LANGERHANS CELL HISTIOCYTOSIS OF LYMPH NODES: A Morphological Assessment of 43 Biopsies

The morphology of Langerhans cell histiocytosis (LCH) involving lymph nodes was analyzed in 43 biopsies from 39 patients and findings were correlated with clinical data. Five histological motifs were recognized: sinusoidal, limited sinusoidal, epithelioid granulomatous, partial effacement, and total effacement. Lesions were composed of histiocytes of the Langerhans cell (LC) family, macrophages, multinucleated giant histiocytes, T lymphocytes, and eosinophils in varying proportions. Proliferative fractions ranged from 2.6 to 48 and 2 of 25 specimens showed a hyperdiploid aneuploid DNA ploidy profile. Epithelioid granulomas composed of histiocytes with the LC phenotype dominated three abdominal specimens, reflecting a picture of LCH not previously reported. Total effacement, seen in three patients, was associated with unmarked histiocytoid cells, high proliferative fraction, aneuploid DNA ploidy profile, and, in two, a fatal outcome. Different histologic appearances in lesions from separate sites of the same patient were seen in the cases with epithelioid granulomas and in those with total effacement. The diverse histopathology in lymph nodes involved by LCH is considered in the context of current knowledge of this enigmatic disease.     

Liver Involvement in the Histiocytic Disorders of Childhood

The liver can be involved directly, by infiltration, and indirectly—by remote effects—in the histiocytoses of childhood. Langerhans cell disease, the most well recognized of these, infiltrates the liver directly but has a remarkable selectivity for the bile ducts. Early involvement is by Langerhans cell histiocytosis (LCH) infiltration leading to a sclerosing cholangitis and, eventually, biliary cirrhosis. Gamma glutamyl transpeptidase is a sensitive indicator of liver infiltration in a child with LCH. The indirect effects on the liver of LCH elsewhere in the body are mediated through an accompanying macrophage activation syndrome that is most likely responsible for hepatomegaly and hypoalbuminemia but without direct infiltration. These indirect effects are completely reversible. Juvenile xanthogranuloma/xanthoma disseminatum, a related dendritic cell disorder that can have systemic manifestations, has a strikingly different pattern, with a predominantly portal infiltrate spilling over into the adjacent lobule but sparing the biliary tree. The biology of the liver lesions is not clear but regression has been documented. Myeloproliferative disorders and myeloid leukemias can express CD1a and/or S100 protein, mimicking LCH but distinguished by their sinusoidal pattern. The primary macrophage histiocytoses such as the familial hemophagocytic syndromes can lead to severe liver damage. Although a portal lymphohistiocytic infiltrate is most characteristic, it is probably cytokine-mediated hepatocellular damage that can cause substantial functional impairment or even hepatic failure as a presenting feature. Liver involvement in other, more unusual histiocytic disorders, is also illustrated.     

RADIOLOGICAL EVALUATION OF PATIENTS WITH PITUITARY LANGERHANS CELL HISTIOCYTOSIS AT DIAGNOSIS AND AT FOLLOW-UP

This study evaluated pituitary imaging findings in 13 patients with Langerhans cell histiocytosis (LCH) with diabetes insipidus. Nine patients were evaluated with pituitary magnetic resonance imaging (MRI), 3 with brain computed tomography, and 1 with brain MRI. The infundibulum was thickened in 11 (84.6%) patients, thread-like in 1 (7.7%), and normal in 1 (7.7%). Posterior pituitary intensity was absent in 10 patients (76.9%); in 4 patients, the pituitary gland was small in size, and 2 patients had atrophic pituitary. Three had a small sella. Infundibular thickening and absence of posterior pituitary intensity were the most common radiological findings. MRI imaging should be used to follow up patients with pituitary histiocytosis, and patients with LCH and diabetes insipidus should be followed for pituitary atrophy.     

PREPUBERTAL MALIGNANT MELANOMA: Report of Three Cases

Prepubertal malignant melanoma (MM) is an extremely rare tumor. In Slovenia, 13 MM cases were registered between 1968 and 1996 by the Cancer Registry of Slovenia. The diagnosis of MM was confirmed by histology in 3 children. In 3 other children the lesions initially diagnosed as MM were reclassified as Spitz nevus. In the remaining cases, the slides were not accessible for histological review, and the clinical course of disease corroborated the diagnosis of a benign nevus. In the present report, 3 of 13 cases with histologically confirmed prepubertal MM are described. The difficulties encountered in the diagnosis and management of this rare condition are discussed.     

