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.

An advanced multisystem histiocytic sarcoma in a pregnant woman: A case report.

Histiocytic sarcoma is an extremely rare disease that's hard to diagnose and treat, often leading to a poor prognosis. Here, we present a case report detailing a rare occurrence of HS in a 37-year-old pregnant woman who first presented with left shoulder pain, palpitations, and a productive cough at 20 weeks of gestation. Her diagnostic evaluations were performed, including different imaging modalities such as chest X-rays, CT scans, and MRI. Imaging revealed a large mediastinal mass with extensive involvement of the adrenal glands, lungs, and lymph nodes. The definitive diagnosis of HS is based on pathological and morphological features, and the immunohistochemistry report plays a key role. In our case, the diagnosis of HS was confirmed through pathological evaluation and immunohistochemistry, with a positive CD68 result obtained from a supraclavicular lymph node biopsy. A hospital committee comprising medical specialists like hematologists-oncologists, pathologists, pulmonologists, and obstetricians was brought together to assess the case collectively. The patient received chemotherapy, which alleviated her symptoms and maintained her condition. Based on the committee's recommendations, despite a healthy fetus and normal obstetric sonograms, the decision was made to terminate the pregnancy with the consent of the patient and her family. Despite initial improvement postchemotherapy, the patient's condition worsened, necessitating intubation. Tragically, two months after the initial admission, the patient passed away due to severe complications. In this case report, we provide a literature review and review of the patient's imaging reports. Since the patient is pregnant and HS is uncommon, it's important to highlight that this case is unique and worth sharing.

Primary Histiocytic Sarcoma of the Breast: A Case Report and Review of the Literature.

Histiocytic sarcoma (HS) is a rare cancerous tumor that originates from fully developed histiocytes. It is most often identified by the presence of certain proteins such as the cluster of differentiation (CD) 68, CD163, or lysozyme. HS has been recorded in different sites outside of the lymph nodes such as the gastrointestinal tract, nasal cavities, skin, and bone marrow. Because HS shares similar clinical features with other forms of malignant diseases, diagnosing it becomes incredibly challenging. We report a case of a 40-year-old female who presented with a breast mass for one year. A preliminary diagnosis of a phyllodes tumor was made. However, the morphology along with the immunophenotype picture was diagnostic for HS. Microscopic features showed a well-defined neoplastic growth arranged in sheets and fascicles. Diffuse immunoreactivity was seen for CD45, CD4, CD68, CD163, and vimentin. We present the important histopathological and immunohistochemical characteristics of the tumor in this case.

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.

Population Pharmacokinetics, Pharmacodynamics and Safety Properties of Trametinib in Dogs With Cancer: A Phase I Dose Escalating Clinical Trial.

MAPK has been reported as a key oncogenic pathway for canine histiocytic sarcoma, which can be pharmacologically targeted with trametinib, a small inhibitor of MEK1/2. Preliminary data showed promising antitumor activity in in vitro and in vivo models and represented a proof of concept to translate the findings from bench to bedside. In this phase I, dose escalating study using a 3 + 3 cohort design, trametinib was evaluated in 18 dogs with cancer. Adverse events were graded according to VCOG-CTCAE v2. Blood samples and tumour biopsies were collected for pharmacokinetic and pharmacodynamic assessment. Trametinib was well tolerated with a maximum tolerated dose of 0.5 mg/m2/day, PO. Dose-limiting toxicities included systemic hypertension, proteinuria, lethargy and elevated ALP, and were all Grade 3. The drug exposures increased more than linearly with dose since the elimination of trametinib was saturable. At a dose of 500 µg Q24h (0.5 mg/m2/day in a 30 kg dog), approximately 70% of dogs had an average steady-state concentration of 10 ng/mL, achieved after approximately 2 weeks. This threshold was associated with clinical efficacy in humans. Target engagement was not observed in biospecimens collected on Days 0 and 7. In conclusion, trametinib was considered safe in dogs with cancer, and the dose of 0.5 mg/m2/day was the recommended dose for phase II studies.

Establishment of a histiocytic sarcoma cell line and anti-tumor effect of bortezomib in the African pygmy hedgehog (Atelerix albiventris).

The African pygmy hedgehog (Atelerix albiventris) is known to have a high incidence of tumor. However, investigating the tumors of this species has been constrained by the limited availability of research materials such as cell lines and genome information. In this study, we successfully established a novel cell line from a histiocytic sarcoma (HS) of an African pygmy hedgehog, allowing us to conduct a drug screening. We investigated using FDA-approved drug library screening to determine which anticancer drug this tumor cell line is sensitive to, and as a result of apoptosis experiments, bortezomib among the three proteasome inhibitors was found to induce cell death of cancer cells by significantly increasing caspase-3 cleavage (P<0.01). Thus, we elucidated that the proteasome inhibitors, particularly bortezomib, exhibit anti-tumor effects on a cell line derived from an HS in an African pygmy hedgehog through a mechanism comparable to that described in human tumors. This study reports the first characterized cell line from the African pygmy hedgehog and also highlights the potential utility of bortezomib as an anti-tumor treatment for HS in this species.

