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.

Florid histiocytic reaction to oxidized cellulose masquerading as ovarian malignancy: Report of two cases.

Bioabsorbable hemostatic agents like oxidized regenerated cellulose (ORC) are widely used in surgical practice. Rarely, adverse events due to retained ORC may occur and can pose a diagnostic dilemma. The unique tissue response to ORC may be misdiagnosed as signet ring type of adenocarcinoma. This article aims to highlight this rare phenomenon. We report two such cases involving the ovaries. Both the patients presented with ovarian cysts and tubo-ovarian adhesions 1-2 years following surgery for benign ovarian pathology. The present biopsies were featured by sheets of large cells with abundant vacuolated cytoplasm and often small peripherally displaced nuclei having "signet ring" appearance. These cells were negative for pan-cytokeratin and strongly positive for CD68, indicating the histiocytic nature of the cells. It was confirmed that in both the patients, at the time of the initial surgeries, hemostasis was ensured by packing with ORC.

Intralymphatic histiocytosis in a patient with lung adenocarcinoma treated with pembrolizumab: a case report.

BACKGROUND: Pembrolizumab, an anti-programmed cell death-1 protein monoclonal antibody, is effective for patients with advanced non-small-cell lung cancer. However, immune checkpoint inhibitors such as pembrolizumab induce various immune-related adverse events, involving the lung, liver, gastrointestinal, endocrine system, and skin. Intralymphatic histiocytosis (ILH) is a rare, chronic cutaneous disorder with a reactive inflammatory component, which often occurs in patients with rheumatoid arthritis. CASE PRESENTATION: We present a 67-year-old man with lung adenocarcinoma who developed ILH associated with pembrolizumab treatment. He was treated with palliative thoracic radiotherapy for superior vena cava syndrome. Subsequently, he received four cycles of pembrolizumab. Approximately 2.5 months after the initiation of pembrolizumab, he developed erythema on the trunk of his body. Based on findings of skin biopsies, he was diagnosed with pembrolizumab-induced ILH. Moreover, the upregulation of tumor necrosis factor-α was observed during pembrolizumab therapy. CONCLUSIONS: This is the first report of ILH induced by pembrolizumab in a patient with lung adenocarcinoma.

Clinical and pathological manifestations of cardiovascular disease in rat models: the influence of acute ozone exposure.

Rodent models of cardiovascular diseases (CVD) and metabolic disorders are used for examining susceptibility variations to environmental exposures. However, cross-model organ pathologies and clinical manifestations are often not compared. We hypothesized that genetic CVD rat models will exhibit baseline pathologies and will thus express varied lung response to acute ozone exposure. Male 12-14-week-old healthy Wistar Kyoto (WKY), Wistar (WIS), and Sprague-Dawley (SD) rats and CVD-compromised spontaneously hypertensive (SH), fawn-hooded hypertensive (FHH), stroke-prone SH (SHSP), obese SH heart-failure (SHHF), obese diabetic JCR (JCR) rats were exposed to 0.0, 0.25, 0.5, or 1.0 ppm ozone for 4 h and clinical biomarkers, and lung, heart and kidney pathologies were compared immediately following (0-h) or 20-h later. Strain differences were observed between air-exposed CVD-prone and WKY rats in clinical biomarkers and in kidney and heart pathology. Serum cholesterol was higher in air-exposed obese SHHF and JCR compared to other air-exposed strains. Ozone did not produce lesions in the heart or kidney. CVD-prone and SD rats demonstrated glomerulopathy and kidney inflammation (WKY = WIS = SH < SD = SHSP < SHHF < JCR = FHH) regardless of ozone. Cardiac myofiber degeneration was evident in SH, SHHF, and JCR, while only JCR tends to have inflammation in coronaries. Lung pathology in air-exposed rats was minimal in all strains except JCR. Ozone induced variable alveolar histiocytosis and bronchiolar inflammation; JCR and SHHF were less affected. This study provides a comparative account of the clinical manifestations of disease and early-life organ pathologies in several rat models of CVD and their differential susceptibility to lung injury from air pollutant exposure.

Calcium lignosulphonate: re-evaluation of relevant endpoints to re-confirm validity and NOAEL of a 90-day feeding study in rats.

