Clinical Profile:

A one and half year-old boy was brought by his mother when she noticed gradual, diffuse abdominal distension, swelling over both feet, progressive yellowish discoloration of eyes and clay-coloured stools for three months. He also had intermittent low to moderate grade fever episodes since last four months with skin rashes

Radiological diagnosis:

One and half year boy with presence of moderate grade hepatosplenomegaly , ascites, generalized lymphadenopathy(predominantly cervical) , soft tissue nodule, pulmonary involvement in the form of multiple nodules, fibrosis and cystic changes, periportal hypodensities with discrete tiny liver lesions reveals multifocal multisystem involvement.

And with further clinico-biochemical correlation presence of skin lesions ,anemia, jaundice and bleeding tendencies- diagnosis of Multifocal multisystem LCH is made(Letterer Siwe disease)

Pathological diagnosis:

Skin biopsy was performed from one of the palm lesion displayed diagnostic features of Langerhans cell histiocytosis

Treatment

Received conservative management , received blood transfusion once in view of anemia.

Baby succumbed due to multiorgan failure.

Discussion

Langerhans cell histiocytosis (LCH) or formerly Histiocytosis X is the disease complex which includes eosinophilic granuloma, Letterer–Siwe disease and Hand–Schuller–Christian disease [1].

LCH can present in a variety of ways from a spontaneously regressing solitary lesion of bone to a multisystem life-threatening disorder. In all cases, the unifying histological finding is proliferation of the Langerhans cell [2].

The diagnostic imaging findings in paediatric LCH are diverse and challenging. In the paediatric population, the differing radiological findings are highly dependent on age and clinical presentation.

Letterer-Siwe disease

The term Letterer-Siwe disease first described in detail by Letterer (1924) and later recognized by Siwe (1933) as a well defined clinicopathological syndrome.

Letterer-Siwe disease is an illness of infants with age of incidence from two months to two years, almost invariably fatal, and of unknown etiology. [3]

The main clinical features are an indefinite onset with no specific symptomatology; a febrile course lasting for a few weeks or a few months to death; generalized enlargement of the lymph nodes, enlargement of the spleen and liver; haemorrhagic tendency, commonly producing a purpuric or ecchymotic skin rash most marked shortly before death; hypochromic anaemia, sometimes severe; destructive lesions in bone, commonly in the skull, rarely, if ever, in the bones of the hands and feet, but often occurring elsewhere in the skeleton, e.g. in the ribs, pelvis, humerus, femur, and may be clinically silent or associated with pain and tenderness, with or without overlying soft tissue swelling; sometimes mottling of the lung fields on x-ray examination; less commonly, secondary bacterial infection, such as otitis media or angina of the throat, and leucocytosis; no apparent hereditary or familial incidence.[3]

The characteristic pathological feature is excessive hyperplasia of the reticulo-endothelial tissue throughout the body, particularly in the spleen, lymph nodes, and skin.

Radiological features and differential diagnosis

Bones

Bone lesions are commonly found in patients with LCH. Any bone can be involved, but more than 50% of cases occur in the skull, spine, pelvis, ribs and mandible[4]

Skull

In the skull, the lesions are round and osteolytic with sharp borders and a “punched out” appearance.

In the acute phase, the differential diagnosis includes metastases and leptomeningeal cysts.

As the lesions start to heal and develop surrounding sclerosis, the differential includes fibrous dysplasia, epidermoid, meningocele and chronic osteomyelitis.

Involvement of both the outer and inner tables in varying degrees gives the characteristic beveled edge appearance on tangential views. Residual bone within a skull lesion can form a “button” sequestrum.

Orbit

Involvement of the orbital wall is a common manifestation and often results in proptosis. When the mastoid is involved, features can mimic mastoiditis, and extension to the petrous bone and middle ear can cause destruction of the ossicles and deafness. It has been estimated that between 15 and 61% of patients with LCH have otologic involvement, although this is more common with associated multisystem involvement [5].

Mandible

Mandibular involvement gives the typical appearance of “floating teeth” within the lytic lesion and is often associated with soft tissue swelling

Spine

In the paediatric spine, the thoracic vertebrae are most often involved (54%), followed by lumbar (35%) and cervical vertebrae (11%) [4] The body of the vertebra is more commonly affected than the posterior elements. Imaging often shows vertebral body collapse with the characteristic “vertebra plana” appearance.

LCH is the commonest cause of a vertebra plana in a child, however, the differential diagnosis includes metastases, lymphoma, trauma, Gaucher’s disease and haemangioma.

Long bones

Of the long bones, the diaphysis of the femur, tibia and humerus are most often involved, with endosteal scalloping, cortical thinning and widening of the medullary cavity[6]

The radiographic appearance of lesions depends on the phase of the disease and the site of involvement.

In the early stage, bony lesions may have an aggressive pattern of osteolysis and appear permeative with a wide zone of transition and a laminated periosteal reaction. The differential diagnosis includes osteomyelitis, Ewing’s sarcoma, leukemia and lymphoma.

