Treatment of Cerebral Histiocytosis With Low Dose of Cobimetinib: A Report of 2 Cases.

OBJECTIVES: Histiocytic disorders are pathologic expansions of myeloid cells in multiple organs, including the CNS. They share activation of the MAP kinase pathway due to either BRAFV600E variant or other variants in the RAS-RAF-MEK-ERK pathway. The rarity and heterogeneity of the disease only enable therapy through pathophysiologic considerations. METHODS: We present 2 histiocytosis cases without BRAF sequence variants that affect the CNS, one with Erdheim-Chester disease and the other with an unspecified histiocytosis, and their diagnostic and therapeutic challenges. RESULTS: In both cases, comprehensive analysis of the RAS-RAF-MEK-ERK signaling pathway secured the diagnosis. Treatment with the MEK inhibitor cobimetinib brought the disease to a complete halt. However, side effects such as thrombosis and serous macular edema made it necessary to reduce cobimetinib dosage. Low-dose cobimetinib maintenance medication was successful in preventing recurrence of histiocytic disease. DISCUSSION: CNS involvement of histiocytic disorders can lead to detrimental neurologic symptoms. MEK inhibitors are effective treatment options for some of these patients. Since side effects are common, according to our cases we propose a low-dose treatment of 20 mg per day to balance treatment effects with side effects. CLASSIFICATION OF EVIDENCE: This case report provides Class IV evidence. This is a single observational study without controls.

Anaplastic lymphoma kinase-positive histiocytosis with multisystem involvement: A case report.

Anaplastic lymphoma kinase (ALK)-positive histiocytosis is a rare disease that usually occurs in infants and young children and is characterized by ALK-positive histiocytes infiltrating organs. We present a case of multisystem involvement of ALK-positive histiocytosis in a female infant with skin nodules as the initial presentation. Despite multiorgan involvement, most tumors had spontaneously regressed, and all bones were partially healed after 40 months of regular follow-up without treatment. However, gait abnormalities persisted, indicating that early treatment may have greater impact in maintaining a child's quality of life when the disease involves the brain or the critical period of bone development.

Ocular Crystal-Storing Histiocytosis with Co-existing MALT Lymphoma-A Rare Case with Cytologic and Heretofore Not Reported Findings on Frozen Section.

BACKGROUND: Crystal-storing histiocytosis (CSH) is a rare disorder which most commonly occurs in the setting of concurrent lymphoproliferative disease. Morphologically, it consists of aggregates of histiocytes containing eosinophilic crystalline material, which in most cases is composed of aggregated abnormal light chains. METHODS: Using histomorphology, immunohistochemistry and in situ hybridization, the authors characterize a rare case of orbital CSH associated with extranodal marginal zone (MALT) lymphoma and report for the first time the frozen section features of CSH. RESULTS: The frozen section featured plump histiocytes with ample weakly basophilic to grayish cytoplasm with a microvacuolated appearance and focal stippling. These features stand in contrast with the formalin-fixed, paraffin embedded histomorphological appearance of aggregates of plump histiocytes with densely eosinophilic crystalline cytoplasmic material. CONCLUSION: CSH is a challenging diagnosis to make on frozen section. The artifacts that preclude its recognition, as well as differential diagnoses of this entity in the head and neck are discussed.

Loss of function of ENT3 drives histiocytosis and inflammation through TLR-MAPK signaling.

Histiocytoses are inflammatory myeloid neoplasms often driven by somatic activating mutations in mitogen-activated protein kinase (MAPK) cascade genes. H syndrome is an inflammatory genetic disorder caused by germ line loss-of-function mutations in SLC29A3, encoding the lysosomal equilibrative nucleoside transporter 3 (ENT3). Patients with H syndrome are predisposed to develop histiocytosis, yet the mechanism is unclear. Here, through phenotypic, molecular, and functional analysis of primary cells from a cohort of patients with H syndrome, we reveal the molecular pathway leading to histiocytosis and inflammation in this genetic disorder. We show that loss of function of ENT3 activates nucleoside-sensing toll-like receptors (TLR) and downstream MAPK signaling, inducing cytokine secretion and inflammation. Importantly, MEK inhibitor therapy led to resolution of histiocytosis and inflammation in a patient with H syndrome. These results demonstrate a yet-unrecognized link between a defect in a lysosomal transporter and pathological activation of MAPK signaling, establishing a novel pathway leading to histiocytosis and inflammation.