A 90-day feeding study in Han/Wistar rats with calcium lignosulphonate was evaluated by the EFSA. The study was considered to be inadequate due to potentially impaired health status of the animals based upon a high incidence of minimal lymphoid hyperplasia in mesenteric/mandibular lymph nodes and Peyer's patches, and minimal lymphoid cell infiltration in the liver in all animals. The EFSA Panel further disagreed with the conclusion that the treatment-related observation of foamy histiocytosis in mesenteric lymph nodes was non-adverse and asked whether this observation would progress to something more adverse over time. A PWG was convened to assess the sections of lymph nodes, Peyer's patches and liver. In addition, all lymphoid tissues were re-examined. The clinical pathology and animal colony health screening data were re-evaluated. The question whether the foamy histiocytosis could progress to an adverse finding with increasing exposure duration was addressed by read-across. In conclusion, the animals on the 90-day feeding study were in good health, the study was adequate for safety evaluation, and the foamy histiocytes in the mesenteric lymph nodes were not considered adverse, but rather an adaptive response that was considered unlikely to progress to an adverse condition with time. The NOAEL was re-affirmed to be 2000 mg/kgbw/d.

Clofazimine-induced enteropathy in a patient of leprosy.

Clofazimine-induced crystal-storing histiocytosis is a rare but well-recognized condition reported in literature. In addition to common reddish discoloration of the skin, clofazimine produces gastrointestinal disorder, sometimes severe abdominal pain. Also, the pathologic and radiologic findings can produce diagnostic difficulties if the pathological changes caused by it are not known. The authors report a case in a patient of leprosy to emphasize the importance of history, radiologic, and pathologic findings in small intestine. Clofazimine crystals are red in the frozen section and display bright-red birefringence. With the knowledge of this rare condition caused by clofazimine, appropriate management to avoid an unnecessary laparotomy is possible.

Drug-associated histiocytoid Sweet's syndrome: a true neutrophilic maturation arrest variant.

Histiocytoid Sweet's syndrome is a recently described entity which has clinical features identical to typical Sweet's syndrome but is distinguished by a dermal cellular infiltrate composed not of mature neutrophils but of immature granulocytes. Herein, we report a case of bone marrow granulocytic maturation arrest and a histological histiocytoid Sweet's-like reaction pattern following trimethoprim-sulfamethoxazole therapy.

Intralymphatic histiocytosis with granuloma formation associated with orthopaedic metal implants.

A 75-year-old man presented with a 1-year history of asymptomatic reddish-brown nodules on his left knee, in which orthopaedic metal implants had been inserted for a transformation-related knee joint disorder. Histopathological examination revealed typical features of mixed cell granuloma with many dilated lymphatics that contained many histiocytes from the upper dermis to subcutaneous fat tissue. Results of qualitative analysis of biopsy specimens by energy-dispersive X-ray spectroscopy were positive for molybdenum, which was one of the constituents of the metal implant. We describe the first observation of intralymphatic histiocytosis with granuloma formation in the skin occurring in a patient bearing orthopaedic metal implants for a transformation-related knee joint disorder.

Toxicity and carcinogenicity studies of 4-methylimidazole in F344/N rats and B6C3F1 mice.

4-Methylimidazole (4MI) is used in the manufacture of pharmaceuticals, photographic chemicals, dyes and pigments, cleaning and agricultural chemicals, and rubber. It has been identified as a by-product of fermentation in foods and has been detected in mainstream and side stream tobacco smoke. 4MI was studied because of its high potential for human exposure. Groups of 50 male and 50 female F344/N rats were fed diets containing 0-, 625-, 1,250-, or 2,500 ppm 4MI (males) or 0-, 1,250-, 2,500-, or 5,000 ppm 4MI (females) for 106 weeks. Based on the food consumption the calculated average daily doses were approximately 30, 55, or 115 mg 4MI/kg body weight to males and 60, 120, or 250 mg 4MI/kg to females. Survival of all exposed groups of males and females was similar to that of the control groups. The mean body weights of males in the 1,250- and 2,500 ppm groups and females in the 2,500- and 5,000 ppm groups were less than those of the control groups throughout the study. Feed consumption by 5,000 ppm females was less than that by the controls. Clonic seizures, excitability, hyperactivity, and impaired gait were observed primarily in 2,500- and 5,000 ppm females. The incidence of mononuclear cell leukemia in the 5,000 ppm females was significantly greater than that in the controls. The incidences of hepatic histiocytosis, chronic inflammation, and focal fatty change were significantly increased in all exposed groups of male and female rats. The incidences of hepatocellular eosinophilic and mixed cell foci were significantly increased in 2,500 ppm males and 5,000 ppm females. Groups of 50 male and 50 female B6C3F1 mice were fed diets containing 0-, 312-, 625-, or 1,250 ppm 4MI for 106 weeks. Based on the food consumption the calculated average daily doses were approximately 40, 80, or 170 mg 4MI/kg body weight to males and females. Survival of all exposed groups of males and females was similar to that of the control groups. Mean body weights of males and females in the 1,250 ppm groups and that in the 312- and 625 ppm females were less than those of the control groups. Feed consumption by exposed groups of male and female mice was similar to that by the controls. The incidences of alveolar/bronchiolar adenoma in all exposed groups of females, alveolar/bronchiolar carcinoma in 1,250 ppm males, and alveolar/bronchiolar adenoma or carcinoma (combined) in 1,250 ppm males and 625- and 1,250 ppm females were significantly greater than those in the control groups. The incidence of alveolar epithelial hyperplasia was significantly increased in the 1,250 ppm females. 4MI is carcinogenic inducing alveolar/bronchiolar adenoma and carcinoma in male and female mice. 4MI may also induce mononuclear cell leukemia in female rats.

