Impact of graft-versus-host disease on the clinical outcome of allogeneic hematopoietic stem cell transplantation for non-malignant diseases.

The impact of acute and chronic graft-versus-host disease (GVHD) on clinical outcomes was retrospectively analyzed in 960 patients with non-malignant diseases (NMD) who underwent a first allogeneic hematopoietic stem cell transplantation (HSCT). Grade III-IV acute GVHD (but not grade I-II) was significantly associated with a lower rate of overall survival (OS), and higher non-relapse mortality (NRM) than that seen in patients without acute GVHD. Extensive (but not limited) GVHD was significantly associated with a lower OS rate and higher NRM than that seen in patients without chronic GVHD. Any grade of acute (but not chronic) GVHD was significantly associated with a lower incidence of relapse and a lower proportion of patients requiring a second HSCT or donor lymphocyte infusion for graft failure or mixed chimerism, but its impact on OS was almost negligible. Acute GVHD was significantly associated with lower OS rates in all disease groups, whereas chronic GVHD was significantly associated with lower OS rates in the primary immunodeficiency and histiocytosis groups. In conclusion, acute and chronic GVHD, even if mild, was associated with reduced OS in patients receiving HSCT for NMD and effective strategies should, therefore, be implemented to minimize GVHD.

Crystal-storing Histiocytosis in the Stomach: A Clue to Subtle Hematolymphoid Malignancies.

Crystal-storing histiocytosis (CSH) is an under-recognized entity with a striking association with lymphoproliferative disorders. To study the typical morphologic features of gastric CSH, all lymphomas diagnosed on in-house gastric specimens at The Ohio State University between January 1, 2008 and January 1, 2017 were retrieved. This search yielded 66 specimens from 51 unique patients. All cases were reviewed with CSH identified in 7 stomach biopsies from 4 patients (2 men:2 women; average age, 69 y; range, 56 to 82 y). Endoscopic findings were all abnormal: diffuse nodularity and white discoloration (n=1), patchy nodularity (n=1), and malignant-appearing fundic mass with lymphadenopathy (n=2). We report the typical gastric CSH lesion displays full-thickness expansion of the lamina propria by a lymphohistiocytic infiltrate that distorts the usual gastric glandular architecture. On high power, all cases were defined by the presence of macrophages with abundant eosinophilic cytoplasm containing nonrefractile, nonpolarizable fibrillary cytoplasmic inclusions. Three of the 4 patients had a kappa-restricted lymphoma; the 1 patient with a lambda-restricted lymphoma had the fewest macrophages. Follow-up data were available up to 228 weeks. All 4 patients had persistent/recurrent lymphoma, and 2 patients died of lymphoma-related complications. None of the CSH cases were prospectively recognized as CSH, and 1 case was initially misdiagnosed as a xanthoma. In summary, CSH is an under-recognized lesion historically associated with lymphoproliferative disorders and we found associated with a high mortality in this small series. Since CSH can be so florid as to obscure the concomitant lymphoma, awareness is crucial for accurate diagnosis.

Outcome After Radiation Therapy for Langerhans Cell Histiocytosis Is Dependent on Site of Involvement.

PURPOSE: To characterize the efficacy and safety of radiation therapy in a contemporary Langerhans cell histiocytosis (LCH) cohort and to explore whether there are sites at higher risk for local recurrence. PATIENTS AND METHODS: Between 1995 and 2015 we identified 39 consecutive LCH patients who were treated primarily with radiation therapy. Patients were staged by single/multisystem involvement and established risk organ criteria. In 46 irradiated lesions, clinical and radiologic responses were evaluated at multiple time points after radiation therapy. Patient demographics, treatment, and local failure were compared by site of lesion. RESULTS: Median age at radiation therapy was 35 years (range, 1.5-67 years). Twelve patients had multisystem involvement, and of those, 5 patients had disease in organs considered to be high risk. The following sites were irradiated: bone (31), brain (6), skin (3), lymph node (3), thyroid (2), and nasopharynx (1). Median dose was 11.4 Gy (range, 7.5-50.4 Gy). At a median follow-up of 45 months (range, 6-199 months), local recurrence or progression was noted in 5 of 46 lesions (11%). There were no local failures of the 31 bone lesions evaluated, whereas the 3-year freedom from local failure in the 15 non-bone lesions was 63% (95% confidence interval 32-83%; P=.0008). Local failures occurred in 2 of 3 skin lesions, in 2 of 6 brain lesions, and 1 of 3 lymph node lesions. Deaths were recorded in 5 of 39 patients (13%), all of whom were adults with multisystem disease. CONCLUSION: Radiation therapy is a safe and effective measure for providing local control of LCH involving the bone. Whereas bone lesions are well controlled with low doses of radiation, disease in other tissues, such as the skin and brain, may require higher doses of radiation or additional treatment modalities.