Crystal storing histiocytosis forming a mass lesion in temporal lobe.

Crystal storing histiocytosis is a disorder characterized by local or diffuse infiltration of histiocytes containing crystalline inclusions. This entity has been reported in several organs, however the involvement of the central nervous system (CNS) is extremely rare and to date only 7 cases of crystal storing histiocytosis (CSH) of CNS have been reported in the English literature. More than 90% patients with CSH had an underlying lymphoproliferative or plasma cell disorders, especially multiple myeloma, lymphoplasmacytic lymphoma or monoclonal gammopathy. Radiologically and intraoperatively, CSH may mimic an infectious process or neoplasm, hence its histopathological confirmation is important to facilitate appropriate treatment. In this report, we describe an additional case of crystal storing histiocytosis in a 48 year old female who presented with a mass lesion in the right temporal lobe of the cerebrum.

[Pulmonary crystal-storing histiocytosis: a case report].

A 45-year-old female patient was found to have a nodule in the right lower lobe on physical examination. Chest CT showed the nodule was lobulated measuring 24 mm×23 mm, with obvious enhancement and adjacent pleural traction. As the PET-CT showed increased 18F-FDG uptake suggesting malignancy, the wedge resection of the right lower lobe was performed. Grossly, the mass was adjacent to the pleural area with indistinct boundary. On cut sections, the lesion was solid and tough, with a greyish-pink colour. Microscopically, the lesion had an ill-defined margin, and was composed of spindle and polygonoid histiocytes with rich eosinophilic cytoplasm similar to rhabdoid muscle cells. The cytoplasm of histiocytes was filled with diamond-shaped or club-shaped crystals. Immunohistochemistry (IHC) showed the histiocytes were positive for CD68, κ, λ, IgG, IgM and IgA. The patient had been followed up for 41 months and had shown neither recurrences nor new diseases. CSH is a rare non-neoplastic histiocytic proliferative disease. Pulmonary CSH should be differentiated from multiple diseases. Accurate pathological diagnosis depends on its morphology and immunophenotype. This disease is often related to potential lymphoproliferative or plasma cell disorder. After diagnosis, a systemic examination is required and long-term follow-up is recommended.

[Transient thickening of the pituitary stalk followed by a supra-pituitary Langerhansian histiocytosis : consequence or mere coincidence ?] / Cas clinique. Épaississement transitoire de la tige pituitaire suivi d'une histiocytose langerhansienne supra-hypophysaire : conséquence ou simple coïncidence ?

One of the difficult challenges in endocrinology is the etiological diagnosis of isolated thickened pituitary stalk (PS). We report the case of a woman in whom a thickened PS was diagnosed following the onset of central diabetes insipidus revealed by polyuria-polydypsia syndrome of late pregnancy and postpartum. The pituitary exploration showed panhypopituitarism with disconnecting hyperprolactinemia. An etiological investigation for an inflammatory, granulomatous or tumour cause was carried out, but was negative. Postpartum lymphocytic hypophysitis was then retained. However, the course was puzzling with a control pituitary MRI showing disappearance of the PS thickening with paradoxical appearance of a supra-pituitary tumour, the biopsy of which concluded of being a Langerhansian histiocytosis. This paradoxical sequence is unusual and has not been reported before. It called into question the autoimmune lymphocytic origin of the thickened PS, initially considered, and raised the likelihood of a causal relationship between this PS thickening and Langerhansian histiocytosis.