In later stages, lesions have a more benign appearance with well defined sclerotic margins, a narrow zone of transition and a mature or absent periosteal reaction [6]. The differential diagnosis includes healing metastases, intraosseous haemangioma, fibrous dysplasia, giant cell tumor, aneurysmal and simple bone cysts, enchondroma and non-ossifying fibroma

Lymph nodes , Skin and Soft tissue

Cutaneous lesions are often the first manifestation of LCH, and consist of scaly erythematous red or brown papules. . When the skin is the only organ involved, the patient is usually a male infant less than 1 year of age [7].

Lymph node involvement usually affects the cervical chain and may reach a massive size with resultant local pressure effects such as airway compromise [8].

Isolated soft tissue masses may be found without associated bone disease.

Thymus

The thymus gland is commonly involved in LCH, especially in multisystem disease. Radiologically the gland is enlarged, may contain multiple cysts and has a heterogeneous contrast media enhancement pattern (Fig. 8) [9] The finding of punctate calcification in an enlarged thymus of an infant with skin, bone or lung disease is highly suggestive of LCH [10].Differentiating LCH from teratomas, calcification is larger and more discrete in teratoma[7].

Respiratory system

Pulmonary involvement usually manifests itself as part of multisystem LCH, having been reported in 42% of cases [11]. Isolated pulmonary involvement is rare [15].

Initial investigation with a chest radiograph, which shows reticular shadowing and in some cases nodules.

The best way to assess pulmonary involvement, is with high-resolution CT (HRCT). The HRCT findings of LCH are those of reticular or reticulonodular opacities, which progress to form cysts, and ultimately honeycombing [7]. Features predominate in the upper and mid-zones with sparing of the costophrenic angles [14].

Liver

The cause of liver pathology in LCH is due to either direct or indirect effects of the Langerhans cells. The indirect effects are reversible and occur due to activation of macrophages in our body leading to hepatomegaly, splenomegaly and hypoalbuminemia; however the Langerhans cells are absent on liver biopsy [12]. In case of direct liver involvement-two patterns are seen; first one is an infiltration of portal tracts without Langerhans cells; and the second one is characterized by the domination of Langerhans cells in the portal tracts and bile ducts [13]

Early imaging is usually by ultrasound, which shows periportal well-defined hypoechoic lesions in the proliferative, granulomatous and fibrous phases and hyperechoic lesions in the xanthomatous phase, relative to normal liver [16]. There is corresponding low attenuation on CT with enhancement after contrast media administration [16]. MRI shows the periportal distribution of lesions, which are of low signal intensity in the proliferative and granulomatous phases and of high signal intensity in the xanthomatous or fatty phase on T1- weighted images. T2-weighted images are ideal for demonstrating the dilatation and distortion of the intrahepatic bile ducts seen with the sclerosing cholangitis type appearance. Lesions have been shown to improve after chemotherapy [17].

Gastrointestinal tract

Enteric involvement has been described on barium studies as showing alternating segments of dilated and stenotic small and large bowel. However, as the findings are non-specific, biopsies are often needed for diagnosis [18].

Endocrine glands

Diabetes insipidus is more common in extensive disease. It is present in 5% of patients at the time of diagnosis, and presents with polydipsia and polyuria [19]. The imaging method of choice to assess the hypothalamus and pituitary stalk is MRI. Features include thickening of the pituitary stalk (>2.5 mm), which is best appreciated in either the coronal or sagittal plane. The thickened stalk enhances avidly after intravenous contrast media. In addition there is loss of the bright signal seen in the posterior pituitary on T1-weighted images [19]. (Ref image 1 and 2)The differential diagnosis includes germ cell tumors and granulomatous diseases.

Central Nervous System

Disease in the central nervous system (excluding diabetes insipidus) is seen in approximately 4% of cases. found in association with extensive disease and multiple bone lesions typically presents ~5 years after diagnosis. Presentations include ataxia, dysarthria, nystagmus and cranial nerve palsies [19].

Three patterns are described on MRI [20] (1) symmetrical, poorly defined white matter change involving predominantly the cerebellum and brainstem, which return low signal on T1-weighted images and high signal on T2-weighted images. (2) Well-defined high-signal changes on T2- weighted images in white and grey matter. (3) Extra parenchymal dural-based masses that are isointense to brain on T1- weighted images, hypointense on T2-weighted images and show contrast enhancement [20]. .

On biopsy these lesions have been shown to contain Langerhans cells [20].

Histopathological findings

Infiltration of multinucleate giant cells(langerhans/dendritic cells).

The infiltrate is composed of cells with irregular to folded nuclei with prominent nuclear grooves, vesicular chromatin, distinct nucleoli and moderate amounts of pale eosinophilic cytoplasm. Frequent admixed eosinophils are seen.

Immunohistochemical studies demonstrate that the lesional cells are strongly positive for CD1a, langerin, S100 and cyclin D1

Prognosis

In general, patients who are young and those in which the disease is present in many parts of the body and organ dysfunction tend to have a poorer prognosis. However newborns who present only with skin lesions show good outcome, therefore age at presentation is only important when multiple organs are affected.LCH involving liver, spleen, or bone marrow involvement is called “high-risk disease” and usually have a worse prognosis.