Pediatric histiocytoses in the United States: incidence and outcomes.

BACKGROUND: Histiocytoses are rare disorders affecting the pediatric population. MATERIALS AND METHODS: Surveillance, Epidemiology, and End Results database was searched for pediatric cases (<20 y old) of histiocytosis diagnosed between 1973 and 2010. Demographics, clinical characteristics, and survival outcomes were analyzed using standard statistical methods. Class I disease (Langerhans cell histiocytosis) and class III (malignant histiocytosis) were included in the data set. RESULTS: A total of 828 cases were identified. Overall incidence was 0.142/100,000 persons per annum. Incidence was highest in younger children and those of Asian or Native American descent. Class III disease had a higher incidence versus class I. Adolescents tended to present with class III, whereas young children presented with class I. Disseminated disease was present in most cases of class III, whereas class I had more localized cases. Surgical excision was more likely to be performed in class I. Overall median survival was 349 mo. Patients 15-19 y old and children<1 y old had the worst outcomes. Class I had higher survival compared with class III, which had a median survival of 33 mo. Cases with hematologic spread carried the worst prognosis. Surgical excision conferred a survival advantage while radiation had no effect. Survival improved over the study period. Gender and race had no association with survival. CONCLUSIONS: Class I disease had localized cases and showed benefit from surgical intervention. Class III disease had a higher incidence and was associated with disseminated disease and lower survival. Radiation therapy did not affect survival. Overall survival increased over the previous 40 y.

Clinical features and treatment outcomes of Langerhans cell histiocytosis: a nationwide survey from Korea histiocytosis working party.

A nationwide survey was conducted to clarify the clinical features and outcomes of Korean children with Langerhans cell histiocytosis (LCH). Korea Histiocytosis Working Party analyzed the data of 603 patients who were diagnosed with LCH between 1986 and 2010 from 28 institutions in Korea. Median age at diagnosis was 65 months (range, 0 to 276 mo). Bone was the most frequently affected organ (79.6%) followed by skin (19.2%). Initially, 419 patients (69.5%) had single-system involvement (SS), 85 (14.1%) with multisystem (MS) disease without risk organ involvement (MS-RO), and 99 (16.4%) multisystem disease with risk organ involvement (MS-RO). The 5-year overall survival (OS) rates in the SS, MS-RO, and MS-RO groups were 99.8%, 98.4%, and 77.0%, respectively (P<0.001), and the 5-year reactivation rates were 17.9%, 33.5%, and 34.3%, respectively (P<0.001). The OS rate was lower in patients with RO involvement (P=0.025) and lack of response to initial treatment (P=0.001). MS involvement (P=0.036) was an independent risk factor for reactivation. Permanent consequences were documented in 99 patients (16.4%). Reactivation of disease, MS involvement, and age at diagnosis ≤ 2 years were associated with higher incidence of permanent consequences. This study emphasized that further efforts are required to improve survival of MS-RO patients and reduce reactivation in younger patients with MS involvement.

Analysis of histiocytosis deaths in the US and recommendations for incidence tracking.