Le diagnostic étiologique d'un épaississement isolé de la tige pituitaire (TP) constitue l'un des grands défis en endocrinologie. Nous rapportons le cas d'une patiente chez qui un épaississement de la TP a été diagnostiqué suite à la survenue d'un diabète insipide central révélé par un syndrome polyuro-polydypsique de fin de grossesse et du post-partum. Le bilan hypophysaire a montré un panhypopituitarisme avec une hyperprolactinémie de déconnexion. Une enquête étiologique à la recherche d'une cause inflammatoire, granulomateuse ou tumorale a été menée et s'est avérée négative. Une hypophysite lymphocytaire du post-partum a alors été retenue. Cependant, l'évolution a été déroutante avec, à l'IRM hypophysaire de contrôle, la disparition de l'épaississement de la TP et l'apparition paradoxale d'une tumeur suprahypophysaire dont la biopsie a conclu à une histiocytose langerhansienne. Cette évolution paradoxale est inhabituelle et n'a pas été rapportée auparavant. Elle a remis en question l'origine lymphocytaire auto-immune de l'épaississement de la TP, retenue initialement, et a soulevé la possibilité d'une relation de cause à effet entre cet épaississement de la TP et l'histiocytose langerhansienne.

Histiocytoid melanoma: Diagnostic pitfall and mimicker of non-Langerhans cell histiocytoses including reticulohistiocytoma.

Melanoma and benign histiocytic proliferations can sometimes show considerable clinical and histopathologic overlap. Recently, cases of melanomas resembling xanthogranuloma and Rosai-Dorfman disease have been reported, and herein we report a case of melanoma closely mimicking reticulohistiocytoma. An 84-year-old man presented with a 1 cm purple-red nodule on his arm concerning for squamous cell carcinoma. While the biopsy findings resembled reticulohistiocytoma, the clinical context and regression changes at the lesion perimeter raised stronger concern for melanoma, which was confirmed with immunohistochemistry. We review prior rare reports of melanomas resembling non-Langerhans cell histiocytic proliferations and summarize helpful clinical and histopathologic clues to avoid a diagnostic pitfall when confronted with this unusual quandary.

PU.1 is a useful nuclear marker to distinguish between histiocytosis and histiocyte-rich tumours.

AIMS: The aim was to test the expression of PU.1 on different types of histiocytoses and to test the utility of PU.1 in confirming or excluding a histiocytic origin in tumour samples with suspicion of histiocytosis. METHODS AND RESULTS: We analysed 66 biopsies of nonmalignant histiocytoses represented by Langerhans-cell histiocytosis (n = 13), Erdheim-Chester disease (ECD) (n = 19), Rosai-Dorfman disease (RDD) (n = 14), mixed ECD-RDD (n = 3), ALK-positive histiocytosis (n = 6), and juvenile xanthogranuloma (n = 11). All cases were positive for PU.1 in reactive and neoplastic histiocytes. In addition, 39 cases of tumours with high-grade cytological atypia were referred to our center as suspicion of malignant histiocytosis/histiocytic sarcoma and only 18 were confirmed. Indeed, more than half of these tumours (21/39) were either undifferentiated malignant tumours with a stroma rich in histiocytes, diffuse large B-cell lymphoma, or high-grade dedifferentiated liposarcoma. PU.1 was useful to distinguish between the negativity of large atypical nuclei and the positivity of stromal reactive histiocytes. CONCLUSION: PU.1 is expressed by all types of histiocytosis. It distinguishes histiocytosis from histiocyte-rich tumours with an easy interpretation due to its sharp nuclear staining. Its negativity in lesional/tumour cells in histiocyte-like lesions is useful to eliminate a histiocytosis.

Generalized crystal-storing histiocytosis with noncirrhotic portal hypertension: an autopsy case report.