Florid histiocytic hemophagocytosis following therapy with long acting G-CSF (pegfilgrastim).

We describe a case of histiocytic hemophagocytosis and increase in blasts in the bone marrow after administration of long acting G-CSF (pegfilgrastim) in a 71-year-old man with underlying myelodysplasia. Pegfilgrastim was discontinued, with resolution of the hemophagocytosis and marked decrease in blasts from 30 to 5%. We postulate that pegfilgrastim provided a continuous stimulation of the monocyte/macrophage system, resulting in histiocytic hemophagocytosis. We recommend caution in defining indications for the use of long acting preparations of G-CSF.

Intra-abdominal, crystal-storing histiocytosis due to clofazimine in a patient with lepromatous leprosy and concurrent carcinoma of the colon.

We report a case with abdominal complications of clofazimine treatment which included blackish discolouration of the lymph nodes, omentum and peritoneum. A 44-year-old female with lepromatous leprosy and a history of adverse reaction to clofazimine 2 years previously, presented with rectosigmoid junction adenocarcinoma. Laparotomy revealed an inoperable tumour with pigmentation of the bowel, serosa and peritoneum. A second operation had o be performed for transverse loop colostomy and a mesenteric lymph node biopsy sent for frozen section showed typical clofazimine crystals. Despite widespread use for many years in the treatment of leprosy, this drug is not known to be carcinogenic and this case provides no evidence for an association or link between its use and the patient's cancer. Apart from its use in leprosy, clofazimine may be used in the treatment of disseminated Mycobacterium avium-intracellulare infection, Buruli ulcer due to M. ulcerans and occasionally in other mycobacterial infections. An awareness of the rare side-effect described above may help in the clinical assessment and management of such cases, including the avoidance of unnecessary laparotomy.

Hemophagocytic syndrome associated with retinoic acid syndrome in acute promyelocytic leukemia.

A 56-year-old woman with an acute promyelocytic leukemia (APL) developed a severe all-trans-retinoic (ATRA) syndrome on day 17 of treatment. Shortly after, she presented a picture of pancytopenia, hepatosplenomegaly, increased triglycerides, ferritin, and liver enzymes. A bone marrow biopsy showed abundant macrophages and no evidence of leukemia. Tests for secondary hemophagocytic syndrome (HPS) were negative. A diagnosis of HPS was made. Treatment with dexamethasone and high-dose immunoglobulins was unsuccessful. Consolidation chemotherapy with idarubicin and ATRA rapidly reversed the HPS. The HPS in this patient could be related to the release of macrophage-stimulating cytokines by APL cells during ATRA syndrome.

Clofazimine-induced crystal-storing histiocytosis producing chronic abdominal pain in a leprosy patient.

Clofazimine-induced crystal-storing histiocytosis is a rare but well-recognized condition in the literature. Besides the common reddish discoloration of the skin, clofazimine produces gastrointestinal disturbances-sometimes severe abdominal pain, prompting exploratory laparotomy, because pathologic and radiologic findings can produce diagnostic difficulties if the pathologic changes caused by clofazimine are not recognized. The authors report such a case in a leprosy patient to emphasize the importance of history taking, the radiologic abnormalities of the small intestine, and the pathologic findings in small intestine and lymph node biopsies. Clofazimine crystals are red in the frozen section and exhibit bright-red birefringence. However, they are clear in routinely processed histologic sections because they dissolve in alcohol and organic solvents. They also appear as clear crystal spaces during electron microscopic study, but some osmiophilic bodies can be observed. Histiocytosis caused by clofazimine crystals produces infiltrative lesions in radiologic studies mimicking malignant lymphoma or other infiltrative disorders. Associated plasmacytosis in the histologic sections can simulate lymphoplasmacytic lymphoma or multiple myeloma with crystal-storing histiocytosis. With the knowledge of this rare condition caused by clofazimine, appropriate management to avoid an unnecessary laparotomy is possible.

