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CASE REPORT |
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| Systemic xanthogranuloma involving bone marrow and skin in a case of B-Lymphoblastic Leukemia |
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Manasi C Mundada1, Faiq Ahmed1, Suseela Kodandapani1, Veerendra Patil2
1 Department of Laboratory Medicine, Basavatarakam Indo American Cancer Hospital, Banjara Hills, Hyderabad, Telangana, India
2 Department of Medical Oncology, Basavatarakam Indo American Cancer Hospital, Banjara Hills, Hyderabad, Telangana, India
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| Date of Submission | 27-Dec-2021 |
| Date of Decision | 29-Apr-2022 |
| Date of Acceptance | 29-Apr-2022 |
| Date of Web Publication | 27-Jan-2023 |
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 Abstract | | |
Juvenile xanthogranuloma is a benign self-limiting lesion commonly described in infants and young children. It most commonly involves the skin presenting as single or multiple yellowish-brown papules. Clinical scenario with the classic histomorphology showing histiocytic aggregates in the dermis with xanthomatous cytoplasm, toutan type giant cells, immunohistochemistry with positive CD68, CD163, factor XIIIa and negative CD1a and S-100 help in diagnosis. However, diagnosis becomes challenging with predominant systemic bone marrow involvement in post-B-lymphoblastic leukemia settings.
Keywords: Bone marrow involvement, juvenile xanthogranuloma, post –lymphoblastic leukemia
How to cite this URL:
Mundada MC, Ahmed F, Kodandapani S, Patil V. Systemic xanthogranuloma involving bone marrow and skin in a case of B-Lymphoblastic Leukemia. Indian J Pathol Microbiol [Epub ahead of print] [cited 2023 Mar 27]. Available from: https://www.ijpmonline.org/preprintarticle.asp?id=368576 |
| Introduction | |  |
Histiocytic neoplasms are known to occur concurrently or post hematopoietic neoplasms like mature non-Hodgkin lymphoma, acute leukemia (B, T, or myeloid), and chronic myelomonocytic leukemia to name a few.[1] A variety of histiocytic lesions have been described post acute leukemia like Langerhan cell histiocytosis (LCH), juvenile xanthogranuloma, Rosai Dorfman Destombes disease, histiocytic sarcoma, and Langerhan cell sarcoma.[2] Disseminated juvenile xanthogranuloma with systemic involvement is rare and has a more aggressive clinical course.
| Case Report | | |
A 14-year-old boy presented to the hospital with complaints of generalized weakness of a 4-month duration with pain in the abdomen on and off. The peripheral blood examination showed a hemoglobin of 12 gm/L, a WBC count of 67,000 × 109/L, and a platelet count of 4 × 109/L. Differential leucocyte count revealed 85% blasts, 14% lymphocytes, and 1% neutrophils [Figure 1]. Flow cytometry was done, and the diagnosis of B-lymphoblastic leukemia (B-LL), common acute lymphoblastic leukemia-associated antigen (CALLA) positive was rendered. The prognostic panel for mutations (BCR-ABL1, MLL, and TEL-AML) was negative. Cytogenetics showed a normal genotype (46 XY). The patient was started on chemotherapy as per Berlin-Frankfurt-Munich protocol for Acute lymphoblastic leukemia (BFMALL) protocol. He had IV cannula site mucormycosis post day 22 of induction chemotherapy, which had disseminated to the liver and lung. He was treated with antifungals (amphotericin B and posaconazole combination) and underwent surgical debridement of all affected sites. A postinduction marrow examination showed disease in remission, and minimal residual disease testing was negative (<0.01%). The patient was started on consolidation chemotherapy with 6-mercaptopurine and intrathecal methotrexate along with antifungal therapy. The fungal disease showed a good response to the treatment. Four months after the initial diagnosis of B-lymphoblastic leukemia, the patient presented with severe back pain of few days' duration, clinically there was tenderness over the lower spine. Also noticed were a few papular skin lesions over the chest and abdomen. A peripheral blood examination showed bicytopenia. A magnetic resonance imaging of the spine showed diffuse infiltration of the dorsal and lumbar vertebral bodies and both the femurs [Figure 2]. A bone marrow aspiration and biopsy were done. Aspiration smears showed hypercellular marrow with areas of normal hematopoiesis and sheets of histiocytes. The histiocytes showed bland nucleus, and binucleation at places with abundant cytoplasm showing the xanthomatous change. Very occasionally nuclear grooving was noted, and no malignant cells were seen [Figure 3]. Focally, hemophagocytic activity was seen. However, the workup for systemic hemophagocytic lymphohistiocytosis (HLH) with the serum ferritin, serum triglyceride, and serum fibrinogen were within the normal range. | Figure 1: Leishman stained peripheral smear showing the presence of blasts. The cells are 11/2–2 times the size of mature lymphocytes, high nucleo-cytoplasmic ratio, open chromatin with occasional nucleoli, and scant cytoplasm. (400×)