Crystal-storing histiocytosis (CSH) is a rare disease associated with the accumulation of histiocytes containing crystalline matter within their cytoplasm. Herein, we present the case of a female patient who was diagnosed with Tolosa-Hunt syndrome at 45 years of age and idiopathic retroperitoneal fibrosis when she was 48 years. She developed portal hypertension (PH), but did not present with cirrhosis; as such, the cause of PH was not identified. Her PH gradually worsened when she was 54 years, and at the age of 60 years, she died from an acute subdural hematoma. Autopsy revealed retroperitoneal fibrosis with severe fibrosis extending around the hepatic veins and into the porta hepatis. Histologically, the retroperitoneal tissue showed a dense infiltrate of eosinophilic histiocytes with crystal structures in the cytoplasm, which was pathologically diagnosed as CSH. Nodular regenerative hyperplasia was observed in the liver parenchyma, whereas cirrhosis was not. In the present case, CSH caused fibrosis, which was believed to be the cause of PH. In addition, we considered that nodular regenerative hyperplasia caused by the altered hepatic blood flow due to treatment of gastric varices contributed to worsening PH. Hence, CSH should be considered as an underlying disease in noncirrhotic portal hypertension.

Multisystem ALK-positive histiocytosis: a multi-case study and literature review.

BACKGROUND: Anaplastic lymphoma kinase (ALK)-positive histiocytosis, a novel rare histiocytic proliferation, was first described in 2008; it occurs in early infancy with liver and hematopoietic involvement. The spectrum was subsequently broadened to include localized diseases in older children and young adults. However, its full clinicopathological features and molecular lineage have not been fully elucidated. RESULTS: Here, we report four cases of multisystem ALK-positive histiocytosis without hematopoietic involvement. Clinically, three patients were adults aged between 32 and 51 years. Two patients', whose main manifestations were intracranial mass and numerous micronodules in the thoracoabdominal cavity organs and skin papules respectively, had a partial response to ALK inhibitors after surgery. One patient presented with mediastinal neoplasm without surgical treatment, and progressive disease occurred after two years of ALK inhibitor therapy. The fourth patient was a 17-month-old male with a large intracranial mass and presented with a poor response to ALK inhibitor and chemoradiotherapy; he died eight months after surgery. Pathologically, the histiocytes were large, with abundant eosinophilic cytoplasm, and mixed with variable numbers of foamy cells and Touton giant cells. Interstitial fibrosis was also observed. Histiocytes were positive for macrophage markers (CD68 and CD163) and ALK. KIF5B-ALK fusions were detected in two cases, EML4-ALK in one, and both DCTN1-ALK and VRK2-ALK fusions were detected in one case. CONCLUSIONS: We observed that ALK inhibitors present robust and durable responses in adult patients but a poor response in young children with central nervous system involvement. There is no consensus on the optimal treatment regimen and long-term prognosis requires further observation. Moreover, every unusual histiocytic proliferative lesion, especially unresectable and multisystem involvement, should be routinely tested for ALK immunohistochemical staining to identify this rare disease.

Combined crystal-storing histiocytosis, light chain proximal tubulopathy, and light chain crystalline podocytopathy in a patient with multiple myeloma: a case report and literature review.

BACKGROUND: Crystal-storing histiocytosis (CSH), light chain proximal tubulopathy (LCPT), and light chain crystalline podocytopathy (LCCP) are rare complications of multiple myeloma (MM) or monoclonal gammopathy of renal significance, and their diagnoses are challenging. CASE PRESENTATION: In this case, a 69-year-old Chinese woman presented with suspicious Fanconi syndrome with renal insufficiency. Immunofixation electrophoresis of both serum and urine revealed elevated immunoglobulin G kappa (IgGkappa) and kappa light chain. Bone marrow aspirate revealed 15% plasma cells with considerable cytoplasmic granular inclusions and needle-shaped crystals. Renal biopsy confirmed the final pathologic diagnosis of kappa-restricted CSH, combined LCPT and LCCP by immunoelectron microscopy. A number of special casts were present which could easily be misdiagnosed as light chain cast nephropathy. Immunofluorescence on frozen tissue presented false negative for kappa light chain, as ultimately proven by paraffin-embedded tissue after pronase digestion. MM and CSH were diagnosed, and two cycles of chemotherapy were given. The patient subsequently refused further chemotherapy, and her renal function remained relatively stable during a 2.5-year follow-up period. CONCLUSIONS: In conclusion, we report a rare case of generalized kappa-restricted CSH involving bone marrow and kidney, combined with LCPT and LCCP, provide a comprehensive summary of renal CSH, and propose a new nomenclature of monoclonal immunoglobulin-induced crystalline nephrology. The presentation of monoclonal immunoglobulin and Fanconi syndrome should suggest the presence of monoclonal immunoglobulin-induced crystalline nephrology. Use of paraffin-embedded tissue after pronase digestion and immunoelectron microscopy is beneficial to improve the sensitivity of diagnosis.

