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.

Histiocytic sarcoma following CAR T-cell therapy: a case report.

BACKGROUND: Development of secondary tumor after CART treatment is not well investigated. We report a pediatric B-cell acute lymphoblastic leukemia (B-ALL) patient who developed histiocytic sarcoma shortly after CART therapy. CASE REPORT: A 9-year-old boy diagnosed with relapsed B-ALL presenting the KRAS A146T mutation received autologous mouse-derived CD19 and CD22 chimeric antigen receptor T-cell therapy at our center (Chinese Clinical Trial Registry: ChiCTR2000032211). Thirty days post-CART therapy, the bone marrow showed complete remission. At 85 days post-CART therapy, the boy presented with fever and chills. An abdominal CT scan showed massive hepatomegaly with multiple low-density lesions in the liver. At 130 days post-CART therapy, a bone marrow smear showed abnormal proliferation of macrophages, some of which exhibited phagocytosis. On day 136 post-CART therapy, laparoscopic liver biopsy was performed, revealing multiple yellow-white lesions on the surface of the liver. Microscopically, multifocal lesions were observed, predominantly composed of cells with abundant cytoplasm. Immunohistochemical staining indicated histiocytic origin. Based on the immunohistochemical results, histiocytic sarcoma was diagnosed. The same cytogenetic markers were identified in histiocytic sarcoma. CONCLUSION: Our case illustrates a rare complication after CART therapy. The diagnosis and treatment of histiocytic sarcoma pose many challenges.

Multimodal Management With Immunotherapy, Radiation, and Surgery of Histiocytic Sarcoma Following Acute Lymphoblastic Leukemia: An Unusual Presentation of a Rare Disease.

Histiocytic sarcoma (HS) is a rare neoplasm with no known cause. This sarcoma is characterized by morphology similar to that demonstrated by mature tissue histiocytes and mostly afflicts adults. HSs typically have a poor prognosis due to a rapidly progressive clinical course. Our patient's case was unique due to its presentation four years after completion of treatment for B-cell acute lymphoblastic leukemia. The patient experienced progression with initial therapy for HS. With dual immunotherapy and radiation, however, the patient has remained clinically stable without detectable disease. Immunotherapy may be a successful and tolerable therapeutic option for histiocytic disease.

A chronic eyelid lesion in a child: multi-disciplinary approach to diagnosis, treatment and management of a highly atypical histiocytic lesion.

Malignant histiocytic neoplasm with histiocytic sarcoma phenotype is a rare malignant neoplasm, distinguished by malignant cells with phenotypic characteristics of mature tissue histiocytes. Histiocytic sarcoma typically presents as a primary malignancy, although can also present as a secondary malignancy, and is rarely seen in the pediatric population. Due to the rarity of this condition, diagnosis of histiocytic sarcoma is difficult and considered a diagnosis of exclusion. We describe a unique case of a chronic upper eyelid lesion with biopsy findings of a highly atypical histiocytic neoplasm initially concerning for histiocytic sarcoma; however, after integration of clinical findings, non-progressive and quiescent molecular profile, concluded to be an atypical juvenile xanthogranuloma in a child treated with excision and observation alone. This report highlights the importance of an integrated team approach to diagnosis of unusual histiocytic neoplasms.

Distribution of histopathologic types of primary pulmonary neoplasia in dogs and outcome of affected dogs: 340 cases (2010-2019).

OBJECTIVE: To provide updated information on the distribution of histopathologic types of primary pulmonary neoplasia in dogs and evaluate the effect of postoperative adjuvant chemotherapy in dogs with pulmonary carcinoma. ANIMALS: 340 dogs. PROCEDURES: Medical records of dogs that underwent lung lobectomy for removal of a primary pulmonary mass were reviewed, and histopathologic type of lesions was determined. The canine lung carcinoma stage classification system was used to determine clinical stage for dogs with pulmonary carcinoma. RESULTS: Pulmonary carcinoma was the most frequently encountered tumor type (296/340 [87.1%]), followed by sarcoma (26 [7.6%]), adenoma (11 [3.2%]), and pulmonary neuroendocrine tumor (5 [1.5%]); there was also 1 plasmacytoma and 1 carcinosarcoma. Twenty (5.9%) sarcomas were classified as primary pulmonary histiocytic sarcoma. There was a significant difference in median survival time between dogs with pulmonary carcinomas (399 days), dogs with histiocytic sarcomas (300 days), and dogs with neuroendocrine tumors (498 days). When dogs with pulmonary carcinomas were grouped on the basis of clinical stage, there were no significant differences in median survival time between dogs that did and did not receive adjuvant chemotherapy. CLINICAL RELEVANCE: Results indicated that pulmonary carcinoma is the most common cause of primary pulmonary neoplasia in dogs; however, nonepithelial tumors can occur. Survival times were significantly different between dogs with pulmonary carcinoma, histiocytic sarcoma, and neuroendocrine tumor, emphasizing the importance of recognizing the relative incidence of these various histologic diagnoses. The therapeutic effect of adjuvant chemotherapy in dogs with pulmonary carcinoma remains unclear and warrants further investigation.