Histiocytic cytophagic panniculitis which developed during interferon-alpha therapy.

A 59-year-old woman developed edema of the face and eyelids during interferon (IFN)-alpha-2b therapy for chronic hepatitis C with a cumulative dose of 6 million x 47 units. Despite cessation of the therapy, the edema progressed and was followed by exophthalmos, pyrexia, liver dysfunction, pancytopenia, and disseminated intravascular coagulation. Two months after initial presentation, she died of hemorrhagic shock and was diagnosed with histiocytic cytophagic panniculitis at autopsy. This may be a hitherto unrecognized adverse effect of therapeutic IFN alpha.

Florid xanthomatous pelvic lymph node reaction to metastatic prostatic adenocarcinoma. A sequela of preoperative androgen deprivation therapy.

We describe a florid xanthomatous histiocytic reaction in the pelvic lymph nodes of a patient treated with androgen deprivation therapy prior to radical prostatectomy. The xanthomatous reaction was so marked that it nearly obscured the presence of metastatic carcinoma in the same lymph nodes. A similar histiocytic reaction was also present in association with carcinoma in the prostatectomy specimen, a finding that was not identified in pretreatment biopsy specimens. No other known cause of pronounced histiocytic lymph node proliferation was present in this patient. Only one brief description of a xanthomatous reaction in lymph nodes associated with this treatment has been previously recorded in the literature to our knowledge. Other patients from our institution who were treated similarly preoperatively all had lymph nodes negative for tumor, and none demonstrated a xanthomatous tissue reaction, suggesting that this reaction may be a marker for metastatic tumor in the same lymph node.

Comparative 90-day feeding study with low-viscosity white mineral oil in Fischer-344 and Sprague-Dawley-derived CRL:CD rats.

A 90-day study was conducted to compare the effects of dietary administration of a food-grade white oil in female Fischer-344 (F-344) and Sprague-Dawley-derived (CRL:CD) rats. Animals were fed a low viscosity (15 mm2/sec at 40 degrees C) paraffinic white oil (designated as P 15[H]) at 0, 0.2, or 2.0% of the diet for 30, 61, or 92 days. There were no significant adverse clinical observations or unscheduled deaths. In the F-344 rats, occasional treatment-related changes were seen in hematology and clinical chemistry parameters. At necropsy, mesenteric lymph nodes were enlarged, and there was an increase in absolute and relative liver, mesenteric lymph node, and spleen weights as compared to controls. Histopathologic effects included hepatic and mesenteric lymph node microgranulomas and mesenteric lymph node histiocytosis. In CRL:CD rats, the only effects noted were accumulations of chronic inflammatory cells in the liver at the high dose only, without the formation of discrete microgranulomas. A dose-related increase in mineral hydrocarbon (MCH) material in the liver and mesenteric lymph nodes was observed in both F-344 and CRL:CD rats. Although increased, liver MhC content was significantly less (approximately 50%) in CRL:CD rats than the levels detected in the F-344 rats. Mesenteric lymph node MHC levels did not differ significantly between the strains. This study demonstrated strain differences among rats in histopathologic effects of white oil, with the CRL:CD rat essentially showing no response compared to the F-344 rat.(ABSTRACT TRUNCATED AT 250 WORDS)

Fatal hematophagic histiocytosis after granulocyte-macrophage colony-stimulating factor and chemotherapy for high-grade malignant lymphoma.

Fatal hematophagic histiocytosis occurred in two patients after they had received granulocyte-macrophage colony-stimulating factor (GM-CSF) in addition to chemotherapy for malignant non-Hodgkin's lymphoma. In one patient GM-CSF promoted the activity of subclinical hematophagic histiocytosis, resulting in severe pancytopenia and multiorgan failure. In the other patient the syndrome that caused persistent bone marrow failure began after the institution of GM-CSF therapy. Exogenous GM-CSF appears to upregulate preexisting hematophagic histiocytosis and may even contribute to its de novo initiation. It is therefore conceivable that endogenous GM-CSF also plays an essential role in the pathogenesis of this syndrome.