Treatment of Langerhans cell histiocytosis with a modified risk‐adapted protocol—experience from a tertiary cancer institute in India

Background

Involvement of risk‐organs (RO+) in Langerhans cell histiocytosis (LCH) and inadequate early response identifies patients at high risk for relapse and mortality requiring intensive salvage therapy including stem cell transplant, adding cost and toxicity. To mitigate this, we used a standard induction, augmented with metronomic etoposide, and prolonged maintenance—similarly augmented for RO+, and retrospectively analyzed its impact.

Procedure

LCH patients from 2009 through 2014 were included. Patients received standard vinblastine and prednisolone therapy weekly till week 25 for RO+. Single site (SS) and multisystem (MS) without risk organ involvement (RO?) received 3‐weekly pulses from week 13 till week 25. Maintenance was 3‐weekly vinblastine and 5‐day prednisolone pulses, daily 6‐mercaptopurine (60 mg/m²) and weekly methotrexate (15 mg/m²) for 18 and 9 months for RO+ and MSRO?, respectively. RO+ also received oral etoposide (50 mg/m²) for 21 of every 28‐day cycle for the first year.

Results

Fifty consecutive patients were analyzed. Median age was 36 months (4–189 months). SS, MSRO?, and RO+ were 29 (58%), 12 (24%), and nine (18%), respectively. Four were lost to follow‐up and excluded from further evaluation. On response evaluation at week 6, 24 (52%) had no active disease (NAD), 17 (37%) had AD‐better (where AD is active disease), and one (2%) had AD‐worse. In RO+, eight (66.6%) had AD‐better and three (25%) had NAD. Forty‐five patients had NAD by week 12. Three patients relapsed. With median follow‐up of 39 months (8–84), 5‐year event free survival was 85.6% (RO? and SS), and 100% for RO+. One patient's death in remission from unrelated causes resulted in overall survival of 97%.

Conclusions

RO+LCH receiving oral etoposide augmented induction and maintenance had early and durable responses. Prolonging maintenance lowered reactivation rates in RO+ and RO?LCH, resulting in excellent survival.

     

Langerhans cell histiocytosis in childhood: Results from the Italian cooperative AIEOP-CNR-H.X '83 study

Ninety patients with biopsy-proven Langerhans cell histiocytosis (LCH) were enrolled from June, 1983, to December, 1988, in the multicenter AIEOP-CNR-H.X. '83 study. They were divided into two groups: poor prognosis (PP), comprising 11 children with organ dysfunction (OD), and good prognosis (GP), made up of 79 patients without OD. Eighty-four patients were evaluable for treatment results. Among GP patients, 16 with a single lesion received only local treatment, while 59 entered a clinical trial of immunotherapy and/or monochemotherapy with vinblastine (VBL). Nonresponders, sequentially received doxorubicin (ADM) and then etoposide (VP16). PP patients were treated with 4 week cycles of vincristine, ADM, cyclophosphamide, and prednisone for nine courses. The overall survival was 92.8% (100% for GP patients and 45.5% for PP patients) at 48 months. The complete response (CR) rates for immunotherapy, VBL, ADM, and VP16 were 10%, 62.9%, 42.8%, and 88.2%, respectively. Two of the 11 PP patients had a CR (18.2%), while six died and three are still alive with recurrent disease. The overall incidence of disease-related disabilities was 47.7%, while that of diabetes insipidus was 20%. Monochemotherapy is probably adequate in GP patients, while more effective treatments are needed for PP patients. © 1993 Wiley-Liss, Inc.     

MALIGNANT HYPERTENSION IN A CHILD WITH HEMOLYTIC-UREMIC SYNDROME TREATED WITH CAPTOPRIL

ABSTRACT. Monnens, L., Drayer, J. and de Jong, M. (Departments of Paediatrics and Internal Medicine, University of Nijmegen, Nijmegen, The Netherlands). Malignant hypertension in a child with hemolytic-uremic syndrome treated by captopril. Acta Paediatr Scand, 70:577,.–A 5-year-old boy is presented suffering from malignant hypertension due to hemolytic-uremic syndrome. Captopril, an oral angiotensin-1-converting enzyme inhibitor, was able to curb the natural course of the malignant hypertension. Haemodialysis could be discontinued after 2 months. The glomerular filtration rate recovered to 63 ml/min/1.73 m² 11 months after the acute phase.     