Histiocytic and follicular dendritic cell sarcoma: Diagnostically challenging rare entities.

BACKGROUND: Follicular dendritic cell sarcomas (FDCSs) and histiocytic sarcomas (HSs) are exceedingly rare tumors. Most of the data on those entities are based on case reports or small case series. The natural history and response to different treatment modalities have not been well established. AIMS: To analyze the clinicopathologic features, immunophenotypic profile, treatment responses and to add to the existing data on FDCS and HS. STUDY DESIGN: Retrospective descriptive study. MATERIALS AND METHOD: The study was conducted at the department of Oncopathology at a tertiary care cancer hospital in India, retrospectively within the time period of four years (2016-2019). Total eight (8) cases were diagnosed: four cases of FDCS and four cases of HS involving nodal and extra-nodal sites. Clinical, histopathological, immunohistochemistry (IHC) and therapeutic data of the eight cases were retrieved and analyzed. STATISTICS: Descriptive statistics. RESULT: Among the four patients of FDCS, two had nodal and two had extra-nodal disease. Mean tumor size was 6 cm. Tumor cells expressed CD23, CD21, CD45, CD68 and S100. One patient received adjuvant chemotherapy (Gemcitabine and Docetaxel). Median survival was 36 months. None of them developed distant metastasis. Two of the patients having HS, developed bone metastasis. Median survival was 8.5 months. CD68 was consistently expressed in all cases of HS. Other applied IHC markers were negative in all the eight cases. CONCLUSION: FDCS and HS are under-recognized and easily prone to a wrong diagnosis. Therefore, considering these rare entities in differential diagnoses and inclusion of proper IHC biomarkers are necessary to avoid potential misdiagnosis.

Histiocytic Sarcoma Arising From a Long Bone: Report of Two Cases.

Histiocytic sarcoma is a rare, but aggressive malignant neoplasm of monocyte/macrophage lineage with a wide age distribution. Bone involvement is exceedingly rarer compared to the lymph node, skin, and soft tissue, and no long bone involvement has been reported in the English literature. We here report 2 cases of histiocytic sarcoma involving the long bone: one from the femur of a 77-year-old female, status post the placement of an intramedullary nail for subtrochanteric hip fracture; the other from the radius of a 3-year-old female with no significant medical history. Radiologic imaging showed highly destructive lesions in both cases with soft-tissue extension. Microscopy in both cases showed sheets of polygonal mononuclear cells with abundant eosinophilic cytoplasm, prominent nucleoli, and frequent mitosis. Hemophagocytosis were also identified. Immunohistochemistry showed that the lesional cells were strongly diffusely positive for CD68 and CD163. The first patient deteriorated rapidly, despite the aggressive treatment of amputation and chemotherapy. However, the second patient is disease free 36 months post the treatment of amputation only. We conclude that the long bone could be the primary site of histiocytic sarcoma. Its prognosis could be very variable and it is difficult to predict its behavior based on morphological evaluation only.

Successful Treatment of Incidental Histiocytic Sarcoma Concomitant with Laryngeal Carcinoma.

Histiocytic sarcoma (HS) is an extremely rare non-Langerhans cell disorder with an aggressive course and limited treatment options. HS most often presents at an advanced clinical stage, with a limited response to chemotherapy and high mortality. No standard treatment has been established for HS. We herein describe the first case of HS concomitant with laryngeal carcinoma that was promptly diagnosed and successfully treated; the condition of the patient has remained stable for 4 years with no recurrence.

