[Histiocytic sarcoma derived from the same origin as splenic marginal zone lymphoma revealed by exome analysis].

Histiocytic sarcoma (HS) is a rare aggressive hematological malignancy reported to occur secondary to B cell lymphoma. We report a case of HS secondary to splenic marginal zone lymphoma (SMZL) complicated by autoimmune hemolytic anemia (AIHA) in a 64-year-old man. He was referred to our department with anemia and was diagnosed as having AIHA. After starting treatment with prednisolone, atypical lymphocytes appeared in his blood tests, and a bone marrow biopsy revealed invasion by B cell lymphoma. A CT scan showed splenomegaly and a pancreatic mass, which confirmed the diagnosis of SMZL. The patient received bendamustine and rituximab as chemotherapy, which rapidly improved the anemia and splenomegaly and reduced atypical lymphocytes. However, left lumbar back pain appeared along with an increase in the pancreatic mass, and he died suddenly of acute renal failure. An autopsy revealed that the tumor had invaded several organs including the pancreas, and immunohistochemistry was positive for CD163, leading to the diagnosis of HS. Furthermore, the specimens of SMZL and HS were positive for IgH gene reconstitution, and exome analysis showed genetic abnormalities in 226 genes including CARD11, suggesting that the SMZL and HS had the same origin.

Histiocytic neoplasms: a brief review and differential diagnosis.

Histiocytic neoplasms (HNs) include juvenile xanthogranuloma, Erdheim-Chester disease, Rosai-Dorfman disease, ALK-positive histiocytosis, and histiocytic sarcoma in the 5th edition of the World Health Organization Classification of Haematolymphoid Tumours. These entities are clinicopathologically distinctive, and typical histological findings have been established. However, the common feature of a proliferation of histiocytic cells often leads to morphological overlap among HNs, and also necessitates a differential diagnosis from several non-HNs or non-neoplastic conditions. In this review, we provide a brief summary of the clinical findings, molecular features, histopathologies, and immunophenotypes of HNs, as well as to discuss their differential diagnosis.

Pembrolizumab Combined With GDP Regimen Inducing Sustained Remission in Histiocytic Sarcoma: A Case Report.

Histiocytic sarcoma (HS) is a rare hematopoietic neoplasm with an aggressive clinical course and a poor response to conventional chemotherapy. Currently, no standard treatment paradigms are available. Herein, we present a case of de novo HS treated with pembrolizumab combined with a GDP regimen (gemcitabine, cisplatin, and dexamethasone) that resulted in sustained complete remission with progression-free survival exceeding 4 years. Immunohistochemical analysis demonstrated significant overexpression of programmed death ligand 1 (PD-L1) on biopsy samples. Additionally, fluorescence in situ hybridization (FISH) with a JAK-2 probe indicated 9p24.1 amplification, suggesting reliance on the JAK-STAT pathway. Polymerase chain reaction (PCR) analysis did not reveal any BRAF-V600 mutations. Consequently, an immune checkpoint inhibitor (ICI) was administered alongside chemotherapy, resulting in sustained complete remission and progression-free survival for over 4 years. Our findings suggest that a combination of ICI and chemotherapy could represent a promising therapeutic approach for HS.

Canine Histiocytic and Hemophagocytic Histiocytic Sarcomas Display KRAS and Extensive PTPN11/SHP2 Mutations and Respond In Vitro to MEK Inhibition by Cobimetinib.