Intralymphatic Histiocytosis Associated With Tubo-ovarian High-grade Serous Carcinoma: Case Report and Review of the Literature.

Intralymphatic histiocytosis is a condition characterized by the accumulation of mononuclear phagocytes within lymphatic vessels and lymph nodes that may be isolated or secondary to autoimmune or neoplastic diseases. Secondary intralymphatic histiocytosis frequently involves the skin and is associated with malignancies in up to a tenth of cases. We describe a case of intralymphatic histiocytosis associated with high-grade serous carcinoma and reviewed the literature on neoplasia associated with the broader category of histiocytoses with raisinoid nuclei. Moreover, we try to elucidate the pathogenesis of these rare and intriguing disorders.

Progressive mucinous histiocytosis treated successfully with thalidomide: a rare case report.

Hereditary progressive mucinous histiocytosis (HPMH) is an extremely rare progressive non-Langerhans cell histiocytic disorder presenting with only cutaneous manifestations. Patients typically present with multiple asymptomatic dome-shaped erythematous papules, usually involving the face and upper extremities. Twenty-six cases have been reported worldwide, with no spontaneous regression. Treatment with thalidomide stopped the progression of the disease in two cases. We report a case of progressive mucinous histiocytosis in a 31-year-old female patient with a history of tuberculosis who presented papular lesions on the face that later extended to the hands. She was treated with isoniazid for tuberculosis and isotretinoin for the skin lesions; the improvement was minimal during the next two months, with new lesions appearing on both hands. Thalidomide stopped the progression of the disease. The cause and pathogenesis of HPMH are undetermined. The pathogenesis of HPMH may be similar to that of lysosomal storage disease, considering the intra-cytoplasmic phospholipid deposition in both diseases, in addition to the likelihood of a role of macrophages in triggering the disease. In our patient, tuberculosis may have contributed.

Hodgkinoid histiocytosis: an atypical nodal CD30 and S100-positive histiocytosis with eosinophilia.

Histiocytes and dendritic cells may display cytological atypia and an aberrant immunophenotype even in reactive processes. Herein, we describe two cases of "Hodgkinoid histiocytosis" that show distinctive clinicopathological features, mimicking morphologically classic Hodgkin lymphoma (CHL), but suggesting reactive histiocytic/dendritic cell proliferation in lymph nodes. Both the patients presented with peripheral lymphadenopathy and blood eosinophilia with skin manifestations. Lymph node biopsy revealed scattered large histiocytes resembling Hodgkin cells with a round or stellate shape, abundant cytoplasm, and distinct nucleoli admixed in a predominant inflammatory background. The Hodgkinoid histiocytes occasionally showed emperipolesis. They expressed CD30, S100, and PD-L1 proteins but lacked PAX5 and CD1a expressions, Epstein-Barr association, BRAF V600E mutation, and PD-L1 gene amplification. Neither of the patients showed overt progression to malignant haematopoietic neoplasms during the disease course. An identical case series of four patients has been reported to date. Both these series highlight the potential of being interpreted as CHL due to the presence of Hodgkinoid histiocytes with CD30 positivity.