OBJECTIVE: We determined the frequency of deaths associated with histiocytosis in the United States (US) for which incidence data are lacking and could be potentially important in understanding outcomes for patients with these disorders. METHODS: National death data collected by the US Vital Statistics Reporting System and aggregated using wonder.cdc.gov were analyzed for underlying cause of death due to malignant histiocytosis (MH), Langerhans cell histiocytosis (LCH) and Letterer-Siwe disease (LS, a form of LCH) for 3 periods: 1979-1988, 1989-1998, and 1999-2006. To capture histiocytosis, International Classification of Diseases (ICD)-9 codes 202.3, 202.5, and 277.8 and ICD-10 codes C96.1, C96.0, and D76.0-76.1 were used. Deaths were calculated for US residents stratified according to sex, race, region, and age. Other listed contributing causes of death with a histiocytosis diagnosis were also examined. RESULTS: A total of 2,416 deaths primarily due to histiocytosis as underlying cause occurred between 1979 and 2006. On comparison of the underlying and contributory cause for the period 1999-2006, histiocytosis mentioned on the death certificate as a contributory cause (N=562) occurs nearly as often as does underlying cause alone (N=648). The age-adjusted (year 2000) death rate was highest for MH (2.62 deaths per 10 million, 95% CI: 2.40-2.83) and for LCH and LS disease (2.17, 95% CI: 1.98-2.36) during the period 1979-1988. Death rates of each type of histiocytosis dropped significantly from 1979 to 1988 to 1999-2006 (p-value <0.0001). Distribution of the conditions showed the majority of deaths were due to LCH and LS (67%) across all time periods. LCH/LS was significantly more common in persons younger than 5 years of age irrespective of gender (p-value <0.0001) whereas death rates from MH were significantly greater in ages >54 years (p-value <0.00001). There were more MH deaths among males than females whereas no gender differences were seen for LCH/LS. CONCLUSIONS/DISCUSSION: Death due to histiocytosis or histiocytosis-related causes is a rare event that is trackable in the US by person, place and time characteristics. However, a population-based, disease incidence registry has begun to accurately ascertain incidence cases, which will facilitate study of these conditions.

Clinicopathologic features of histiocytic lesions following ALL, with a review of the literature.

We describe the clinicopathologic features of 15 patients who had histiocytic lesions that followed acute lymphoblastic leukemia (ALL). Twenty-one separate histiocytic lesions were evaluated that covered a wide spectrum, some conforming to the usual categories of juvenile xanthogranulomas (5), Langerhans' cell histiocytosis (1), Langerhans' cell sarcoma (4), Rosai-Dorfman disease (1), and histiocytic sarcoma (4). Most were atypical for the category by histology, phenotype, or abnormally high turnover rate. Seven low-grade lesions defied easy categorization and were characterized only as "atypical histiocytic lesion" following ALL. For those evaluated, the molecular signature of the prior leukemia was present in the histiocytic lesion. In 3 of 15 patients, the leukemia and histiocytic lesion shared immunoglobulin H or monoclonal TCR gene rearrangements and, in 4 of 15 patients, clonal identity was documented by fluorescence in situ hybridization. Four patients died of progressive disease, 3 of whom had histiocytic sarcoma and 1 who had an atypical lesion. One patient died of recurrent ALL. The other 10 patients are alive, 7 after recurrences and treatment with surgery and/or chemotherapy. The post-ALL lesions are more aggressive than their native counterparts, but despite the demonstration of the presence of the leukemia signature in 7 of 15 patients, the prognosis is generally favorable, except for patients with histiocytic sarcoma. It remains unclear whether the histiocytic lesions arise as a line from the original ALL or whether transdifferentiation is involved.

Histiocytosis disorders in Northeast Egypt: epidemiology and survival studies (a 5-year study).

Histiocytosis disorders include a wide group of disorders characterized by monocytes, macrophages and dendritic cell infiltration of different tissues. There are few clinico-epidemiologic studies of such disease. Our study was designed to look at the clinico-epidemiological features and outcome of patients with histiocytosis disorders in Northeast Egypt. Twenty-seven cases with histiocytosis disorders accrued over a 5-year period were analyzed and classified as having unifocal, multifocal, or multisystem disease. They were 14 males and 13 females. Twenty-two patients representing 81.5% of cases were more than two years of age while 5 patients (18.5%) were less than 2 years. Lymphadenopathy was the commonest presentation (55.55%) followed by bone lesions (44.44%). Involvement was unifocal in 12, multifocal in 10, and multisystem in 5 cases. The histological features were relatively uniform regardless of the clinical severity, and consisted of Langerhans cells, eosinophils, histiocytes, plasma cells, giant cells and fibrosis. The treatment consisted of a combination of surgery, chemotherapy, and/or radiotherapy. Lymphadenopathy was the most common clinical presentation in our locality. Response to treatment was poor in patients with multisystem disease. Patients with age less than 2 years were more likely to have increased risk of morbidity and mortality, due to widespread disease.