LCH in the skin, bones, lymph nodes or pituitary gland usually gets better with treatment and is called “low- risk.” .

The best prognostic indicator is the patient's response to chemotherapy during the first six weeks of therapy. Therefore, it has been recommended by some that individuals who do not respond positively within the first six weeks of treatment should be treated more aggressively.[21]

Treatment and follow up

Conservative medical management

Surgery (lymph node removal to relieve pressure symptoms/liver transplantation etc.)

Chemotherapy, a drug treatment that works by interfering with the cancer cell's ability to grow or reproduce. Different groups of chemotherapy drugs work in different ways. Your child may receive chemotherapy orally (as a pill to swallow), subcutaneously (under the skin), or intravenously (IV – as a direct injection into the bloodstream).

Radiation therapy, which uses high-energy rays (radiation) from a specialized machine to damage or kill abnormal cells and shrink tumors, is very rarely used for LCH therapy. However, in rare situations, small doses of this treatment may be used to help stop the growth of Langerhans cells in specific areas of the body.

Long term follow-up care is needed to detect late complications of the disease or treatment.

Complications due to disease: skeletal deformity or function, liver cirrhosis secondary to sclerosing cholangitis or lung problems, hormone abnormalities, dental issues or neurological and neurocognitive dysfunction.

Complications due to treatment: Malignancy secondary to treatment in the form of lymphoma, acute leukemia or solid tumors arising in the radiation field.

References:

[1]Writing Group of the Histiocyte Society. Histiocytosis syndromes in children. Lancet, 1987;2:41–42

[2] Chu T, Jaffe R. The normal Langerhans cell and the LCH cell. Br J Cancer, 1994;70(Suppl. XXIII):S4–S10.

[3] https://adc.bmj.com/content/archdischild/25/121/93.full.pdf

[4] Seibert D. Eosinophilic granuloma pediatric. Case of the day. AJR Am J Roentgenol, 1994;162:1473–1474

[5] Fernandez-Latorre F, Menor-Serrano F, Alonso-Charterina S, ArenasJimenez J. Langerhans cell histiocytosis of the temporal bone in pediatric patients: imaging and follow-up. AJR Am J Roentgenol, 2000; 174:217–221.

[6] Kumar R, David R, Oria R, et al. Radiologic features of eosinophilic granuloma of bone. AJR Am J Roentgenol, 1989;153:1021–1026.

[7] Smets A, Mortele K, De Practer G, et al. Pulmonary and mediastinal lesions in children with Langerhans cell histiocytosis. Pediatr Radiol, 1997;27:873–876.

[8] Broadbent V, Egeler RM, Nesbit ME. Langerhans cell histiocytosis— clinical and epidemiological aspects. Br J Cancer, 1994;70(Suppl. XXIII):S11–S16.

[9] Junewick J, Fitzgerald N. The thymus in Langerhans cell histiocytosis. Pediatr Radiol, 1999;29:904–907.

[10] Heller G, Haller J, Berdon W, et al. Punctate thymic calcification in infants with untreated Langerhans cell histiocytosis: report of four new cases. Pediatr Radiol, 1999;29:813–815.

[11] Ha SY, Helms P, Fletcher M, et al. Lung involvement in Langerhans cell histiocytosis: prevalence, clinical features and outcome. Paediatrics, 1992;89:466–469.

[12] T Gey, C Bergoin, N Just, T Paupard, D Cazals-Hatem, KH Xuan. Langerhans cell histiocytosis and sclerosing cholangitis in adults. Rev Mal Respir. 2004;21:997–1000.

[13] SL Guthery, JE Heubi. Liver involvement in childhood histiocytic syndromes. Curr Opin Gastroenterol. 2001;17:474–78.

[14] Koh D, Hansell DM. Computed tomography of diffuse interstitial lung disease in children. Clin Radiol, 2000;55:659–667.

[15]Sullivan JL, Woda B. Lymphohistocytic disorders. In Nathan G, Orkin S eds. Nathan and Oski’s Hematology of Infancy and Childhood, 5th edn. Philadelphia: W.B. Saunders, 1998; 1371–1377.

[16]Chan YL, Li CK, Lee CY. Sonographic appearances of hepatic Langerhans cell histiocytosis. Clin Radiol, 1997;52:761–763.

[17] Randall Radin D. Langerhans cell histiocytosis of the liver: imaging findings. AJR Am J Roentgenol, 1992;159:63–64.

[18] Wilman CL. Detection of clonal histiocytes in LCH: biology and clinical significance. Br J Cancer, 1994;70:529–583.

[19] Barkovich AJ. Pediatric Neuroimaging, 3rd edn. Philadelphia: Lippincott, Williams & Wikins, 2000.

[20] Grois N, Tsunematsu Y, Barkovich AJ, Favara BE. Central nervous system disease in Langerhans cell histiocytosis. Br J Cancer, 1994; 70(Suppl. XXIII):S24–S28.