Int J Hematol (2011) 93:389–393 DOI 10.1007/s12185-011-0787-x
CASE REPORT
Juvenile myelomonocytic leukemia characterized by cutaneous lesion containing Langerhans cell histiocytosis-like cells Shuichi Ozono • Hiroko Inada • Shin-ichiro Nakagawa • Koichiro Ueda • Hideki Matsumura • Seiji Kojima • Hiroshi Koga • Takashi Hashimoto • Koichi Oshima • Toyojiro Matsuishi
Received: 8 October 2010 / Revised: 7 February 2011 / Accepted: 9 February 2011 / Published online: 25 February 2011 Ó The Japanese Society of Hematology 2011
Abstract We present a 1-year-old boy who developed a cutaneous lesion on the trunk and hepatosplenomegaly. Laboratory examination showed leukocytosis with peripheral blasts, atypical monocytosis, anemia, hyper IgG, and a mild elevation of C-reactive protein. Clinical features and skin biopsy findings matched the diagnostic criteria of both juvenile myelomonocytic leukemia (JMML) and Langerhans cell histiocytosis (LCH). Histopathology revealed atypical mononuclear cells that had infiltrated around vessels throughout the dermis in a skin biopsy specimen. These cells were CD1a (?), S-100 (?), CD68 (?), CD207 (2), lysozyme (?), and myeloperoxidase (2). The diagnosis of JMML was confirmed by detection of spontaneous colony formation and granulocyte–macrophage colonystimulating factor hypersensitivity in vitro, and a somatic
NRAS point mutation. Transplantation of bone marrow from an HLA-matched unrelated donor was performed, and the marrow was successfully engrafted. The cutaneous lesion and hepatosplenomegaly were improved at the time of discharge. It is often difficult to distinguish between JMML and LCH-like infiltrates by assessing clinical and light microscopic features of various cutaneous lesions. In the current case, molecular biological analysis enabled us to develop a precise diagnosis. Keywords Juvenile myelomonocytic leukemia Langerhans cell histiocytosis Cutaneous lesion Somatic NRAS mutation
1 Introduction
S. Ozono (&) H. Inada S. Nakagawa K. Ueda T. Matsuishi Department of Pediatrics and Child Health, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka 830-0011, Japan e-mail:
[email protected] H. Matsumura S. Kojima Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan H. Koga T. Hashimoto Department of Dermatology, Kurume University School of Medicine, Kurume, Japan K. Oshima Department of Pathology, Kurume University School of Medicine, Kurume, Japan
Juvenile myelomonocytic leukemia (JMML) is a rare pediatric hematological malignancy, which is classified as a myelodysplastic/myeloproliferative neoplasm (MDS/ MPN) [1]. JMML is characterized by prominent hepatosplenomegaly, frequent cutaneous lesions, monocytosis, leukocytosis, and the presence of immature precursors in peripheral blood. The main diagnostic criteria are as follows: peripheral blood monocytosis [1 9 109/L, blasts (including promonocytes) compose less than 20% of both the leukocytes in the blood and the nucleated bone marrow cells, absence of the Philadelphia (Ph1) chromosome or the BCR–ABL fusion gene, elevated HbF levels, immature granulocytes in the peripheral blood, and granulocyte– macrophage colony-stimulating factor (GM-CSF) hypersensitivity of myeloid progenitors in vitro [2]. Since JMML is refractory even to various chemotherapeutic agents, hematopoietic stem cell transplantation is recommended for curable treatment [3, 4].
