95% CI 10-92 months). Of these patients, 61.1% (n=44) were White, 16.7% (n=12) were Hispanic, 13.8% (n=10) were Black, 5.6% (n=4) were Asian or Pacific Islander, and 2 patients were of unknown race. IDCS/IDCT was more common in males than females with a ratio of 1.77. The most common primary sites of involvement were connective tissue in 40.2% (n=29), head and neck in 16.7% (n=12), lymph nodes in 11.1% (n=8), and bone marrow in 8.3% (n=6). Patients with bone marrow involvement had a trend towards worse OS (median OS of 5 months). IDCS/IDCT is more common in adults but does occur in children and adolescents. Only 6 cases were diagnosed in patients under the age of 20 years. Patients who were under the age of 60 years at diagnosis had a median OS of 155 months compared to a median OS of only 10 months for patients who were 60 years or older at diagnosis (Figure 1, p<0.001). Staging was unknown in 12 patients. Of patients with known staging, 56.7% (n=34) had localized disease and 43.3% (n=26) had metastatic disease. Patients with localized disease at diagnosis had a better prognosis with a median OS of 120 months compared to 5 months for patients with metastatic disease at diagnosis (Figure 2, p<0.001). Treatment modality was unknown in 29 of the patients. Of patients with known treatment, 34.9% (n=15) had surgery alone, 20.9% (n=9) had chemo alone, 16.3% (n=7) had radiation alone, and 27.9% (n=12) had combination treatment. Single modality treatment regimens were most popular in patients with localized disease with 48% (n=12) of the patients with known treatment modality getting surgery alone, followed by radiation alone at 24% (n=6).The most common cause of death in this cohort was IDCS/IDCT with 76% of deaths being attributed to the cancer (n=35, there were 46 total deaths). Conclusions Though cases of IDCS and IDCT have more than tripled since 2008, it still remains the rarest type of dendritic cell neoplasm. Connective tissue, head and neck, and lymph nodes were the most common sites involved. Surgical resection was the most common treatment modality followed by chemotherapy. Clinical presentation is rare in patients under the age of 20 years. Age 60 years and older and metastatic disease were associated with poor outcomes with a signal towards worse survival when bone marrow was involved. Our study updates current knowledge of IDCS/IDCT and highlights some of the unknowns in this type of neoplasm, particularly regarding other prognostic factors including treatment effect on survival.

Malignant Histiocytosis Comprises a Phenotypic Spectrum That Parallels the Lineage Differentiation of Monocytes, Macrophages, Dendritic Cells, and Langerhans Cells

Malignant histiocytoses (MHs), or the ‘M group’ of the Histiocyte Society classification, are characterized by neoplastic histiocytes with large pleomorphic nuclei. MH encompasses the diagnoses of histiocytic sarcoma, interdigitating dendritic cell sarcoma, and Langerhans cell sarcoma. We aimed to define the phenotypic spectrum of MH and examine the genotypic features across this spectrum. Using immunohistochemistry, we arranged the 22 cases into 4 subtypes that correspond to the lines of differentiation from monocytic and dendritic cell precursors as follows: (1) macrophage (n = 5): CD68+, CD163+, CD14+, and Factor 13a+; (2) monocyte-macrophage (n = 5): CD68+, CD163+, CD14+, S100+, and OCT2+; (3) dendritic cell (n = 6): CD68+, CD11c+, S100+, lysozyme+, ZBTB46+, and CD1a/langerin < 5%; and (4) Langerhans cell (n = 6): CD68+, CD11c+, S100+, ZBTB46+, CD1a+, and langerin+. The phenotypic subtypes align with those seen in low-grade histiocytic neoplasms as follows: MH-macrophage type correlates with Erdheim-Chester disease phenotype; MH-monocyte-macrophage type with Rosai-Dorfman disease phenotype, and MH-Langerhans cell type with Langerhans cell histiocytosis. Activating mutations in MAPK-pathway genes were identified in 80% of MH cases; 29% had mutations in the PI3k-AKT-mTOR pathway and 59% had mutations in epigenetic modulating genes. Strong expression of cyclin D1 was present in all cases, whereas p-ERK and p-AKT were not uniformly expressed. Eight of 22 (36%) MH cases were proven to be clonally related to a prior B-cell lymphoma. Defining the phenotypic spectrum of MH provides a guide to diagnosis and allows further exploration into the potential biological and clinical significance.

An extremely rare case of interdigitating dendritic cell sarcoma of the parotid gland with a 40‑month disease‑free survival time after only surgery: A case report.

