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Table of Contents
Year : 2020  |  Volume : 3  |  Issue : 1  |  Page : 71-73

A puzzling case of brain disease following cutaneous lesions in childhood: A spectrum of disease or induced by therapy?

1 Department of Pathology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
2 Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia

Date of Submission11-Feb-2019
Date of Decision23-Apr-2019
Date of Acceptance11-Jul-2019
Date of Web Publication06-Jan-2020

Correspondence Address:
Khaldoon Aljerian
Department of Pathology, College of Medicine, King Saud University, P. O. Box: 11472, Riyadh 7805
Saudi Arabia
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/JNSM.JNSM_7_19

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How to cite this article:
Aljerian K, Alanazi L, Al Rajban W, Mubarak M, Khalifah M, Alsultan A. A puzzling case of brain disease following cutaneous lesions in childhood: A spectrum of disease or induced by therapy?. J Nat Sci Med 2020;3:71-3

How to cite this URL:
Aljerian K, Alanazi L, Al Rajban W, Mubarak M, Khalifah M, Alsultan A. A puzzling case of brain disease following cutaneous lesions in childhood: A spectrum of disease or induced by therapy?. J Nat Sci Med [serial online] 2020 [cited 2020 Apr 6];3:71-3. Available from: http://www.jnsmonline.org/text.asp?2020/3/1/71/266076

Our patient was a 20-year-old male, diagnosed at the age of 3 years with multiple skin plaques.

The cutaneous lesions were biopsied, and immunohistochemistry was positive for CD207 (langerin), CD1a, and S100. We also found bean-shaped nuclei and Birbeck granules under electron microscopy [Figure 1]. Our center did not have the capability to conduct an analysis for gene mutations.
Figure 1: Histopathology of the cutaneous lesion and electron microscopy images. Lesion cells were positive for (a) CD1a and (b) S100. Under electron microscopy, lesions cells showed (c) Birbeck granules and (d) grooved bean-shaped nuclei

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The patient was treated with vinblastine and prednisolone and at first had a complete response to therapy. However, he had recurrence of the skin disease 1 year after starting therapy. He was switched to etoposide and responded well, with no evidence of disease afterward. He completed therapy at the age of 6 years.

Then, 2 years later, at the age of 8 years, the patient presented with a seizure. A brain magnetic resonance imaging (MRI) showed bilateral enlarged choroid plexus as a result of intraventricular lesions; the patient was followed up frequently for signs of progression [Figure 2]. A follow-up brain MRI 2 years later showed progression of intraventricular lesions; the patient underwent surgical resection followed by radiotherapy at the age of 10 years.
Figure 2: Serial brain magnetic resonance imaging. (a) Age 8 years: bilateral enlarged choroid plexus with strong enhancement, in addition to mild thickening of pituitary stalk. (b) Age 10 years: further enlargement of choroid plexus with enlargement of temporal horns bilaterally, right more than left. (c) Age 12 years: postsurgical resection of intraventricular lesion with new enhancing lesion along the frontoparietal convexity. (d) Age 14 years: enlargement of the lesions in right trigone, along tentorium cerebelli and right frontoparietal convexity

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Subsequent follow-up brain MRIs showed new progressive lesions [Figure 2]. The patient was managed conservatively, but he presented with intractable seizures at the age of 18 years that required intensive care admission, and he subsequently underwent surgical resection of the frontoparietal lesions. The brain was biopsied again and revealed similar histopathology to the brain lesion resected when he was 10 years old [Figure 3].
Figure 3: Hematoxylin. and eosin-stained biopsies. (a) Diffuse dermal infiltrate of the lesion cells. (b) Foamy macrophages with some plasmacells and rare eosinophils. Some of the foamy macrophages were formed of multinucleated cells and contained several nuclei in a ring formation. (c and d) Brain tumor cells were positive for factor XIIIa and CD68

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The lesion was formed of sheets of foamy macrophages with some plasma cells and rare eosinophils. Some of the foamy macrophages were formed of multinucleated cells and contained several nuclei in a ring formation surrounding a central homogeneous eosinophilic cytoplasm with a surrounding foamy cytoplasm around the nuclei. The lesion cells were positive for expression of CD68 and factor XIIIa, as well as CD163 and fascin, and they were negative for CD207 (langerin), CD1a, and S100.

At age 20, the patient still has stable residual lesions in the right frontal lobe and right lateral ventricle.

  What Is the Diagnosis? Top


Langerhans cell histiocytosis (LCH) and juvenile xanthogranuloma (JXG) show a complex overlap at both clinical and histopathological levels, especially in children.[1] Most cases of JXG present as solitary cutaneous lesions.[2] Extracutaneous or systemic involvement is exceedingly rare,[3] and lesions of the nervous system account for only 1%–2.3% of JXG.[2] Both LCH and JXG have a chronic course and a tendency to affect the skin; both may also involve the soft tissues, internal organs, and bone.[1]

Some pathologists consider LCH and JXG to be dendritic cell disorders.[4] However, it is debatable whether JXG originates from macrophages or dendritic cells.[5] Some authors prefer to consider JXG under the monocyte/macrophage line,[1],[4] and JXG has a macrophage phenotype.[5] However, JXG has been documented to consist of dermal dendrocytes,[2] and like dermal/interstitial dendritic cell disorders, it shares factor XIIIa and fascin immunostaining.[5]

LCH is so named because the morphology and immunophenotype of these abnormal cells are similar to that of Langerhans cells – specialized dendritic cells found in the skin and mucosa.[4] Although it has been proposed that Langerhans cells are the cell of origin of LCH, gene expression arrays and other molecular investigations have shown that this is not the case.[4],[6] Rather, LCH is a myeloid dendritic cell[6] that expresses the same antigens (CD1a, CD207) as the skin Langerhans cell.[4] As well, advances in immunology and molecular biology have enhanced our ability to compare differences at the molecular level. We now know that LCH cells express CD1a, CD207 (langerin), and S100 but fail to express markers typical of a more mature dendritic cell, such as CD83.[7]