Treatment of juvenile xanthogranuloma

Juvenile xanthogranuloma (JXG) is generally a benign, self-limited histiocytic disorder of the skin. We report two cases of multisystem JXG presenting with clinical features more commonly seen in Langerhans cell histiocytosis (LCH), including diabetes insipidus and lytic bony lesions. Histologically, the skin lesions demonstrated a histiocytic dermal infiltrate that stained for CD-68, but S-100 and CD1a stains were negative. Treatment according to LCH-based chemotherapy regimens resulted in prompt resolution of symptoms. A literature review of multisystem JXG cases treated with chemotherapy suggests that symptomatic patients can successfully be treated with LCH-based regimens that include both corticosteroids and vinca alkaloids.     

Oral methotrexate and alternate-day prednisone for low-risk langerhans cell histiocytosis

Many treatments for low-risk Langerhans cell histiocytosis (LCH) involve unpleasant side-effects or risks of late effects. To provide treatment with minimal toxicity and no known risk of late effects, we have used oral alternate-day prednisone (PDN, 40 mg/sq.m./day) and weekly methotrexate (MTX, 20 mg/sq.m. once weekly) in a series of 13 children with 17 episodes of LCH. Patients were monitored with monthly physical examinations, blood counts and chemistry panels, and radiographs and scans obtained at the treating physician's discretion. Patients who responded had the prednisone tapered and MTX discontinued after three months of treatment. Recurrences while treatment was being tapered, or after its discontinuation, were managed with resumption of MTX and PDN. Treatment was successful in 16 of the 17 episodes, meaning that symptoms resolved and abnormal physical or radiographic findings improved. Symptomatic relief occurred in two weeks or less in 14 of 17 episodes; objective improvement generally occurred within one month, and in all cases by three months. The median duration of treatment was 5 months. Toxicity was limited to slight, transient elevations in hepatic enzymes in three patients. We conclude that oral chemotherapy with alternate-day PDN and weekly MTX is effective and non-toxic in patients with low-risk LCH. © 1995 Wiley-Liss, Inc.     

Langerhans cell histiocytosis with central nervous system involvement: follow-up by FDG-PET during treatment with cladribine

The prognosis of patients with Langerhans cell histiocytosis (LCH) involving the central nervous system (CNS) is generally poor, despite reports of clinical responses to chemotherapy, surgery, and radiation. We report on a patient with a 20-year history of relapsing multisystem LCH who developed progressive neuropsychiatric symptoms, including diplopia, ataxia, and mental deterioration. There was a regression of lesions in the brain stem and cerebellum following chemotherapy with cladribine (2-CdA) as evidenced by positron emission tomography (PET) scans. In conclusion, our experience is encouraging for the use of cladribine in CNS LCH. PET may be a useful modality for the monitoring of CNS disease activity in LCH and provides additional information in comparison with NMR imaging.     

DISSEMINATED MALIGNANT ECTOMESENCHYMOMA (MEM): Case Report and Review of the Literature

Malignant ectomesenchymoma (MEM) is a rare soft tissue tumor believed to arise from a pluripotent migratory neural crest cell and composed of both a mesenchymal element and a neuroectodermal element. The authors report the case of an 11-month-old male who presented with a local abdominal MEM and systemic metastases into lungs, liver, bones, and bone marrow. This is the first reported case of an MEM with initial bone marrow dissemination. The tumor consisted of a neuroblastoma component and a mesenchymal component with sarcomatous features. Diagnosis and therapy were complicated by the histological heterogeneity of the tumor, which also influenced the clinical appearance and course in this case. A literature search revealed 15 other evaluated cases that arose in soft tissue and had adequate clinicopathologic data. Complete surgical resection was the mainstay of treatment, and chemotherapy also appeared to be important. In all reported patients ( n = 3) with initial metastases or bone marrow dissemination, as in this case, no cure could be achieved. In patients with disseminated MEM, new therapeutic approaches such as high-dose chemotherapy followed by stem cell rescue should be considered, similar to the current strategy in patients with stage IV neuroblastoma or soft tissue sarcoma.     