One Health: Therapies Targeting Genetic Variants in Human and Canine Histiocytic and Dendritic Cell Sarcomas.

The precise cause of HS/DCS is still unknown. The relatively low incidence in humans urges for an animal model with a high incidence to accelerate knowledge about genetics and optimal treatment of HS/DCS. Namely, until now, the therapies targeting genetic variants are still more experimental and sparsely used, while consensus is missing. In addition, the literature about variants and possible mutation-targeted therapies in humans and dogs consists mainly of case reports scattered throughout the literature. Therefore, an overview is provided of all currently known genetic variants in humans and dogs with HS/DCS and its subtypes, their possible mutation-targeted therapies, their efficacy, and a contemplation about the future. Several genetic variants have already been discovered in HS/DCS, of which many are shared between canine and human HS/DCS, but unique variants exist as well. Unfortunately, none of these already found variants seem to be specifically causal for HS/DCS, and the puzzle of its landscape of genetic variation is far from complete. The use of mutation-targeted therapies, including MAPK-/MEK-inhibitors and the future use of PTPN11-, CDK4/6- and PD-1-inhibitors, seems to be promising for these specific variants, but clearly, clinical trials are needed to determine optimal inhibitors and standardised protocols for all variants. It can be concluded that molecular analysis for variants and subsequent mutation-targeted therapy are an essential addition to cancer diagnostics and therapy. A joint effort of humans and dogs in research is urgently needed and will undoubtedly increase knowledge and survival of this devastating disease in dogs and humans.

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.

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.

Primary pulmonary histiocytic sarcoma with high PD-L1 expression benefited from immunotherapy: A case report and bioinformatic analysis.

Histiocytic sarcoma is an aggressive haematopoietic malignancy accounting for less than 1% of haematolymphoid neoplasms with a diagnosis based on morphology and immunophenotype of tissue biopsies with a very poor prognosis. Here, we report a 45-year-old man who was diagnosed with primary pulmonary histiocytic sarcoma with systemic metastases, with partial remission (PR) treated with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy, but it relapsed soon after therapy above. Tests demonstrated that TMB was 21 Muts/Mb PD-L1 expression was 90% positive, and the disease has been well-controlled over 3 years using immune checkpoint inhibitors (nivolumab and pembrolizumab). Bioinformatic pan-cancer analysis verified that there was the highest genetic alteration frequency of PD-L1 in which amplification accounted for the majority of sarcoma tumour samples. Following that, we found that the genetic alteration of PD-L1 was associated with poor prognosis in sarcoma patients in terms of overall survival (OS) (p = 1.51 × 10-4 ), progress-free survival (PFS) (p = 4.90 × 10-2 ) and disease-specific survival (DSS) (p = 4.90 × 10-2 ). To our knowledge, this may be the first reported case with high PD-L1 expression in primary pulmonary histiocytic sarcoma who may benefit from immunotherapy such as nivolumab and pembrolizumab significantly and safely.

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.

Histiocytic Sarcoma in a Captive Hybrid Orangutan (Pongo sp.): Morphological and Immunohistochemical Features.

Histiocytic sarcoma (HS), an infrequent highly aggressive hematopoietic tumor, has been observed in diverse animal species, with isolated occurrences in non-human primates. This study describes the first case of disseminated HS in a 45-year-old female hybrid captive orangutan. The clinical profile mirrored symptoms seen in human HS cases, encompassing anorexia and ascites. Detailed histopathological examination demonstrated characteristic features of this tumor and immunohistochemistry, using markers such as Iba-1 and HLA-DR, confirmed the diagnosis. Significantly, the absence of CD163 and CD204 expression challenges their diagnostic utility in non-human primates. This investigation enhances our understanding of HS diagnosis in non-human primates, underscoring the necessity for standardized markers and diagnostic protocols.

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.

Histiocytic sarcoma mimicking localized tenosynovial giant cell tumor in the pediatric foot: A rare case report with MRI Findings.

We present a rare case of histiocytic sarcoma (HS) occurring in the foot of a 12-year-old male, initially misdiagnosed as localized tenosynovial giant cell tumor (TSGCT). HS is an exceptionally uncommon hematologic malignant neoplasm, with its occurrence in children and extranodal sites being even rarer. To our knowledge, this is the first reported case of extranodal HS in the foot, emphasizing comprehensive MRI findings. Initially, the patient was diagnosed with TSGCT based on histological results following surgical resection. However, after recurrence and subsequent surgical resection, histological and immunochemical analyses led to a revised diagnosis of HS. This report focuses on the MRI findings of HS, highlighting the distinctions from localized TSGCT. While both conditions share histopathological similarities, immunohistochemical tests are crucial for accurate diagnosis. The report underscores the importance of differentiating HS for appropriate treatment.

Utility of the second-generation curcumin analogue RL71 in canine histiocytic sarcoma.