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 | Figure 2: MRI short tau inversion recovery (STIR) images showing multiple lesions in the lumbar spine and both femurs
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 | Figure 3: (a) Bone marrow aspirate showing sheets of histiocytes admixed with normal hematopoietic marrow cells (Leishaman, 100×). (b) Bone marrow aspirate showing sheets of histiocytes with xanthomatous cytoplasm (400 ×, Leishman). (c) Bone marrow aspirate showing few histiocytic cells with nuclear grooves (400×, Leishman). (d) Clinical photograph showing the presence of papular skin lesions predominantly on the chest and abdomen. (e) Microphotograph of skin biopsy showing sheets of histiocytes occupying the upper and deep dermis. The cells show predominantly pink cytoplasm and a few toutan giant cells are also seen (100×, H and E)
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The trephine biopsy showed patchy involvement by sheets of histiocytes, and no leukemic cells were seen [Figure 4]. Skin biopsy from the lesions showed thinned epidermis with sheets of monomorphic cells infiltrating the superficial and deep dermis [Figure 3]. The cells showed a delicate nuclear membrane, grooving at places, and eosinophilic cytoplasm. Few toutan-type giant cells were seen. Lymphoplasmacytic infiltrate or eosinophils were not seen. Immunohistochemistry (IHC) done in parallel on trephine biopsy and skin showed CD68, CD163, factor XIIIa, and patchy S100 [Figure 4] and [Figure 5]. CD1a, Langerin, and serine–threonine protein kinase B-RAF (BRAF) (by IHC and polymerase chain reaction) were negative. A diagnosis of non-Langerhan's histiocytosis favoring a juvenile xanthogranuloma, the disseminated type was rendered. He was started on weekly vinblastine and prednisolone therapy. The skin lesion showed a good response, but the cytopenia persisted along with refractory thrombocytopenia. He also developed the drug vinblastin-induced syndrome of inappropriate antidiuretic hormone secretion (SIADH) requiring frequent hospitalizations. The patient was lost to follow-up as the parents opted for alternative medicine therapy. | Figure 4: (a) Trephine biopsy showing sheets of histiocytes with normal marrow elements (H and E,100×). (b) CD163 highlights sheets of histiocytes (100×). (c) Factor XIIIa showing membranous and cytoplasmic staining (100 ×). (d) CD1a negative in trephine biopsy (100×). (e) S100 cytoplasmic and membranous positive in histiocytes (100×)
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 | Figure 5: (a) Diffuse positive for CD163 in skin biopsy (100×). (b) Patchy S100 positive in neoplastic cells (skin, 400×). (c) CD1a negative in neoplastic cells (skin, 100×). (d) Diffuse positive for factor XIII a (skin, 100×)
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| Discussion | | |
Disseminated juvenile xanthogranuloma (JXG) shows proliferation of histiocytes with foamy cytoplasm and toutan-type giant cells.[3],[4] Generally, the disease presents itself in infancy, with a localized form involving the skin. The lesions can be single or multiple, yellowish to brown papules, generally more in the head and neck region. However, in disseminated disease, multiple systems like a mucous membrane, central nervous system, eye, liver, lung, and lymph nodes might be involved.[4] Bone marrow involvement is also described. These patients present with acute bony pain with cytopenia depending on the extent of involvement.[5],[6] In the present case, the patient had bicytopenia due to extensive bone marrow infiltration by sheets of histiocytes. However, the classic toutan giant cells noted in skin biopsy were not seen in bone marrow aspirate smears. Skin biopsy failed to show the xanthomatous cytoplasm; however, these lesions are known to show polymorphic morphological patterns.[3] Immunohistochemistry (IHC) was directed to rule out Langerhans cell histiocytosis (LCH) (CD1a, langerin, and BRAF), all the three markers were negative, and the IHC markers are of limited help in non-LCH cases due to considerable phenotypic overlap. However, the typical immunophenotype described in JXG is macrophage markers (CD68, CD163, factor XIIIa), S100 is generally negative, however, has been reported positive in few cases.[7]
Erdheim Chester disease (ECD) and Rosai Dorfman Destombes (RDD) disease form close differential diagnoses in systemic histiocytosis with skin involvement.[3] ECD was ruled out in the absence of typical radiological features (symmetric bony sclerotic lesions, hairy kidney, cardiovascular system involvement). RDD can show both bony/bone marrow involvement with skin lesions; however, typical histopathological features of histiocytes showing abundant transparent cytoplasm, lymphoplasmacytosis were not seen. Xanthoma disseminatum can also present with systemic involvement but was ruled out in the absence of the peculiar dominating flexural skin lesions.