Interdigitating dendritic cell sarcoma (IDCS) is an extremely rare neoplasm arising from dendritic cells and is mainly located in the lymph nodes. To the best of our knowledge, no treatment strategy has yet been established for IDCS, despite its aggressive clinical features. The present study presents the case of a patient with IDCS who experienced a 40-month disease-free survival time after surgery alone. The patient, a 29-year-old woman, presented with a painful right subaural swelling. Diagnostic MRI and 18F-fludeoxyglucose positron emission tomography/computed tomography revealed a right parotid gland tumour and ipsilateral cervical lymph node. The patient underwent surgical resection, and histological examination of the resected tissue specimens confirmed IDCS diagnosis. To the best of our knowledge, this is only the fifth report of an IDCS located in the parotid gland, with the longest follow-up period among cases of IDCS reported in this region. The positive outcome of this patient suggests that surgical resection may be an effective treatment option for local IDCS. Nonetheless, further studies are required to establish a definitive diagnosis and treatment strategy for IDCS.

Two Sides of the Same Transdifferentiated Coin: A Case Vignette and Review of the Literature Exploring the Relationship between B Cell Non-Hodgkin Lymphoma, Histiocytic Sarcoma and Interdigitating Dendritic Cell Sarcoma

WHO classifies Histiocytic Sarcoma (HS) and Interdigitating Dendritic Cell Sarcoma (IDCS) as separate, unrelated, entities under histiocytic/dendritic cell neoplasms. We do not fully understand the pathogenesis of HS and IDCS, yet both have been shown to transdifferentiate from B cell non-Hodgkin lymphomas. Diagnosis is challenging and requires application of a wide variety of immunohistochemical studies, flow cytometry and molecular analysis. We present a case of HS which evolved from CLL/SLL and presented as a diagnostic challenge due to unusual features overlapping with what is typically seen in IDCS. An 82-year-old male with a history of CLL/SLL presented with right infiltrative tonsillar mass and cervical lymphadenopathy. Biopsy of the lymph node revealed two abnormal populations of cells : Twenty percent of cells were consistent with CD20+ kappa surface light chain restricted CLL/SLL cells. Eighty percent of cells were histiocytic cells with an abnormal immunophenotype showing expression of CD4, CD43, fascin, HLA-DR, PU.1, (weak) S100 and CD1a without CD163, lysozyme, CD34, CD117, CD21, CD23 or CD14. Expert consultation favored the diagnosis of HS with transdifferentiation from CLL/SLL. PCR for IgH gene rearrangement, performed on separate HS-rich and CLL-rich areas of the biopsy detected identical clonal peaks. Next generation sequencing detected pathogenic KRAS mutations (p.G12D, p.A146P) and likely pathogenic BCOR (p.K839fs*17) and FBXW7 (p.R465S) mutations. While HS was the favored diagnosis, some immunophenotypic features were unusual, including diffuse fascin immunoreactivity, weak S100, and CD1a immunoreactivity which raised the possibility of so-called IDCS. While clonal evolution of HS and IDCS from B cell Non-Hodgkin lymphomas has been reported, there is a paucity of literature on these entities. We suggest that there may be a pathogenic relationship between these two neoplasms that has yet to be elucidated due to their rarity and diagnostic challenge. Few clinical laboratories can perform the breadth of markers required for diagnosis. Both neoplasms have varied clinical presentations with nodal or extranodal involvement and portend poor prognosis. Review of the literature shows significant overlap in immunophenotypic and genomic characteristics of IDCS and HS, suggesting they may be related manifestations of the same neoplasm. A case report has described the initial presentation of IDCS that subsequently developed into HS, although sampling may have been an issue. We identified 11 cases, including our case in the literature presenting with positive histiocytic and dendritic cell markers referred as hybrid dendritic-histiocytic sarcomas or histiocytic sarcoma with interdigitating dendritic cell differentiation. Immunohistochemical analysis of these cases showed positivity rates of S100 (100%), lysozyme (82%) and CD1a (18%). One case in the literature described fascin immunoreactivity, as was observed in our case. Four of six cases had CD163 immunoreactivity. A hybrid neoplasm with overlapping features of follicular and interdigitating dendritic cells has also been reported, further confounding our understanding of these neoplasms. Large studies analyzing genomic features of these neoplasms have shown recurrent mutations in RAS-MAPK pathway, as was seen in our case. Further studies of the relationship between HS, IDCS should include gene expression profiling of these entities which may also yield therapy targets. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Interdigitating dendritic cell sarcoma: analysis of two original extra-nodal cases and review of literature.