Fetal and neonatal histiocytoses.

PURPOSE: The histiocytoses are a group of disorders of the monophagocytic system having a variety of clinical and pathological findings. They occur less often during the perinatal period than later in life. Their biologic behavior, response to therapy, and histologic types are not the same. METHODS: The study consisted of 221 fetuses and neonates collected from the literature and from personal files. RESULTS: Langerhans' cell histiocytosis (LCH), the hemophagocytic lymphohistiocytoses (HLH), and juvenile xanthogranuloma (JXG), in order of rank, were the main histiocytoses occurring in the perinatal period. HLH accounted for the highest mortality (74%) followed by disseminated LCH (52%) and JXG (11%). All neonates with LCH and JXG limited to the skin and/or subcutaneous tissue survived with or without treatment. CONCLUSIONS: This study suggests that there is an increased incidence of spontaneous regression of certain histiocytic lesions in neonates as compared to older individuals. Cutaneous forms JXG and LCH had the highest incidence of regression followed by infection associated HLH.

Familial erythrophagocytic lymphohistiocytosis: adverse prognostic significance of delayed diagnosis.

Familial erythrophagocytic lymphohistiocytosis (FEL) is a rare disorder of the monocyte-macrophage system, for which an autosomal recessive mode of inheritance has been postulated. It is characterized by a dismal prognosis and is peculiar of early infancy. Three new cases of infants affected by FEL are reported. All three patients were diagnosed about three months after the onset of symptoms, and all three died shortly after diagnosis. The need for early diagnosis and prompt, intensive cytotoxic chemotherapy is emphasized.

Pediatric histiocytosis. Characterization, prognosis, and oral involvement.

PURPOSE: Forty-five children with histiocytosis were reviewed to characterize such a group and to establish the prevalence of oral involvement. In addition, patients with and without oral disease were compared for severity of disease, response to treatment, and incidence of recurrent disease. PATIENTS AND METHODS: There were more boys (62.2%) than girls (37.8%) among the patients studied. About half (53.3%) were < 2 years of age. Approximately half of all patients had two or fewer affected organ systems at diagnosis. The average length of treatment was 46 weeks. RESULTS: A total 75.6% of patients were alive without disease at the completion of data collection, 15.6% died from the disease, 4.4% were alive with active disease, and 4.4% were alive with unknown status. Of the patients, 55.6% had long-term sequelae, and oral sequelae were present in 22.2% of the sample. In all, 28.8% of the patients exhibited oral symptoms at diagnosis, while 44.4% had oral involvement at some point during the course of the disease. Patients with oral symptoms were treated significantly longer and had more systemic therapy when compared with those without oral disease.

Status of allogeneic bone marrow transplantation in childhood in the GDR.

Of 25 HLA-identical, MLC negative transplants 10 patients had acute lymphoblastic leukaemia (ALL), 8 acute nonlymphoblastic leukaemia (ANLL), 3 severe aplastic anaemia, 2 malignant histiocytosis, 1 patients neuroblastoma and 1 Fanconi anaemia. 3 HLA nonidentical, MLC positive transplants were performed, two children had malignant infantile osteopetrosis and 1 child had a severe combined immunodeficiency disease. Patients with ALL and ANLL received cyclophosphamide and single dose total body irradiation. 3 patients received fractionated TBI. The results for the allogeneic group overall indicate that the actuarial disease free survival rate is 0.62. 16 of 25 patients are in continuous complete remission (CCR) periods of 3-78 months posttransplant. All three transplanted children with severe aplastic anaemia alive disease-free for periods of 21-81 months. 10 patients with ALL were transplanted (2 in first remission for high risk ALL, 8 in second remission). 7 of 10 patients are alive and disease-free (CCR rate 0.67). 8 patients underwent BMT for ANNL while in first remission in 7 patients and in third partial remission in 1 patient. 4 of 8 patients are alive and disease-free for periods of 25-56 months (CCR rate 0.50). 1 patient with neuroblastoma stage IV survives 24 months, 1 child with Fanconi anemia died on day +25 of GVHD and septicaemia. 1 of the 2 patients transplanted for malignant histiocytosis relapsed 3 months posttransplant, 1 patient is alive and disease-free 5 months posttransplant. In none of the HLA-nonidentical and MLC positive transplantations T-cell depleted marrow engrafted.