Clinical Profile:

A 1.5 years old boy born of non-consanguineous marriage presented with fever since 15 days. He has been having  yellowish discoloration of eyes ,clay colored stools and dark urine since one month . He has a swelling on head since five months.

Examination Findings: The boy was icteric. There was a 3 cm. diameter non-tender, non-fluctuant, swelling over the left frontoparietal region of skull of approximate. There was moderate hepatomegaly.

             Fig. 1: Clinical images of the patient’s head reveal numerous raised, rough papules over the vertex region and a soft tissue swelling over the left fronto-parietal region.

Investigations: On presentation

- SGOT/SGPT = 153/92 IU

- TB/DB = 8.7/5.4 mg/dl

- Serum GGT = 663 U/l

- Urine routine microscopy = Bile salts and bile pigments ++

Radiological findings:

AP and lateral radiographs of skull are shown in Fig, 2.

FIG 2  AP and lateral radiographs of skull reveal a well-defined, solitary, lytic lesion with irregular margins and bevelled edges in the left fronto-parietal region.

Fig. 3 : Ultrasonography of the skull reveals a well-defined, heterogeneously hypoechoic lesion measuring approximately 3 x 1 cm within the diploic space of the left fronto-parietal region.  The calvarium is destroyed with the brain parenchyma een separately from the lesion. Doppler study reveals minimal venous vascularity within the lesion.

Ultrasonography of the abdomen revealed altered echotexture of the liver with dilatation of left biliary radicle demonstrating peripheral IHBRD. (Fig 4)

Fig. 4 Ultrasonography of the abdomen reveals altered echotexture of the liver with dilatation of left biliary radicle demonstrating peripheral IHBRD

MRCP revealed hepatomegaly with left lobe hypertrophy. There were areas of focal dilatation and constriction of intra-hepatic biliary radicles in left sectoral ducts suggestive of sclerosing cholangitis. (Fig 5)

Fig. 5: MRCP reveals hepatomegaly with left lobe hypertrophy. There are area of focal dilatation and constriction of intra-hepatic biliary radicles in left sectoral ducts suggestive of sclerosing cholangitis.T

FDG PET CT revealed uptake in lytic lesion over left frontal region of skull (SUV max 4.79), left humerus (SUV max 10.99), both tibia (SUV max 7-8). (Fig 6)

Fig. 6 : FDG PET CT reveals uptake in lytic lesion over left frontal region of skull (SUV max 4.79), left humerus (SUV max 10.99), both tibia (SUV max 7-8).

Radiological diagnosis:

In view of the bevelled edges of the skull lesion, a diagnosis of histiocytosis was made.

Pathological diagnosis: 

Histopathology: Skin biopsy was done from the left fronto-parietal lesion. It revealed acanthotic epidermis and few cells showing abundant eosinophilic cytoplasm with rounded, kidney shaped nuclei within lymphocytes. However, there were no multinucleated cells with necrotic areas and mitotic figures. (Fig 7) Hence, possibility of Langerhans Cell Histiocytosis was given.

Fig. 7: Histopathology of skin biopsy from the left fronto-parietal lesion reveals acanthotic epidermis and few cells showing abundant eosinophilic cytoplasm with rounded, kidney shaped nuclei within lymphocytes. 

Treatment:

The patient has been  started on a six week regimen of oral Prednisolone and IV Vinblastine. The patient tolerated the regimen well. Post chemotherapy, a  PET CT revealed increased FDG uptake compared to pre-chemotherapy PET CT suggestive of flare reaction. This was confirmed on histopathology from a CT guided biopsy of the right humerus.

 Timeline:     

Discussion

Langerhans Cell Histiocytosis (LCH) presents in a continuum of systemic involvement, ranging from a solitary eosinophilic granuloma to widespread disseminated disease with organ dysfunction (1).  The current classification system is based on the site of lesions, number of involved sites (single or multisystem/local or multifocal), and whether the disease is involving risk organs (hematopoietic system, liver, spleen). In a large cohort review, single-system and multisystem disease accounted for approximately half of the patients each. Among the patients with multisystem disease, approximately 15% of them had involvement of a risk organ (2).  The skeleton is the most commonly affected system, as bone lesions are present in approximately 80% of patients with LCH, and in half of them, lesions are single (3). The most common site of bone involvement is the skull, followed by spine, limbs, and pelvis (4). Our patient presented with involvement of bones and hepatobiliary system.

Lytic lesions of pediatric skull presenting as visual or palpable lesions have limited differentials including LCH, osteomyelitis, Ewing tumor, osteosarcoma and neuroblastoma metastasis. Our patient presented with a solitary lytic skull lesion with overlying soft tissue with “punched-out” morphology showing bevelled edges suggestive of LCH (5). 

Liver involvement in pediatric LCH typically presents with hepatomegaly, abnormal liver enzymes, or jaundice, associated with multiorgan involvement (6). As mentioned above, our patient presented with all these features. Hepatomegaly is a key sign of liver involvement and, along with other hepatic signs and symptoms, indicates the need for further investigations (7).

Liver involvement in LCH drastically changes a patient’s prognosis and treatment. It is associated with a high mortality rate in patients with LCH (8). Liver belongs to the risk organs. With liver involvement, the 3-year survival rate is 51.8% as compared to 96.7% in patients without (9).