Interdigitating dendritic cell sarcoma (IDCS) is a rare, highly malignant tumor with a poor prognosis, and current knowledge of this tumor is limited. It is reported that lymph nodes are the primary localization sites. However, in recent years, many primary IDCS have also been reported in the extra-nodal sites, which undoubtedly increases the difficulty of diagnosis. There are very few reports that systematically analyze the clinicopathologic features of IDCS. Here we described two cases of extra-nodal IDCS and reviewed the literature of 44 other published cases of extra-nodal IDCS. Thus, the clinical symptoms, pathological diagnosis, and therapeutic effects of 46 cases of extra-nodal IDCS were summarized in detail. Considering the paucity of available data with regard to IDCS, a thorough and detailed summary would help to better diagnose and treat this neoplasm.

Head-to-head evaluation of [18F]FDG and [68 Ga]Ga-DOTA-FAPI-04 PET/CT in recurrent soft tissue sarcoma

PurposeWe aimed to evaluate the value of [68 Ga]Ga-DOTA-FAPI-04 PET/CT for the diagnosis of recurrent soft tissue sarcoma (STS), compared with [18F]FDG PET/CT.MethodsA total of 45 patients (21 females and 24 males; median age, 46 years; range, 18–71 years) with 13 subtypes of STS underwent [18F]FDG and [68 Ga]Ga-DOTA-FAPI-04 PET/CT examination within 1 week for assessment local relapse or distant metastasis. Positive lesions on PET/CT images were verified by biopsy or 3-month follow-up. Wilcoxon matched-pairs signed-rank test was used to compare the semiquantitative values (SUVmax and TBR) of [18F]FDG and [68 Ga]Ga-DOTA-FAPI-04 in tumor lesions, and McNemar test was applied to test for differences of both tracers.ResultsAmong the 45 patients, 282 local relapses and distant metastases were identified. Compared to [18F]FDG, [68 Ga]Ga-DOTA-FAPI-04 PET/CT detected more lesions (275 vs. 186) and outperformed in sensitivity, specificity, PPV, NPV, and accuracy for the diagnosis of recurrent lesions (P < 0.001). [68 Ga]Ga-DOTA-FAPI-04 demonstrated significantly higher values of SUVmax and TBR than [18F]FDG PET/CT in liposarcoma (P = 0.011 and P < 0.001, respectively), malignant solitary fibrous tumor (MSFT) (P < 0.001 and P < 0.001, respectively), and interdigitating dendritic cell sarcoma (IDCS) (P < 0.001and P < 0.001, respectively). While mean SUVmax and TBR presented favorable uptake of [18F]FDG over [68 Ga]Ga-DOTA-FAPI-04 in undifferentiated pleomorphic sarcoma (UPS) (P = 0.003 and P < 0.001, respectively) and rhabdomyosarcoma (RMS) (P < 0.001 and P < 0.001, respectively).Conclusion[68 Ga]Ga-DOTA-FAPI-04 PET/CT is a promising new imaging modality for recurrent surveillance of STS, and compares favorably with [18F]FDG for identifying recurrent lesions of liposarcoma, MSFT, and IDCS.

Rare variants of histiocytic tumors: peculiarities of diagnosis and choice of treatment (literature review)

Histiocytic tumors are a highly heterogeneous group of diseases, with Langerhans cell histiocytosis occupying the main place among it. Despite the rare frequency of occurrence, long-term analysis of clinical, morpho-immunological and molecular-biological features has allowed the development of effective treatment protocols (especially in the pediatric cohort of patients). In addition to Langerhans cell histiocytosis, the histiocytic tumors group includes rare and casuistic variants, which include histiocytic sarcoma, Langerhans cell sarcoma, indeterminate dendritic cell tumor, interdigitating dendritic cell sarcoma, follicular dendritic cell sarcoma, and fibroblastic reticular cell tumor. The incidence of certain nosological variants is several cases per hundreds of millions of the population. Not surprisingly, the diagnostic criteria for this group of tumors need to be clarified, as do the therapeutic approaches. This review presents current data on rare histiocytic tumors, clinical features as well as morphological and immunobiological characteristics of the tumor substrate. The results of modern surgical and therapeutic treatment approaches are presented.

Histiocytic and Dendritic Cell Sarcomas of Hematopoietic Origin Share Targetable Genomic Alterations Distinct from Follicular Dendritic Cell Sarcoma.