Histiocytic sarcoma (HS) is a rare and highly aggressive cancer in humans and dogs. In dogs, it has a high prevalence in certain breeds, such as Bernese mountain dogs (BMDs) and flat-coated retrievers. Hemophagocytic histiocytic sarcoma (HHS) is a unique form of HS that presents with erythrophagocytosis. Due to its rareness, the study of HHS is very limited, and mutations in canine HHS patients have not been studied to date. In previous work, our research group identified two major PTPN11/SHP2 driver mutations, E76K and G503V, in HS in dogs. Here, we report additional mutations located in exon 3 of PTPN11/SHP2 in both HS and HHS cases, further supporting that this area is a mutational hotspot in dogs and that mutations in tumors and liquid biopsies should be evaluated utilizing comprehensive methods such as Sanger and NextGen sequencing. The overall prevalence of PTPN11/SHP2 mutations was 55.8% in HS and 46.2% in HHS. In addition, we identified mutations in KRAS, in about 3% of HS and 4% of HHS cases. These findings point to the shared molecular pathology of activation of the MAPK pathway in HS and HHS cases. We evaluated the efficacy of the highly specific MEK inhibitor, cobimetinib, in canine HS and HHS cell lines. We found that the IC50 values ranged from 74 to 372 nM, which are within the achievable and tolerable ranges for cobimetinib. This finding positions cobimetinib as a promising potential candidate for future canine clinical trials and enhances our understanding of the molecular defects in these challenging cancers.

Pathological features of intrathoracic histiocytic sarcoma in an Amami spiny rat (Tokudaia osimensis).

A 4-year 9-month-old Amami spiny rat reared in a zoo died following a history of anorexia, weight loss, and respiratory distress. At necropsy, neoplastic tissues were found along the pleura and adhered to the thoracic wall, heart, and lungs. Histologically, the tumor was composed of diffuse, patternless sheets of large round to polygonal neoplastic cells with abundant eosinophilic cytoplasm, and multinucleated giant cells were often present. Metastatic lesions were observed in the abdominal lymph nodes. Neoplastic cells were immunopositive for vimentin, Iba-1, and CD204, and negative for E-cadherin and S100. Based on these findings, the tumor was diagnosed as histiocytic sarcoma. Compression of the lungs by the tumor may have caused respiratory failure and led to death.

Histiocytic sarcoma affecting the oral cavity: a clinical, pathologic and molecular study.

OBJECTIVE: To investigate the clinicopathological, immunohistochemical and molecular features of histiocytic sarcomas affecting the oral cavity. METHODS: Pathology files of two institutions were searched for cases of histiocytic sarcoma, and new H&E-stained slides and immunohistochemistry reactions evaluated for diagnosis confirmation. Molecular screening for KRAS and PIK3CA mutations was performed through polymerase chain reaction (PCR) followed by Sanger sequencing. BRAFp.V600E mutation was assessed by pyrosequencing. Clinical data regarding sex, age, tumor location, systemic manifestations, clinical presentation, follow-up time, treatment applied and status at last follow-up were collected from patients' pathology and medical files. RESULTS: Three cases were retrieved during the period investigated (2000-2023). Two females and one male were affected, with a wide age range, involving the tongue, palate and gingiva. Histopathologically, the neoplasms presented as highly pleomorphic atypical cells distributed diffusely with infiltration of normal structures. All cases demonstrated histiocytic differentiation expressing CD68 and CD163, and a high Ki67 expression. Genetic mutations were evaluated in two cases. One case harboured BRAF-V600E mutation, but not in KRAS and PIK3CA, while the second case did not show mutation in BRAF-V600E, KRAS and PI3KCA. One patient was lost, and two patients died after eight and four months of follow-up. CONCLUSION: Histiocytic sarcomas involving the oral cavity are extremely rare, and may represent dissemination of a systemic condition. It has an aggressive biological behaviour with a poor overall prognosis.

Long-Term Remission with Novel Combined Immune-Targeted Treatment for Histiocytic Sarcoma Accompanied by Follicular Lymphoma: Case Report and Literature Review.