Improved prognosis in disseminated histiocytosis

The prognosis for children with disseminated histiocytosis, previously considered poor, has improved dramatically with the application of modern principles of chemotherapy. Fourteen children with histiocytosis were staged clinically as follows: those without organ dysfunction, stage I; those with organ dysfunction, stage II; and histologically (B, benign and M, malignant). They were treated with either oral chlorambucil or combination chemotherapy with vinblastine and other agents. Clinical staging was of value in predicting response to treatment and prognosis, while histologic staging was of less value. Thirteen of the 14 children responded to treatment and are alive 4 to 67 months (median 12 months) after diagnosis. Two of these relapsed on treatment, and they have responded to a change in therapy. Two children relapsed after stopping treatment and were reinduced with reintroduction of similar therapy. Initial response to treatment suggests a favourable outcome, for children who initially responded to treatment but relapsed subsequently responded to either reintroduction of the same treatment or a change in treatment.     

A CASE OF MALIGNANT LYMPHOMA IN A PATIENT WITH HIGH LEVELS OF CA125 AND CA19-9

The authors encountered a case of malignant lymphoma in a patient who had high levels of CA125 and CA19-9. These tumor markers showed almost identical changes during the clinical course of the disease. To date, there has been no investigation of these markers as they relate to malignant lymphoma. Unfortunately, the normal values of CA125 and CA19-9 in children were not known and thus this case could not be compared with disease-free children. This study shows CA125 and CA19-9 levels of the children that do not have the malignant diseases, and reports on one case of malignant lymphoma in a patient who presented with high levels of these markers.     

Malignant histiocytosis in adults: Report of 7 patients from north east Italy

The clinical records and histologic material of seven adult male patients with malignant histiocytosis (MH), observed consecutively at our center during a four-year period, have been reviewed; four of these cases were seen in a year. All patients were born and lived within a radius of 30 miles from Pordenone, a town in northeast Italy. The diagnosis of MH was made in all cases on lymph node biopsy on the basis of the established histologic criteria [1]. At presentation, abnormal histiomonocytic cells were found in the bone marrow and peripheral blood of four patients, two of whom also showed cerebrospinal fluid involvement with atypical histiocytes at a relatively early stage of the disease. Staging procedures documented extensive disease in lymphatic, as well as in extralymphatic, sites in four patients; in three patients, the disease was confined to the lymphatic system. Combination chemotherapy was the first treatment employed in all cases. Four patients, three of whom had limited disease, achieved complete remission with quadruple combination chemotherapy (ABVD, CHOP, or MOPP); three patients with extensive disease achieved only partial remission of short duration with HOP. These results further support the view that adult MH is not obligatorily and rapidly fatal. Good responses to treatment with combination chemotherapy are possible, particularly in patients with disease limited to only lymphatic sites.     

CENTROFACIAL MALIGNANT T-CELL LYMPHOMA EXHIBITING RECURRENT FEVER AND SKIN ULCER IN A 3-YEAR-OLD GIRL

A rare case of undetermined fever and skin ulcers is reported. The patient had an 8-month history of recurrent fever, destructive ulceration of the midline facial tissue, and symmetrical skin ulcer in the cheeks and the back of the hand. Pathological examination revealed that the patient had lethal midline granuloma (centrofacial malignant T-cell lymphoma), which is very rare in childhood. Centrofacial malignant T-cell lymphoma should be considered as a differential diagnosis of unexplained fever and skin ulcer in children.     

OLFACTORY NEUROBLASTOMA AS A SECOND MALIGNANT NEOPLASM IN A PATIENT PREVIOUSLY TREATED FOR CHILDHOOD ACUTE LEUKEMIA

Various kinds of second malignant neoplasms after successful treatment for childhood acute leukemia have been reported. The authors describe an unusual case of an olfactory neuroblastoma in a patient previously treated for childhood acute leukemia including autologous bone marrow transplantation. The prophylactic cranial irradiation and the total body irradiation during autologous bone marrow transplantation may have induced the development of their patient's olfactory neuroblastoma. Although a second primary olfactory neuroblastoma is rare, it should be added to the list of second malignant neoplasmsin the sinonasal region.