BackgroundHistiocytic and dendritic cell neoplasms are a diverse group of tumors arising from monocytic or dendritic cell lineage. Whereas the genomic features for Langerhans cell histiocytosis and Erdheim‐Chester disease have been well described, other less common and often aggressive tumors in this broad category remain poorly characterized, and comparison studies across the World Health Organization diagnostic categories are lacking.MethodsTumor samples from a total of 102 patient cases within four major subtypes of malignant histiocytic and dendritic cell neoplasms, including 44 follicular dendritic cell sarcomas (FDCSs), 41 histiocytic sarcomas (HSs), 7 interdigitating dendritic cell sarcomas (IDCSs), and 10 Langerhans cell sarcomas (LCSs), underwent hybridization capture with analysis of up to 406 cancer‐related genes.ResultsAmong the entire cohort of 102 patients, CDKN2A mutations were most frequent across subtypes and made up 32% of cases, followed by TP53 mutations (22%). Mitogen‐activated protein kinase (MAPK) pathway mutations were present and enriched among the malignant histiocytosis (M) group (HS, IDCS, and LCS) but absent in FDCS (72% vs. 0%; p < .0001). In contrast, NF‐κB pathway mutations were frequent in FDCSs but rare in M group histiocytoses (61% vs. 12%; p < .0001). Tumor mutational burden was significantly higher in M group histiocytoses as compared with FDCSs (median 4.0/Mb vs. 2.4/Mb; p = .012). We also describe a pediatric patient with recurrent secondary histiocytic sarcoma treated with targeted therapy and interrogated by molecular analysis to identify mechanisms of therapeutic resistance.ConclusionA total of 42 patient tumors (41%) harbored pathogenic mutations that were potentially targetable by approved and/or investigative therapies. Our findings highlight the potential value of molecular testing to enable precise tumor classification, identify candidate oncogenic drivers, and define personalized therapeutic options for patients with these aggressive tumors.Implications for PracticeThis study presents comprehensive genomic profiling results on 102 patient cases within four major subtypes of malignant histiocytic and dendritic cell neoplasms, including 44 follicular dendritic cell sarcomas (FDCSs), 41 histiocytic sarcomas (HSs), 7 interdigitating dendritic cell sarcomas (IDCSs), and 10 Langerhans cell sarcomas (LCSs). MAPK pathway mutations were present and enriched among the malignant histiocytosis (M) group (HS, IDCS, and LCS) but absent in FDCSs. In contrast, NF‐κB pathway mutations were frequent in FDCSs but rare in M group histiocytosis. A total of 42 patient tumors (41%) harbored pathogenic mutations that were potentially targetable by approved and/or investigative therapies.

Interdigitating Dendritic Cell Sarcoma in Upper Arm Misdiagnosed as Ruptured Epidermal Inclusion Cyst

Interdigitating dendritic cell sarcoma (IDCS) is an extremely rare neoplasm that usually arises in lymph nodes, but also can exist in extranodal sites. This report is about a case study of IDCS in the upper arm skin with axillary lymph node metastasis. A 66-year old woman had a slowly growing mass with tenderness sensation on her right upper arm that was being injected triamcinolone acetonide at local clinic. The presumptive diagnosis was a ruptured epidermal inclusion cyst, and empiric antibiotic therapy was done; however, she had poor respondence to antibiotic therapy. Therefore, magnetic resonance imaging, incisional biopsy, positron emission tomography-computed tomography, and bone scan were performed and a malignant tumor was diagnosed. She received surgical resection and lymph node dissection of the right axilla. No adjuvant chemotherapy was done. Although extremely rare, this case suggests that extranodal IDCS should be considered in differential diagnosis of untreated atypical skin mass and early biopsy should be performed.

Histiocytosis and Neoplasms of Macrophage-Dendritic Cell Lineages: Multimodality Imaging with Emphasis on PET/CT.