The literature review showed 63 cases of disseminated JXG post B-LL, 11 cases of which predominantly involved the bone marrow.[5],[6] Of these cases, only two cases were described in adolescent boys [Table 1]. Both the patients showed good responses to polychemotherapy regimens. However, in the present case, we had a short follow-up as the patient deferred further treatment. | Table 1: Summary of the cases of juvenile xanthogranuloma in adolescent age group, post ALL reported in the literature presenting with predominant bone marrow involvement
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At the molecular level, mitogen-activated protein (MAP) kinase pathway abnormalities have been described in a few cases of systemic JXG, reminiscent of the "L" subgroup of histiocytosis.[8] Similarly, an association of JXG has been reported with neurofibromatosis (NF1 and NF2) abnormalities with an increased risk of developing juvenile myelomonocytic leukemia.
Unique features of the histiocytic neoplasms are that they can occur concurrently or develop later following diagnosis of hematolymphoid malignancies, for instance, the development of histiocytic sarcoma in non-Hodgkin lymphoma by the process of transdifferentiation,[9] which can involve the same immunoglobulin gene,[6],[8] raising the possibility of common progenitor for the hematolymphoid and histiocytic neoplasm.[8] Similarly, the presence of mutations has been described in the circulating blood monocytes, and histiocytes in the case of ECD, supporting the evidence of common hematopoietic progenitor cell. In the present case, we could not establish a common clonal origin for B-LL and JXG due to the paucity of the earlier sample DNA.
Disseminated JXG with extensive bone marrow involvement in the adolescent age group, post B-LL is an uncommon clinical scenario. Non-LCH lesions though a distinct category are difficult to differentiate on histomorphology alone, a complete clinico-radiological correlation is required for a definite diagnosis.
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Conflicts of interest
There are no conflicts of interest.
| References | | |
| 1. | Kemps PG, Hebeda KM, Pals ST, Verdijk RM, Lam KH, Bruggink AH, et al. Spectrum of histiocytic neoplasms associated with diverse haematological malignancies bearing the same oncogenic mutation. J Pathol Clin Res 2021;7:10-26.  |
| 2. | Castro EC, Blazquez C, Boyd J, Correa H, de Chadarevian JP, Felgar RE, et al. Clinicopathologic features of histiocytic lesions following ALL, with a review of the literature. Pediatr Dev Pathol 2010;13:225-37. |
| 3. | Krooks J, Minkov M, Rapperberger K. Histiocytosis: A review of the most recent classification system.Practical Dermatology 2018:41-52. |
| 4. | Brousse N, Pileri SA, Haroche J, Dagna L, Jaffe R, Fletcher CDM, et al. Disseminated juvenile xanthogranuloma. In: Swerdlow SH, Campo E, Harris NL, Elaine JS, Pileri SA, Stein H, et al (eds) WHO classification of tumours of haematopoietic and lymphoid tissues, Revised 4th edn. IARC Press, Lyon.2017;480. |
| 5. | Cheon E, Yang S, Han JH, Lee KC, Park JE. Systemic juvenile xanthogranuloma involving the bone marrow, multiple bones, and the skin that developed during treatment of acute lymphoblastic leukemia in remission state. Pediatr Dev Pathol 2018;21:489-93. |
| 6. | Pawińska-Wa¸sikowska K, Cwiklinska M, Wyrobek E, Balwierz W, Bukowska-Strakova K, Dluzniewska A, et al. Disseminated juvenile xanthogranuloma and hemophagocytic lymphohistiocytosis developed during treatment of acute lymphoblastic leukemia: Case report. Front Oncol 2020;10:921. |
| 7. | Kraus MD, Haley JC, Ruiz R, Essary L, Moran CA, Fletcher CD. "Juvenile" xanthogranuloma: An immunophenotypic study with a reappraisal of histogenesis. Am J Dermatopathol 2001;23:104-11. |
| 8. | Emile JF, Cohen-Aubart F, Collin M, Fraitag S, Idbaih A, Abdel-Wahab O, et al. Histiocytosis. Lancet 2021;398:157-70. |
| 9. | Mundada MC, Ahmed F, Murthy S, Mallavarapu KM. An interesting case of lineage switch to histiocytic sarcoma in a case of diffuse large B cell lymphoma. Asian J Oncol 2019;5:93-6. |
Correspondence Address:
Manasi C Mundada,
Department of Laboratory Medicine, Basvatarakam Indo American Cancer Hospital and Research Institute, Rd No 10 Banjara Hills, Hyderabad, Telangana - 500 034
India
 Source of Support: None, Conflict of Interest: None DOI: 10.4103/ijpm.ijpm_1253_21
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
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