Spectrum of histiocytic neoplasms associated with diverse haematological malignancies bearing the same oncogenic mutation.

Histiocytic disorders are a spectrum of rare diseases characterised by the accumulation of macrophage-, dendritic cell-, or monocyte-differentiated cells in various tissues and organs. The discovery of recurrent genetic alterations in many of these histiocytoses has led to their recognition as clonal neoplastic diseases. Moreover, the identification of the same somatic mutation in histiocytic lesions and peripheral blood and/or bone marrow cells from histiocytosis patients has provided evidence for systemic histiocytic neoplasms to originate from haematopoietic stem/progenitor cells (HSPCs). Here, we investigated associations between histiocytic disorders and additional haematological malignancies bearing the same genetic alteration(s) using the nationwide Dutch Pathology Registry. By searching on pathologist-assigned diagnostic terms for the various histiocytic disorders, we identified 4602 patients with a putative histopathological diagnosis of a histiocytic disorder between 1971 and 2019. Histiocytosis-affected tissue samples of 187 patients had been analysed for genetic alterations as part of routine molecular diagnostics, including from nine patients with an additional haematological malignancy. Among these patients, we discovered three cases with different histiocytic neoplasms and additional haematological malignancies bearing identical oncogenic mutations, including one patient with concomitant KRAS p.A59E mutated histiocytic sarcoma and chronic myelomonocytic leukaemia (CMML), one patient with synchronous NRAS p.G12V mutated indeterminate cell histiocytosis and CMML, and one patient with subsequent NRAS p.Q61R mutated Erdheim-Chester disease and acute myeloid leukaemia. These cases support the existence of a common haematopoietic cell-of-origin in at least a proportion of patients with a histiocytic neoplasm and additional haematological malignancy. In addition, they suggest that driver mutations in particular genes (e.g. N/KRAS) may specifically predispose to the development of an additional clonally related haematological malignancy or secondary histiocytic neoplasm. Finally, the putative existence of derailed multipotent HSPCs in these patients emphasises the importance of adequate (bone marrow) staging, molecular analysis and long-term follow-up of all histiocytosis patients.

Histiocytic Sarcoma

BACKGROUND: Histiocytic sarcoma (HS) is a rare hematopoietic malignancy originating from the monocyte/macrophage bone marrow lineage. HS can occur in isolation or in association with other hematological neoplasms such as non-Hodgkin lymphoma (NHL), myelodysplasia, or acute leukemia. Clinically, HS can affect lymph nodes, gastrointestinal tract, skin, bone marrow, and spleen as well as the central nervous system. Most cases of HS follow an aggressive clinical course, with most patients dying of progressive disease within one year of diagnosis.

A metastatic histiocytic sarcoma case with primary involvement of the tonsil.

Histiocytic sarcoma (HS) is an extremely rare and aggressive hematopoietic tumor. Although it can be seen at any anatomic location, the most common primary sites are skin as extranodal region, locations including the lymph nodes and gastrointestinal tract. To the best of our knowledge, in light of PubMed search, this is the first primary tonsillar HS case presented with disseminated metastases at the time of diagnosis. A 58-year-old male patient applied with swelling on the right side of the neck, difficulty in swallowing, and weight loss. Positron emission tomography computed tomography was performed and increased pathological 18F fluorodeoxy D glucose uptake was detected in the right palatine tonsil, bilateral cervical multiple lymph nodes, liver masses, intra abdominal lymph nodes, and nodular lesion in the left adrenal gland. Tonsillectomy was performed and the pathological result was reported as HS. The patient did not respond to any treatment and had died after 5 months from the date of diagnosis. In conclusion, HS is generally diagnosed at advanced stage, it has limited chemotherapy response and high mortality rates. To understand this rare disease's pathophysiological and clinical features, further investigations are needed.

Histiocytic Sarcoma and Hemangiosarcoma Update.

Histiocytic sarcoma (HS) and hemangiosarcoma (HSA) are uncommon and aggressive neoplasms that develop much more frequently in dogs than in cats. Breed-specific predispositions have been identified for both cancers. The development of novel diagnostics is underway and may aid in earlier diagnosis. Therapeutic approaches to HS and HSA depend on the stage of disease and may include surgery, radiation therapy, and chemotherapy. Such interventions improve outcome; however, aside from a small number of clinical circumstances, both diseases are considered largely incurable. Continued efforts toward the identification of driver mutations and subsequent druggable targets may lead to improvements in long-term prognosis.