Histiocytosis is a rare inflammatory process characterized by pathologic infiltration and accumulation of cells derived from the monocytic lineage in normal tissue. It encompasses more than 100 different subtypes of disorders that were recently classified into five main groups: (a) Langerhans-related histiocytosis, (b) Rosai-Dorfman histiocytosis, (c) cutaneous and mucocutaneous histiocytosis, (d) malignant histiocytosis, and (e) hemophagocytic lymphohistiocytosis and macrophage activation syndrome. Langerhans cell histiocytosis is the most common histiocytic disorder. Less common types include Erdheim-Chester disease, Rosai-Dorfman disease, adult and juvenile xanthogranuloma, necrobiotic xanthogranuloma, histiocytic sarcoma, interdigitating dendritic cell sarcoma, Langerhans cell sarcoma, and hemophagocytic lymphohistiocytosis. Although the pathogenesis of these disorders may be attributable to mutations in the oncogenic driver, recent discoveries have shown that inflammation and fibrosis secondary to mutated histiocytes, rather than a proliferative cell mechanism, result in manifestation of the disease. Diagnosis, which relies on a multidisciplinary approach, is challenging and often delayed because clinical findings are nonspecific and may mimic malignant processes at radiologic evaluation. Compared with conventional imaging, PET/CT allows detection of the increased metabolic activity in histiocytes. Diagnostic algorithms for histiocytic disorders should include functional imaging with fluorine 18 (18F) fluorodeoxyglucose (FDG) PET/CT, which provides a comprehensive whole-body evaluation of their potential involvement with multiple organ systems and allows monitoring of therapeutic response. The most recent revised classification, pathophysiologic and clinical manifestations, sites of involvement, and imaging features of histiocytosis are described in this review and a multimodality approach is used, with emphasis on 18F-FDG PET/CT evaluation. ©RSNA, 2021.

Descriptive Analysis of Histiocytic and Dendritic Cell Neoplasms: A Single-Institution Experience.

PurposeHistiocytic and dendritic cell neoplasms are rare hematologic tumors. This study aimed to describe the epidemiologic features of the entire spectrum of histiocytic and dendritic cell neoplasms, including clinicopathological variables and patient outcomes.Materials and MethodsWe comprehensively reviewed 274 patients who were diagnosed with histiocytic and dendritic neoplasms at Severance Hospital, Seoul, South Korea between 1995 and 2018.ResultsThe most common neoplasm was Langerhans cell histiocytosis (LCH), followed by dermal xanthogranuloma. Among non-LCH sarcomas, histiocytic sarcoma (HS) showed a relatively high prevalence, followed by follicular dendritic cell sarcoma (FDCS). Disseminated juvenile xanthogranuloma (DJG), Erdheim-Chester disease (ECD), indeterminate dendritic cell tumor (IDCT), and interdigitating dendritic cell sarcoma (IDCS) rarely occurred. Generally, these tumors presented in childhood, although the non-LCH sarcoma (HS/FDCS/IDCS/IDCT) group of tumors and ECD occurred in late adulthood. Multiorgan involvement and advanced Ann-Arbor stage, as well as recurrence and death of disease, were not uncommon. The non-LCH sarcoma group had the worst overall survival, compared to the DJG, ECD, and LCH groups.ConclusionOur findings indicate that histiocytic and dendritic cell neoplasms exhibit heterogeneous epidemiologic characteristics and that some patients may have unfavorable outcomes, especially those with non-LCH sarcoma.

New insights inside the interdigitating dendritic cell sarcoma-pooled analysis and review of literature.

Interdigitating dendritic cell sarcoma is a rare haematological neoplasm with high debatable management protocols. The data extracted from 127 case reports published between 1981 and 2018 were analysed. The median age at diagnosis was 58 years with a male to female ratio of 1.65:1. The median OS and PFS of IDCS were 12 and 6 months, respectively, with a disease-specific mortality rate of 36.4%. Two-thirds of patients had a localised disease, while 30% had a disseminated form with 1-year mortality rates of 21.1% and 78.9%, respectively. Twenty per cent of cases were associated with other malignancies. Histologically, the proliferation of large spindle-shaped cells with fascicular growth was described in 84.3% of cases. Based on Cox-regression model, surgical resection was the only treatment modality linked to survival improvement with no recorded survival benefits of radiotherapy and chemotherapy. The 1-year mortality rates in resected and non-resected disease were 17.8% and 63.2%, respectively (P < 0.0001).