Histiocytic sarcoma (HS) is an extremely rare but aggressive hematopoietic malignancy, and the prognosis has been reported to be rather unfavorable with a median overall survival of merely 6 months. We presented a 58-year-old female patient complaining of abdominal pain and fever, who was admitted to our institution in September 2021. Fluorine-18-fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET/CT) scan showed enlargement of generalized multiple lymph nodes. Subsequently, laparoscopic retroperitoneal lesion biopsy and bone marrow aspiration were performed. The pathological findings indicated the diagnosis of HS concurrent with follicular lymphoma. The immunohistochemistry (IHC) staining of the tumor lesion revealed a high expression of CD38 and PD-L1 proteins. Furthermore, KRAS gene mutation was identified by means of next-generation sequencing. The patient exhibited poor treatment response to both first- and second-line cytotoxic chemotherapies. Therefore, she underwent six cycles of Daratumumab (anti-CD38 monoclonal antibody), Pazopanib (multi-target receptor tyrosine kinases inhibitor) combined with third-line chemotherapy, followed by involved-site radiotherapy and maintenance therapy with the PD-1 inhibitor Tislelizumab. Long-term partial remission was finally achieved after multi-modality treatment. Duration of remission and overall survival reached 22 and 32 months, respectively. Our case indicated that immuno-targeted treatment coupled with chemotherapy and radiotherapy might constitute a potential therapeutic option for HS.

It's not always histiocytic sarcoma: Immunocytochemistry to identify two unusual tumors in a Bernese Mountain dog.

A 7-year-old female spayed Bernese Mountain dog was presented for evaluation of hematuria. Incidentally, a right stifle sarcoma was diagnosed via cytology, which raised concern for histiocytic sarcoma (given the patient's signalment) versus another joint-associated sarcoma. Histopathology and immunohistochemistry revealed a CD18-negative, non-histiocytic origin cell population. Findings were consistent with a joint-associated grade II soft tissue sarcoma (STS). The patient's hematuria was progressive over 5 months, and urinary bladder transitional cell carcinoma (TCC) was diagnosed via cystoscopy and histopathology. An enlarged right medial iliac lymph node was identified on routine restaging via abdominal ultrasound 3 months later. Cytology of the lymph node revealed a markedly pleomorphic cell population, again raising concern for histiocytic sarcoma (HS). Other differentials included an anaplastic metastatic population from the joint-associated STS or the TCC. Immunocytochemistry revealed a cytokeratin-positive, CD18-, CD204-, and vimentin-negative cell population, consistent with a carcinoma. DNA was extracted from cytology slides to sequence cells for BRAF mutation status. Sequencing revealed a homozygous V596E (transcript ENSCAFT00845055173.1) BRAF mutation, consistent with the known biology of TCC. In neither case was HS truly present in this patient, but immunocytochemistry provided information that helped to optimize the patient's chemotherapy recommendations.

NF1 mutation and TUBB3 amplification in gastric histiocytic sarcoma: a case report and literature review.

Histiocytic sarcoma is a rare neoplasm of mature histiocytes with an aggressive clinical course and poor response to treatment. Primary gastric histiocytic sarcoma is rarer and just reported sporadically.Histiocytic sarcoma is a rare neoplasm of mature histiocytes with an aggressive clinical course and poor response to treatment. Primary gastric histiocytic sarcoma is rarer and just reported sporadically. A case of a 71-year-old female admitted with a one-year history of upper abdominal pain exacerbated after meals. After CT scans revealed a bulged mass at the lesser curvature of the gastric body, the patient underwent endoscopic submucosal dissection. Microscopically, non-cohesive neoplastic cells diffusely infiltrated lamina propria and submucosa, and diffusely expressed LCA, CD4, CD163, CD68 (KP1), Cyclin D1, Lysozyme, and Vimentin. PD-L1 (22CS) expression evaluated as CPS 60. The final pathological diagnosis was gastric histiocytic sarcoma. Subsequently, next-generation sequencing identified a nonsense mutation in exon 21 of NF1 gene [c.2446C > T (p.R816*)] and the TUBB3 gene amplification (copy number: 4.55). The patient refused further treatment and died of the tumor half a year later. This case broadens the spectrum of differential diagnosis of gastric cancer and emphasizes the value of immunohistochemical and molecular tests in the accurate diagnosis of histiocytic sarcoma. Furthermore, we performed literature review of 11 cases of gastric histiocytic sarcoma so as to strengthen the understanding of the clinicopathologic features, treatment, and prognosis.

Composite Histiocytic Sarcoma and Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma of the Ocular Adnexa.