JXG is characterized by the presence of histiocytes, foam cells, and Touton giant cells; immunohistochemistry expression of factor XIIIa and fascin; and negative staining for CD1a and S100.[2] LCH cells are identified by the expression of CD1a, S100, and CD207 (langerin) and confirmed ultrastructurally by the presence of Birbeck granules.[8]

The development of LCH and non-LCH in the same patient is rare, either concurrently or in sequence, and the pathogenesis of this phenomenon is still unclear.[1]

Non-LCH histiocyte disorders such as JXG are known to occur as a reactive lesion.[1] It is known that LCH lesions produce enormous amounts of different cytokines, referred to as a “cytokine storm.” Chemotherapy itself could also play a role in changes to the cytokine microenvironment.[1] It is possible that the inflammatory reaction associated with LCH or chemotherapy precipitated the development of JXG.[1]

On the other hand, the association could be due to a common histogenetic precursor of the cell types involved. Some authors have suggested that JXG subsequent to LCH may represent a further transformation or “maturation” of LCH cells under the influence of modified cytokine production caused by chemotherapy, adding that this modification of cutaneous LCH lesions could be a favorable prognostic factor.[9]

An association between LCH and Erdheim–Chester disease has been reported, coexisting in the same lesion (mixed histiocytosis).[10] It has also been suggested that this association might involve BRAF V600E mutation.[10],[11],[12]

Histiocytic disorders are being recognized more and more often as our understanding of their molecular pathogenesis results in novel diagnostic tests and targeted drug development. In the present case, JXG likely arose as a reaction to the chemotherapy, because it developed 1 year after systemic chemotherapy, although we cannot be sure. Increased understanding of this phenomenon will expand our knowledge of the pathogenesis of both LCH and JXG, providing opportunities for more effective and personalized therapy in the future. We encourage further reports and research on this matter, with a view to improving treatment and diagnostic methods.

Final diagnosis

LCH, involving skin, bone, and bone marrow, was treated with chemotherapy. Several years later, the patient developed JXG.

  Clinicopathological Pearls Top

  1. LCH is characterized by Birbeck granules on electron microscopy
  2. JXG may follow cases of LCH
  3. Treatment effects may lead to the development of JXG.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

We acknowledge the College of Medicine Research Center for their support.

Conflicts of interest

There are no conflicts of interest.

  References Top

Strehl JD, Stachel KD, Hartmann A, Agaimy A. Juvenile xanthogranuloma developing after treatment of langerhans cell histiocytosis: Case report and literature review. Int J Clin Exp Pathol 2012;5:720-5.  Back to cited text no. 1
Deisch JK, Patel R, Koral K, Cope-Yokoyama SD. Juvenile xanthogranulomas of the nervous system: A report of two cases and review of the literature. Neuropathology 2013;33:39-46.  Back to cited text no. 2
Püttgen K. Juvenile Xanthogranuloma; 2016. Available from: http://www.uptodate.com/contents/juvenile-xanthogranuloma-jxg?source=see_link. [Last cited on 2016 Jun 04].  Back to cited text no. 3
McClain K. Clinical Manifestations, Pathologic Features, and Diagnosis of Langerhans Cell Histiocytosis; 2015. Available from: http://www.uptodate.com/contents/clinical-manifestations-pathologic-features-and-diagnosis-of-langerhans-cell-histiocytosis?source=preview&search=Histiocytic+disorders&language=en-US&anchor=H1& selectedTitle=3~150#H1. [Last cited on 2016 Jun 04].  Back to cited text no. 4
Swerdlow S. Who Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: International Agency for Research on Cancer; 2008.  Back to cited text no. 5
Allen CE, Li L, Peters TL, Leung HC, Yu A, Man TK, et al. Cell-specific gene expression in langerhans cell histiocytosis lesions reveals a distinct profile compared with epidermal langerhans cells. J Immunol 2010;184:4557-67.  Back to cited text no. 6
Ng-Cheng-Hin B, O'Hanlon-Brown C, Alifrangis C, Waxman J. Langerhans cell histiocytosis: Old disease new treatment. QJM 2011;104:89-96.  Back to cited text no. 7
Bains A, Parham DM. Langerhans cell histiocytosis preceding the development of juvenile xanthogranuloma: A case and review of recent developments. Pediatr Dev Pathol 2011;14:480-4.  Back to cited text no. 8
Patrizi A, Neri I, Bianchi F, Guerrini V, Misciali C, Paone G, et al. Langerhans cell histiocytosis and juvenile xanthogranuloma. Two case reports. Dermatology 2004;209:57-61.  Back to cited text no. 9
Hervier B, Haroche J, Arnaud L, Charlotte F, Donadieu J, Néel A, et al. Association of both langerhans cell histiocytosis and erdheim-chester disease linked to the BRAF V600E mutation. Blood 2014;124:1119-26.  Back to cited text no. 10
Ballester LY, Cantu MD, Lim KP, Sarabia SF, Ferguson LS, Renee Webb C, et al. The use of BRAF V600E mutation-specific immunohistochemistry in pediatric langerhans cell histiocytosis. Hematol Oncol 2018;36:307-15.  Back to cited text no. 11
Techavichit P, Sosothikul D, Chaichana T, Teerapakpinyo C, Thorner PS, Shuangshoti S, et al. BRAF V600E mutation in pediatric intracranial and cranial juvenile xanthogranuloma. Hum Pathol 2017;69:118-22.  Back to cited text no. 12


  [Figure 1], [Figure 2], [Figure 3]


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