Comprehensive Genomic Profiling of 104 Rare Histiocytic and Dendritic Cell Neoplasms Reveals Shared and Distinct Targetable Genomic Alterations

Introduction: Histiocytic and dendritic neoplasms are a diverse group of uncommon hematologic tumors arising from monocytic or dendritic cell lineage. While genomic profiles for the more common entities Langerhans cell histiocytosis and Erdheim-Chester disease are established, less common neoplasms in this broad category are poorly characterized. In the current study, we assessed the genomic landscape of these often aggressive histiocytic and dendritic cell neoplasms to identify distinct mutational signatures for each subtype in the current WHO classification system. Methods: 104 histiocytic and dendritic cell neoplasmswere tested during routine clinical care by hybridization capture of 406 cancer-related genes to detect base substitutions, small indels, amplifications (amp), deletions, and rearrangements. Tumor mutational burden (TMB, mutations/Mb) was determined on ~1.1 Mbp of sequenced DNA. Review of pathology reports, histopathology, and patient clinical data was performed. Cases included 48 follicular dendritic cell sarcoma (FDCS), 37 histiocytic sarcoma (HS), 8 interdigitating dendritic cell sarcoma (IDCS), 5 Langerhans cell sarcoma (LCS), 4 indeterminate cell histiocytosis (ICH), 1 fibroblastic reticular cell tumor (FRCT), and 1 inflammatory pseudotumor-like follicular/fibroblastic dendritic cell sarcoma (FDC/FRCS). Results: Pathogenic or likely-pathogenic genomic alterations (GAs) in the four most common sarcoma subgroups are summarized in the Table. CDKN2A and TP53 pathogenic mutations were the most frequent GAs observed in the cohort, present in 27% and 20% of the cases, respectively. Compared to the rest of the cohort, FDCS showed significantly more cases harboring a pathogenic GA in genes involved with NFkB pathway regulation (58% vs. 18%, p&lt;0.0001). Other relevant alterations in FDCS included NTRK1 (2 cases; 1 NTRK1-PDIA3 fusion and 1 amp), NTRK3 (1 case), FGFR3 (1 amp), STAT3 (3 cases) and PTEN (3 cases). Compared to the rest of the cohort, HS showed significantly more cases with pathogenic GAs in the MAPK pathway (59% vs. 19%, p&lt;0.0001), including 3 cases with BRAF fusions. Other relevant alterations in HS included PTEN (3 cases), PDGFRA (2 amp), MET (2 amp), 2 IGH-BCL2 fusions, and 1 IGH-BCL6 fusion. IDCS cases showed pathogenic MAPK GAs in 88% (7/8), and TET2 mutations were identified in 50% (4/8). A single NTRK1-TPR fusion was identified. LCS cases demonstrated GAs in both MAPK and NFkB pathways (4/5 and 3/5 cases, respectively). 2/4 cases of ICH demonstrated NCOA2-ETV3 fusions; TET2 mutations were present in the remaining two cases. The FRCT case contained an NRAS GA, and the FDC/FRCS cases had EBV (HHV-4) sequence reads. Conclusions: Our findings provide a comprehensive view of the shared and distinct genomic features among these rare histiocytic and dendritic cell neoplasms. The frequent inactivation of CDKN2A, which normally encodes an endogenous CDK inhibitor, suggests possible effectiveness of pharmacologic CDK4/6 inhibitors in treatment of this subset of cases. There are significant differences in the molecular profiles of different diseases: 58% of FDCS cases contain at least one pathogenic alteration in the NFkB pathway, while 59% and 88% of HS and IDCS cases contain potentially-actionable MAPK pathway mutations, respectively. LCS cases show frequent mutations in both pathways. Potentially-actionable molecular alterations are identified in 63/104 (61%) histiocytic and dendritic tumors in our cohort. These results illustrate the importance of performing comprehensive genomic profiling to define treatment strategies, including clinical trial "molecular eligibility" and more fully inform personalized therapeutic options. Disclosures Hasserjian: Jazz Pharmaceuticals: Consultancy; Promedior, Inc.: Consultancy. Montesion:Foundation Medicine, Inc.: Employment; F. Hoffman La Roche, Ltd.: Equity Ownership. Sokol:Foundation Medicine, Inc.: Employment; F. Hoffman La Roche, Ltd.: Equity Ownership. Pavlick:F. Hoffman La Roche, Ltd.: Equity Ownership; Foundation Medicine, Inc.: Employment. Shah:F. Hoffman La Roche, Ltd.: Equity Ownership; Foundation Medicine, Inc.: Employment. Danziger:F. Hoffman La Roche, Ltd.: Equity Ownership; Foundation Medicine, Inc.: Employment. Killian:F. Hoffman La Roche, Ltd.: Equity Ownership; Foundation Medicine, Inc.: Employment. Severson:Foundation Medicine, Inc.: Employment; F. Hoffman La Roche, Ltd.: Equity Ownership. Duncan:Foundation Medicine, Inc.: Employment; F. Hoffman La Roche, Ltd.: Equity Ownership. Elvin:Foundation Medicine, Inc.: Employment; F. Hoffman La Roche, Ltd.: Equity Ownership. Miller:F. Hoffman La Roche, Ltd.: Equity Ownership; Foundation Medicine, Inc.: Employment. Ross:Foundation Medicine, Inc.: Employment; F. Hoffman La Roche, Ltd.: Equity Ownership. Vergilio:Foundation Medicine, Inc.: Employment; F. Hoffman La Roche, Ltd.: Equity Ownership. Williams:Foundation Medicine, Inc.: Employment; F. Hoffman La Roche, Ltd.: Equity Ownership.