Histiocytic sarcoma (HS) is a rare and aggressive hematologic neoplasm characterized by the proliferation of malignant histiocytes. It infrequently presents with periorbital involvement. Here we present the first documented case of ocular adnexal histiocytic sarcoma composite with chronic lymphocytic leukemia/small lymphocytic lymphoma and provide compelling evidence for the transdifferentiation of chronic lymphocytic leukemia/small lymphocytic lymphoma to histiocytic sarcoma in an 80-year-old woman. Comprehending the clinicopathological characteristics of histiocytic sarcoma and various other histiocytic proliferations and neoplasms affecting orbital and ocular structures is imperative for ophthalmic surgeons and pathologists.

Anaplastic large cell lymphoma with ALK::ATIC fusion mimicking a histiocytic sarcoma debuting as an anterior thoracic soft tissue tumor with exceptional clinicopathological, morphological and molecular features.

A 56-year-old woman debuted with a palpable painless mass in the anterior thorax wall at the level of the second and third right parasternal intercostal space, which progressively increased in size over 5 months accompanied by localized skin rash, mild dyspnea and chest pain when changing position. Imaging studies showed a soft tissue mass measuring 75 × 62 mm and a density of 34 Hounsfield Units that had caused the lysis of the costal arches and grew expansively towards the anterior mediastinum, without identifying mediastinal adenopathies only by this imaging method. Core biopsy was performed, which was initially diagnosed as histiocytic sarcoma (HS); however, when the diagnostic panel was expanded to include molecular and NGS studies, the final diagnosis was anaplastic large cell lymphoma with ALK::ATIC fusion. Here, we report a very rare neoplasm with unusual clinical presentation, histopathology and molecular features.

Disseminated histiocytic sarcoma in a degu (Octodon degus).

A 7-year-and-8-month-old, male degu (Octodon degus) with anorexia, depression, and labored breathing was found to have a thoracic effusion and enlargement of the right testis on radiographic examination. Despite treatment, the animal died. At necropsy, hepatomegaly, splenomegaly, and multifocal nodules on the intestinal serosa and mesentery were observed. Histologically, the foci were densely cellular invasive neoplasms composed of sheets of round to polygonal cells, with occasional multinucleated giant cells. Immunohistochemically, the neoplastic cells were immunopositive for ionized calcium-binding adapter molecule 1, human leukocyte antigen-DR, and CD204. These findings were consistent with disseminated histiocytic sarcoma.

First description of a primary esophageal histiocytic sarcoma in a dog.

An 11-year-old male Schnauzer dog was referred for investigation of cough and regurgitation of one month duration and gradual hyporexia for the previous five months. Complete blood count showed severe leukocytosis. On ventrodorsal and lateral thoracic radiographs a soft tissue mass was visible in the craniodorsal mediastinum. Endoscopy showed esophageal dilatation and an irregular, nodular, friable, exophytic mass in the thoracic esophagus, which was invasive, vascularized and had ulcerated areas. The mass occluded approximately 90% of the esophageal lumen. The mucosa in the orad portion of the thoracic esophagus was pale and the aborad portion was hyperemic (red) with hemorrhages. The mucosa of the cervical and abdominal esophagus was macroscopically unremarkeble. Multiple biopsies using endoscopic cup biopsy forceps were taken from the mass for histopathologic analysis and a percutaneous endoscopic gastrostomy was performed. Histopathologic analysis of the biopsy samples was inconclusive due to the marked necrosis. The poor clinical condition of the dog precluded a more invasive approach, and palliative and supportive treatment was continued. After 100 days of follow-up, clinical signs worsened, and that day the dog had a fatal cardiac arrest due to aspiration pneumonia and sepsis. Postmortem examination showed a multilobulated mass in the esophageal wall with infiltration into the overlying esophageal mucosa and pulmonary and renal metastases. Histological examination revealed a poorly differentiated sarcoma. On immunohistochemical examination, the neoplastic cells showed marked cytoplasmic staining for vimentin and Iba-1. The proliferative rate was approximately 30% by Ki-67. Histological and immunohistochemical examination revealed the esophageal mass to be a primary histiocytic sarcoma. Histiocytic sarcoma is an extremely rare primary esophageal neoplasm in humans, and so far, there is no description in dogs. To the best of the authors knowledge this is the first case of primary esophageal histiocytic sarcoma in dogs. The clinical information reported here should improve recognition and aid in diagnosis of future cases.