A Rare Case of Primary Histiocytic Sarcoma of the Stomach.

Histiocytic sarcoma is a rare lymphohematopoietic malignancy with aggressive clinical course and poor therapy response. The diagnosis relies on the confirmation of its histiocytic lineage and exclusion of other poorly differentiated tumors. Most of the cases present in extranodal sites, but primary gastric involvement is exceptional. We report a case of a 69-year-old woman with epigastric pain and systemic symptoms. Gastroscopy findings and biopsy report suggested a malignant neoplasm. The patient underwent distal subtotal gastrectomy with a 6-cm tumor in the body and antrum of the stomach and ten associated enlarged perigastric lymph nodes. Microscopically they were infiltrated with atypical tumor cells and immunohistochemical staining was positive for CD68, lysozyme, CD45, and CD4; 45% of the cells stained for Ki-67. The pathologic diagnosis was histiocytic sarcoma. CT body scans showed only enlarged retroperitoneal and abdominal lymph nodes. The patient received six cycles of CHOEP chemotherapy with complete therapeutic response, but three months later she experienced an aggressive systemic sarcoma recurrence and although salvage chemotherapy was initiated she died of progressive disease. The presented case widens the differential diagnosis of gastric malignancies, and emphasizes the significance of immunohistochemical examination for histiocytic sarcoma diagnosis. The collection and evaluation of cases of gastric histiocytic sarcoma are important to obtain further progress in prognosis and treatment.

Primary pulmonary histiocytic sarcoma in dogs: A retrospective analysis of 37 cases (2000-2015).

Primary pulmonary histiocytic sarcoma (PHS) has been reported, but is not well characterized. The aim of this retrospective study was to describe clinical characteristics, characterize prognostic factors and report the outcome of a larger group of dogs with primary PHS. Medical records of dogs diagnosed with primary PHS at 11 institutions were retrospectively reviewed. Thirty-seven dogs were included; 13 received CCNU-based chemotherapy alone, 18 received surgery and adjuvant CCNU-based chemotherapy, 3 received medical management alone and 3 dogs received surgery alone. The overall median progression free survival (PFS) and the median survival (overall survival [OS]) were 197 and 237 days, respectively. Measurable responses were noted in dogs receiving only chemotherapy; however, responses were not durable with PFS (91 days) and OS times (131 days) shorter than overall medians. Dogs that received surgery and chemotherapy had significantly prolonged PFS (276 days, P = 0.001) and OS (374 days, P = 0.001), compared with dogs not receiving surgery. As only three dogs undergoing surgery did not receive chemotherapy, it is not possible to determine the contribution of chemotherapy as an adjuvant to surgery. Dogs without evidence of intra-thoracic metastatic disease were much more likely to undergo surgery (odds ratio = 7.04; P = 0.018). While the presence of metastasis or clinical signs at diagnosis negatively impacted PFS, only the former negatively impacted OS. These data imply that dogs presenting with PHS amenable to surgery (ie, no clinical evidence of metastasis) benefit from surgical intervention; however, the lack of a comparable surgery alone group precludes assessment of the efficacy of post-surgical adjuvant chemotherapy.

Primary histiocytic sarcoma of the central nervous system: a case report with platelet derived growth factor receptor mutation and PD-L1/PD-L2 expression and literature review.