Soft Tissue Fibroblastic Reticular Cell Tumor With Whole-Exome Sequencing Findings: An Unexpected Presentation of Lynch Syndrome

Abstract Fibroblastic reticular cell tumor (FRCT) is an exceedingly rare tumor that is histologically reminiscent of follicular dendritic cell sarcoma or interdigitating dendritic cell sarcoma but lacks the immunophenotypic features of these tumors. This tumor is classically described in lymph nodes and spleen, with only 4 cases described in soft tissues. We report a case of FRCT presenting as a right thigh mass in a 67-year-old woman with no prior malignancies. Gross examination showed a 10.6-cm tan well-circumscribed intramuscular mass. Microscopic examination revealed a discohesive population of cells with indistinct pale cytoplasm and large irregular, atypical vesicular nuclei with variably prominent nucleoli in a collagenous background infiltrated by lymphocytes. The tumor cells were positive for smooth muscle actin, cytokeratins (in a dendritic pattern), and CD163, while negative for CD21, CD35, and CD23, supporting the diagnosis of FRCT. Whole-exome sequencing revealed 631 putative somatic mutations in the tumor (&gt;10 mutations/Mb of sequence). Mutational signature analysis suggested DNA mismatch repair deficiency. Germline mutational analysis revealed a heterozygous pathogenic missense mutation of MLH1 (c.2246 T &gt; C, p.Leu749Pro). Subsequent immunohistochemical analysis showed complete loss of MLH1 and PMS2 in tumor cells. To our knowledge, this is the first case of FRCT characterized by sequencing studies and found to be associated with Lynch syndrome (LS), expanding the spectrum of LS-associated neoplasms. This case demonstrates genetic hypermutation similar to that seen in the more common epithelial lesions arising in LS, and it highlights the potential for high-throughput genetic analysis to identify mismatch repair–deficient tumors of atypical histologies, which may have significant clinical implications in the era of immunotherapy.

Clinicopathological characteristics and differential diagnosis of interdigitating dendritic cell sarcoma

Objective: To analyze the clinicopathological features and differential diagnosis of interdigitating dendritic cell sarcoma (IDCS). Methods: The clinical pathological features of 7 IDCS were analyzed. Among them, the follow-up results of 6 cases were available. Results: Among the 7 IDCS patients, 4 cases were male and 3 were female. The age of the patients ranged from 26 to 69 years.Three cases were originated from lymph nodes and 4 cases were originated from skin, stomach, adrenal gland and mesentery, respectively. Microscopically, the tumor cells presented as fascicular and storiform proliferation and infiltrated by lymphocytes. The tumor cells were short-spindle or ovoid, with indistinct border of cytoplasm. The immunohistochemistry results showed that tumor cells were S-100, Vim, CD68 and CD163 positive, and AE1/AE3, EMA, CD117, CD34, Desmin, SMA, CD1α, CD21, CD23, CD35, HMB45, Melan-A, MelanPan and ALK negative.The BRAF mutation and clonal rearrangement of T and B cells were not detected. Among the follow-up period of 7 IDCS patients, 3 occurred disease progressions. Conclusions: IDCS is extremely rare with unique pathological features, and its lesion is not limited to the lymph node. The IDCS patients with extensive lesions may have worse prognose. The differential diagnosis of IDCS includes other histiocytic and dendritic cell neoplasms, malignant melanoma and soft tissue neoplasms.

Genomic characterization of metastatic ultra-hypermutated interdigitating dendritic cell sarcoma through rapid research autopsy.