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.

Rosai Dorfman Disease with malignant transformation to Histiocytic Sarcoma: A diagnostic conundrum.

ABSTRACT: Histiocytic disorders mostly occur as de-novo nodal or extranodal benign masses with rare secondary malignant transformation. A 10-year-old female presented with 10-cm cervical swelling since 9 months associated with fever. Computed tomography revealed left cervical lymphadenopathy and bilateral lung nodules. Lymph node excision biopsy showed effacement of architecture by atypical histiocytes with marked nuclear pleomorphism and frequent mitosis. Focal areas showed mature histiocytes with emperipolesis. The cells were immunopositive for CD68, CD163, and S100 (focal), whereas they were negative for Langerin and CD1a. The Ki67 proliferative index was 30%. A diagnosis of histiocytic sarcoma in a background of Rosai-Dorfman disease was made.

Atypical disseminated histiocytic sarcoma in a 7-month-old dog.

A 7-month-old intact female bearded collie dog was admitted after a 2-week history of progressive cough, inappetence, and lethargy, with no response to previous treatment with doxycycline and steroids. Mild attenuation of lung sounds in the right middle hemithorax was the only abnormality detected on physical examination. Abdominal ultrasound and thoracic radiographs were performed and revealed multifocally distributed nodules and masses, well-circumscribed and of variable size in the kidneys and pulmonary parenchyma. Ultrasound-guided fine needle aspirates of the renal and pulmonary masses were taken. A cytologic evaluation of these lesions pointed towards a malignant mesenchymal neoplasia. Euthanasia was elected due to the poor prognosis and rapid progression. The post-mortem histopathology, a positive result to IBA1 immunoperoxidase staining, and a lack of detection of infectious agents, and negative E-cadherin immunostaining enabled the final diagnosis of a disseminated histiocytic sarcoma. We report an atypical form, both in breed and age, of canine disseminated histiocytic sarcoma. While all breeds can be affected, there is a clear predisposition in some, and no cases have been previously described in bearded collies. Moreover, to the authors' knowledge, this is the youngest dog with this histiocytic disorder described to date. Disseminated histiocytic sarcoma should be considered as a differential diagnosis of multinodular tumors in dogs, regardless of the anatomic location and age of the dogs, even in puppies.

A rare case of primary central nervous system histiocytic sarcoma harboring a novel ARHGAP45::BRAF fusion: a case report and literature review.

INTRODUCTION: Patients with histiocytic sarcoma occurring in the central nervous system (CNS) are rare and have a very poor prognosis. The increased use of molecular diagnostic approaches in solid tumors has brought more opportunities for the diagnosis and treatment of central nervous system histiocytic sarcoma (CNSHS). CASE DESCRIPTION: A 9-year-old girl was admitted to the hospital with pain in her head and neck, as well as vomiting. Imaging scans showed a prominent abnormality in the anterior falciform region, and histopathology revealed the presence of CD68 (+) and CD163 (+) cells, leading to a preliminary diagnosis of primary intracerebral CNSHS. Molecular profiling tests identified a new variant of ARHGAP45::BRAF fusion in this case, which has not been reported in any other tumor. The patient underwent surgical removal of the tumor and will require long-term monitoring. CONCLUSION: The presence of the BRAF point mutation, predominantly BRAF p.V600E, has been documented in prior literature of CNSHS. This is the first case of pediatric histiocytic sarcoma in the anterior falciform region who has a unique ARHGAP45::BRAF fusion. The findings of our study indicate that a broader range of molecular assays should be employed in the diagnosis of CNSHS and opens up new possibilities for the treatment of the patient.