BACKGROUND: Histiocytic sarcoma (HS) is an aggressive malignant neoplasm. HS in the central nervous system is exceptionally rare and associated with a poor prognosis. This report documents a case of primary HS of the central nervous system with treatment including surgery, radiotherapy, and chemotherapy. CASE PRESENTATION: Our patient was a 47 year old female presenting with progressive ataxia, headaches, imbalance, nausea, vomiting, and diplopia. MRI showed a heterogeneously enhancing lesion approximately 2.9 × 3.0 × 2.3 cm centered upon the cerebellar vermis with mild surrounding vasogenic edema and abnormal enhancement of multiple cranial nerves. The patient underwent surgical debulking, which revealed histiocytic sarcoma with grossly purulent drainage. Staging revealed diffuse leptomeningeal involvement, primarily involving the brain and lower thoracic and lumbar spine. She underwent adjuvant radiotherapy to the brain and lower spine and was started on high dose methotrexate. However, she experienced progressive disease in the cervical and thoracic spine as well as pulmonary involvement. Genomic sequencing of her tumor showed a mutation in the platelet-derived growth factor receptor A (p.V0681) which could be targeted with Dasatinib. However, she did not tolerate Dasatinib and she succumbed to progressive disseminated disease eight months from original diagnosis. Our pathologic evaluation also revealed expression of PD-L1 and PD-L2 by tumor cells raising the potential therapeutic role for immune checkpoint inhibition. CONCLUSIONS: This case provides an example of effective CNS control with resection and moderate doses of radiation therapy. A review of the literature confirms aggressive multidisciplinary treatment is the most effective treatment against this disease. In addition, genomic sequencing may play an important role in determining new therapeutic options. However, CNS histiocytic sarcoma remains an aggressive disease with a propensity for early widespread dissemination and few long term survivors.

Clinicopathologic Features and Clinical Outcome Differences in De Novo Versus Secondary Histiocytic Sarcomas: A Multi-institutional Experience and Review of the Literature.

INTRODUCTION: Histiocytic sarcoma (HS) is a rare malignant neoplasm that can occur in patients with a history of treatment for hematologic or solid tumors. Because no optimal treatment has been defined and standardized, the treatment modalities used and outcomes reported have been highly variable. In the present study, 3 major institutions explored the clinicopathologic features of de novo and secondary HS. MATERIALS AND METHODS: After institutional review board approval, clinical, histopathologic, and immunophenotypic data were collected from patients with a diagnosis of HS and treated at the University of Alabama at Birmingham, University of New Mexico, or Brooke Army Medical Center from January 1, 2003 to December 31, 2016. RESULTS: The databases revealed 23 unique cases of HS. The mean age was 55.4 years (range, 5-84 years) and the male-to-female ratio was 0.92. The mean follow-up period was 89.82 months (range, 14-172 months). Of the 23 patients with HS, 6 had a history of an unrelated malignancy treated with chemotherapy or radiotherapy, with a mean delay of 42.2 months (range, 12-91 months). The mean overall survival during the study period was 54.1 months. The overall survival of those with de novo HS was 70 months compared with 11.8 months for those with secondary HS, with a mean difference of 58.2 months (95% confidence interval, 26.2-90.2 months; P = .001). CONCLUSION: The shorter overall survival with secondary HS suggests a more aggressive course than that with de novo disease. Larger scale studies are needed to further investigate the biology and genetics of HS.

Primary central nervous system histiocytic sarcoma: A case report and review of literature.

RATIONALE: Primary central nervous system histiocytic sarcoma (PCNSHS) is a rare lymphohematopoietic tumor with a histiocytic cell origin. To our knowledge, only 28 cases have been published in English and 2 cases in Chinese. PATIENT CONCERNS: A 49-year-old Asian female presented to the hospital with a 2 month history of hypomnesia, odynophagia, and gait disorder. Physical examination demonstrated decreased lower extremity muscle strength. The patient denied a history of malignancy. DIAGNOSES: Radiology demonstrated a lesion in parietal lobe with uniformenhancement. Histologic analysis showed pleomorphic tumor cells with a loose arrangement, effacing the normal brain tissue. The tumor cells exhibited abundant eosinophilic cytoplasm, highly atypical nuclei and predominant nucleoli. Immunohistochemistry revealed positive immunoreactivity for CD45, lysozyme, CD68, and CD163, and negative for pan-cytokeratin (CK), epithelial membrane antigen (EMA), glial fibrillary acidic protein (GFAP), CD3, CD20, CD1a, CD79a, CD138, oligodendrocyte transcription factor (olig2), CD15, melan-A, CD30, CD21, CD35, Human Melanoma Black-45 (HMB45), and anaplastic lymphoma kinase-1 (ALK-1). The diagnosis of PCNSHS was rendered. INTERVENTIONS: The patient underwent complete surgical resection and adjuvant radiotherapy. OUTCOMES: Follow-up information shows the patient died 8 months following the initial diagnosis. LESSONS: PCNSHS is extremely rare with an aggressive clinical course. Immunohistiochemistry is necessary to make this diagnosis and to exclude other primary intracranial and lymphohematopoietic tumors. Further research is required to improve the outcome of patients with PCNSHS.