Canine histiocytic sarcoma is an aggressive cancer, with a high rate of metastasis. Thus, novel therapeutic approaches are needed. Synthetic analogues of curcumin have elicited potent anti-cancer activity in multiple in vitro and in vivo models of human cancer. Furthermore, the compound 3,5-bis(3,4,5-trimethoxybenzylidene)-1-methylpiperidine-4-one (RL71) has recently exhibited potent cell cycle arrest and apoptotic induction in a canine osteosarcoma cell line. To determine its potency in canine histiocytic sarcoma cells, cell viability of DH82 and Nike cells was measured using the sulforhodamine B assay. Flow cytometry was then used to analyse both cell cycle distribution and apoptosis. Of the five curcumin analogues examined, RL71, had the highest potency with EC50 values of 0.66 ± 0.057 µM and 0.79 ± 0.13 µM in the DH82 and Nike cell lines, respectively. Furthermore, RL71 at the 1x EC50 concentration increased G2/M cell cycle arrest 2-fold, and at the 2x EC50 concentration increased the number of apoptotic cells 4-fold. These findings are consistent with previous work using RL71 in both canine and human cancer cell lines. Future research should be directed on time-dependent changes, and mechanistic investigation in greater detail to elucidate RL71 mechanisms of action.

Impact of palliative-intent radiotherapy with or without chemotherapy on lameness in flat coat retrievers with localised periarticular histiocytic sarcoma - a retrospective cohort, single institution study.

Histiocytic sarcoma (HS) is a common tumour in flat coat retrievers (FCRs) often affecting periarticular tissues and joints. Palliative-intent radiotherapy, seeks to achieve local tumour control, pain relief and improve limb function. However, the effect of palliative-intent radiotherapy on analgesic levels of dogs with localised HS has not been studied. We hypothesised that palliative-intent radiotherapy could improve lameness in dogs affected by localised HS. This study aimed to assess the impact of palliative-intent radiotherapy on lameness of FCRs with localised HS. A retrospective cohort single institution study was performed. Medical records of FCR dogs with HS that received external beam radiotherapy between 2003 and 2022 were reviewed and included demographic, staging, severity of baseline lameness, therapeutic management and outcome data. Descriptive statistics, McNemar's chi-squared test, Fisher's exact test and Kaplan-Meier analysis were used for statistical analysis. Thirty-nine dogs were included with a median age of 7.2 years, 25 were male and 14 were female. HS was most commonly located in the forelimb (29 dogs, 74.3%), affecting the shoulder joint (19 dogs, 48.7%). Staging was performed in all 39 dogs with 22 (56.4%) dogs having localised HS, six (15.3%) dogs had localised HS with node metastasis and 11 (28.2%) dogs had localised HS with systemic metastasis. All dogs received palliative-intent hypo-fractionated radiation therapy, 32 (82%) dogs showed improvement in lameness. In conclusion, palliative intent radiation treatment has an analgesic effect reducing lameness or clinical signs associated with affected tumour-bearing joints.

Immunohistochemical evidence of NF-kB activation in canine lymphomas, histiocytic sarcomas, hemangiosarcomas, and mast cell tumors.

Increased or constitutive activation of nuclear factor kappa B (NF-kB) is a feature of many chronic disease processes, including cancer. While NF-kB overactivation has been documented extensively in human oncology, there is a relative paucity of data documenting the same phenomenon in veterinary medicine. To assess NF-kB activity, antibodies to p65 and p100/p52, which are components of NF-kB heterodimers, were first validated for specificity and canine cross-reactivity via Western blot and labeling of immortalized cell pellets. Then, nuclear labeling for these antibodies was assessed via QuPath software in over 200 tumor tissue samples (10 hemangiosarcomas, 94 histiocytic sarcomas, 71 lymphomas, and 28 mast cell tumors) and compared to immunolabeling in appropriate normal tissue counterparts. Greater than 70% of spontaneous canine tumors evaluated in this study had more nuclear p65 and p100/p52 immunoreactivity than was observed in comparable normal cell populations. Specifically, 144/204 (70.58%) of tumors evaluated had positive p65 nuclear labeling and 179/195 (91.79%) had positive p100/p52 nuclear labeling. Surprisingly, greater nuclear p100/p52 reactivity was associated with a longer progression-free survival (PFS) and overall survival (OS) in canine lymphomas. These results provide support and preliminary data to investigate the role of NF-kB signaling in different types of canine cancer.

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.

Histiocytic Sarcoma Treated with Pembrolizumab: A Case Report and Literature Review.

Histiocytic sarcoma (HS) is a rare hematologic malignancy that has historically been treated with lymphoma-based regimens with a median survival of 6 months. We describe a case of a 51-year-old woman who presented with acute back pain and cord compression. She was diagnosed with HS with diffuse skeletal lesions and high expression of programmed death ligand 1 (PD-L1). She was subsequently treated with chemotherapy plus off-label use of pembrolizumab followed by allogeneic stem cell transplantation. Ultimately, the patient died in the setting of progression of disease 17 months after her stem cell transplantation and 26 months after her diagnosis. This article also presents a literature review of cases of HS treated with programmed death ligand inhibition.