An analysis of peripheral blood mononuclear cells (PBMCs) identified the presence of a small (<1%) but consistent proportion of BRAF-V600E mutations in myeloid cells (CD11c+ myeloid dendritic cell precursors and CD14+ monocytes) in patients with high-risk LCH. Similarly, in bone marrow samples, BRAF-V600E was identified in CD34+ hematopoietic stem cells from many patients with high-risk LCH. In contrast, BRAF-V600E was generally absent in PBMCs from patients with single lesion LCH and rare in the PBMCs of patients with multifocal low-risk LCH (10).

Diagnosis of LCH requires a clonal neoplastic proliferation with expression of CD1a, CD207 (Langerin), and S100. The cells are generally large, round to oval in shape, with a coffee-bean nuclear grove, and without the branching that characterizes inflammatory CD1a+ dendritic cells. On electron microscopy, pentalaminar cytoplasmic rod-shaped inclusions (Birbeck granules) can be identified, although electron microscopy is no longer required for diagnosis in the presence of CD207+ staining (11).

Due to the involvement of the liver in addition to bony lesions, our patient was classified into High Risk LCH. The mainstay of treatment of High Risk LCH is the use of chemotherapy and prednisolone involving an initial six-week course of prednisolone (40 mg/m2/day orally for four weeks followed by tapering over two weeks) and vinblastine (6 mg/m2 weekly intravenous bolus) as per the LCH III trial. The maintenance phase of therapy depends on the response to initial therapy, which is an important prognostic marker, upto a period of 1 year (12)(13).

PET scan is effective in evaluating response to treatment of most lesions except vertebral lesions, which may be better visualized by MRI that will capture changes in soft tissue or enhancement of the bone (14).

Langerhans Cell Histiocytosis is a rare disease entity in pediatric population which has multitude of presentations which require high degree of suspicion for diagnosis. However, a multi-modality radiological approach aids in raising significant possibility of LCH which can subsequently be confirmed by histopathology. Early treatment imitation is key to prolong survival in which radiological diagnosis plays a crucial role.

References: 

1. Allen CE, Merad M, McClain KL. Langerhans-cell histiocytosis. N Engl J Med. 2018;379(9):856-868.

2. Rigaud C, Barkaoui MA, Thomas C, et al. Langerhans cell histiocytosis: therapeutic strategy and outcome in a 30-year nationwide cohort of 1478 patients under 18 years of age. Br J Haematol. 2016;174(6):887-898.

3. Donadieu J, Egeler RM, Pritchard J. Langerhans cell histiocytosis: a clinical update. In: Weitzman S, Egeler RM, eds. Histiocytic disorders of children and adults, Cambridge: Cambridge University Press; 2005:95-129.

4. Morimoto A, Shioda Y, Imamura T, et al; Japan LCH Study Group. Intensification of induction therapy and prolongation of maintenance therapy did not improve the outcome of pediatric Langerhans cell histiocytosis with single-system multifocal bone lesions: results of the Japan Langerhans Cell Histiocytosis Study Group-02 Protocol Study. Int J Hematol. 2018;108(2):192-198.

5. Choudhary G, Udayasankar U, Saade C, Winegar B, Maroun G, Chokr J. A systematic approach in the diagnosis of paediatric skull lesions: what radiologists need to know. Pol J Radiol. 2019 Feb 8;84:e92-e111.

6. Kilborn TN, Teh J, Goodman TR. Paediatric manifestations of Langerhans cell histiocytosis: a review of the clinical and radiological findings. Clin Radiol. 2003;58:269–78.

7. Schmidt S, Eich G, Geoffray A, Hanquinet S, Waibel P, Wolf R, Letovanec I, Alamo-Maestre L, Gudinchet F. Extraosseous langerhans cell histiocytosis in children. Radiographics. 2008;28:707–26. 

8. Savasan S. An enigmatic disease: childhood Langerhans cell histiocytosis in 2005. Int J Dermatol. 2006;45:182–8.

9. Kudo K, Ohga S, Morimoto A, Ishida Y, Suzuki N, Hasegawa D, Nagatoshi Y, Kato S, Ishii E. Improved outcome of refractory Langerhans cell histiocytosis in children with hematopoietic stem cell transplantation in Japan. Bone Marrow Transplant. 2010;45:901–6.

10. Berres ML, Merad M, Allen CE. Progress in understanding the pathogenesis of Langerhans cell histiocytosis: back to Histiocytosis X? Br J Haematol. 2015;169:3–13.

11. Picarsic J, Jaffe R. Nosology and Pathology of Langerhans Cell Histiocytosis. Hematol Oncol Clin North Am. 2015;29(5):799-823.

12. Suthersan S, Ong FM, Maruthamuthu T, Periasamy C, Goh BS. Pediatric Langerhans Cell Histiocytosis: An Aggressive Presentation. Cureus. 2022 Jun 6;14(6):e25684. 

13. Gadner H, Grois N, Arico M, et al. Histiocyte Society. A randomized trial of treatment for multisystem Langerhans’ cell histiocytosis. J Pediatr. 2001;138(5):728–734.

14. Phillips M, Allen C, Gerson P, McClain K. Comparison of FDG-PET scans to conventional radiography and bone scans in management of Langerhans cell histiocytosis. Pediatr Blood Cancer. 2009;52(1):97–101.

Acknowledgement :

We are grateful to the Department of Pathology at our institution for sharing the histopathology images and their legends.