Interdigitating dendritic cell sarcoma (IDCS) is an extremely rare cancer of dendritic cell origin that lacks a standardized treatment approach. Here, we performed genomic characterization of metastatic IDCS through whole exome sequencing (WES) of tumor tissues procured from a patient who underwent research autopsy. WES was also performed on a treatment-naïve tumor biopsy sample obtained from prior surgical resection. Our analyses revealed ultra-hypermutation, defined as >100 mutations per megabase, in this patient's cancer, which was further characterized by the presence of three distinct mutational signatures including UV radiation and APOBEC signatures. To characterize clonal heterogeneity, we used the bioinformatics tool Canopy to leverage single nucleotide and copy number variants to catalog six subclones across various metastatic tumors. Truncal alterations, defined as being present in all clonal tumor cell populations, in this patient's cancer include point mutations in TP53 and CDKN2A and amplifications of c-KIT and APOBEC3A-H, which are likely driver mutations. In summary, we have performed genomic characterization evaluating tumor mutational burden (TMB) and heterogeneity in a patient with metastatic IDCS. Despite ultra-hypermutation, this patient's cancer was not responsive to treatment with PD-1 inhibition. Our results underscore the importance of characterizing clonal heterogeneity in TMB-high cancers.

A case of interdigitating dendritic cell sarcoma studied by whole-exome sequencing.

Interdigitating dendritic cell sarcoma (IDCS) is an aggressive neoplasm and is an extremely rare disease, with a challenging diagnosis. Etiology of IDCS is also unknown and most studies with only case reports. In our case, immunohistochemistry showed that the tumor cells were positive for S100, CD45, and CD68, but negative for CD1a and CD21. This study aimed to investigate the causative factors of IDCS by sequencing the protein-coding regions of IDCS. We performed whole-exome sequencing with genomic DNA from blood and sarcoma tissue of the IDCS patient using the Illumina Hiseq 2500 platform. After that, we conducted Sanger sequencing for validation of sarcoma-specific variants and gene ontology analysis using DAVID bioinformatics resources. Through comparing sequencing data of sarcoma with normal blood, we obtained 15 nonsynonymous single nucleotide polymorphisms (SNPs) as sarcoma-specific variants. Although the 15 SNPs were not validated by Sanger sequencing due to tumor heterogeneity and low sensitivity of Sanger sequencing, we examined the function of the genes in which each SNP is located. Based on previous studies and gene ontology database, we found that POLQ encoding DNA polymerase theta enzyme and FNIP1 encoding tumor suppressor folliculin-interacting protein might have contributed to the IDCS. Our study provides potential causative genetic factors of IDCS and plays a role in advancing the understanding of IDCS pathogenesis.

Expression of enhancer of zeste homolog 2 (EZH2) protein in histiocytic and dendritic cell neoplasms with evidence for p-ERK1/2-related, but not MYC- or p-STAT3-related cell signaling.

EZH2 is an important enzymatic subunit of the epigenetic regulator polycomb repressive complex 2 (PRC2), which controls gene silencing through post-translational modification, and is overexpressed in various carcinomas and hematopoietic neoplasms. We found that the majority of cases of histiocytic and dendritic cell neoplasms, including histiocytic sarcoma, follicular dendritic cell sarcoma, Langerhans cell histiocytosis, and interdigitating dendritic cell sarcoma, show strong EZH2 expression by immunohistochemical staining, in contrast to benign histiocytic lesions and normal cellular counterparts, which did not show EZH2 expression, suggesting that this molecule may function as an oncogenic protein in these neoplasms. We correlated EZH2 expression with that of p-ERK1/2, MYC, and p-STAT3, potential regulators of EZH2, and found that 60-80% of these cases showed strong p-ERK1/2 expression, and only a minority of cases showed positivity for MYC or p-STAT3 in neoplastic cells. In cases of follicular dendritic cell sarcoma, Langerhans cell histiocytosis, histiocytic sarcoma, and interdigitating dendritic cell sarcoma with strong EZH2 expression, 90%, 89%, 70%, and 100% of cases showed co-expression of p-ERK1/2 with EZH2, respectively, while only a small percentage of these cases showed MYC or p-STAT3 co-expression with EZH2 (≤30%). These findings suggest that the p-ERK1/2 signaling cascade, but not the p-STAT3 and MYC signaling cascades, may regulate EZH2 expression in histiocytic and dendritic cell neoplasms, and that EZH2 and the p-ERK1/2 signaling cascade could serve as therapeutic targets for the treatment of these neoplasms. Interestingly, only a minority of cases of blastic plasmacytoid dendritic cell neoplasm exhibited high EZH2 expression, and only a minority of these cases showed p-ERK1/2 co-expression, suggesting that alternative mechanisms may contribute to tumorigenesis in this aggressive neoplasm.