123
390
Langerhans cell histiocytosis (LCH) is characterized by a clonal proliferation of Langerhans cells, resulting in various clinical features. Clinical manifestation varies from a single lytic bone lesion with a curable course to multiorgan involvement with a fatal outcome, mainly from progressive organ dysfunction [5, 6]. The keystone for a diagnosis of LCH includes not only the determination of characteristic clinical features but also the confirmation of histopathological and immunohistochemical findings. Since 50–80% LCH cases show cutaneous involvement, a skin biopsy is the most easily accessible means to confirm the diagnosis [7]. A confirmative diagnosis requires positive staining with S-100 and CD1a in lesional cells by light microscopic findings, and Birbeck granules must be identified on electron microscopy. Although JMML and LCH are pathologically different diseases, JMML and multisystem-type LCH usually demonstrate similar clinical features (e.g., cutaneous lesions, hepatosplenomegaly, repetitive otorrhea, pulmonary lesion, etc.). Several case reports indicate an association of LCH with various malignancies [8, 9]. We report a pediatric patient of JMML with a cutaneous lesion partly demonstrating immunohistochemical findings of LCH.
2 Case report A 1-year-old Japanese boy was admitted to our institute because of a skin eruption and hepatomegaly. He was the second child of healthy parents, weighing 3320 g at fullterm delivery after an uneventful course of pregnancy. Eczematous skin lesions were noticed at his 3-month routine health check. He had a history of having otitis media twice. No family history of malignancy was indicated. Physical examination upon admission revealed a pale listless boy of 70.6 cm in height (-2.1 SD) and 8070 g in weight (-1.4 SD). His body temperature was 37.6°C. Conjunctiva was anemic but not icteric. His right ear drum was slightly reddish. He showed numerous asymptomatic small erythematous plaques measuring less than 0.3 cm in diameter on his chest, back, abdomen, and lower extremities (Fig. 1a). Chest auscultation revealed normal respiratory sounds and a regular heart rhythm with no murmur. The liver was palpable approximately 6 cm below the right costal margin and the spleen 4 cm below the left costal margin. Peripheral blood counts showed a WBC count of 30.0 9 109/L (0.3% blasts, 0.7% myelocytes, 1.0% stab neutrophils, 22.7% segment neutrophils, 54.3% lymphocytes, 12% monocytes, 7.7% atypical lymphocytes, and 0.3% erythroblasts). A peripheral blood smear showed atypical monocytes and rare circulating blasts. RBC count was 4270 9 109/L [hemoglobin 8.8 g/dL, 3.2% hemoglobin F level (age-matched normal value \2.0%), 28.1%
123
S. Ozono et al.
hematocrit], and platelet count was 106 9 109/L. The reticulocyte count was 68.0 9 109/L. Prothrombin time (15.2 s; control 12.0) and activated thromboplastin time (35.1 s; control: 32.5) were normal. Fibrinogen (311 mg/dL) and fibrinogen degradation products (2.5 lg/mL) were normal. Blood chemistries revealed normal levels of transaminase, lactate dehydrogenase, total protein, albumin, total/ direct bilirubin, urea nitrogen, creatinine, and ferritin, as well as low levels of total cholesterol (76 mg/dL) and iron (22 lg/dL). The C-reactive protein level was 1.71 mg/dL. Serum immunoglobulin (Ig) levels were IgG 2088 mg/dL, IgA 249 mg/dL, and IgM 323 mg/dL. Serum sIL2R was elevated (3051 U/mL). Antiviral titers for cytomegalovirus (CMV) revealed an elevation of serum IgM (antibody index of 5.5 by the enzyme immunoassay) and IgG (antibody index of 8.5), indicating recent CMV infection. An X-ray survey and bone and tumor scintigraphies found no focal lesion, including in the cranial bone. A chest and abdominal computed tomography scan revealed bilateral lung infiltration and marked hepatosplenomegaly. Bone marrow aspiration showed mild myeloid hyperplasia with an increased percentage of dysplastic monocytes and lymphocytes (nucleated cell count of 142 9 109/lL; 4.3% blasts, 9.0% monocytes, 32.7% lymphocytes). G-banding analysis revealed a karyotype of 46XY in 20 of 20 metaphases examined. Neither the Philadelphia (Ph1) chromosome nor the BCR–ABL rearrangement was detected. A histopathologic study of a biopsied skin lesion of the popliteal space showed invasion of atypical mononuclear cells around vessels throughout the dermis. Some of these cells had relatively abundant cytoplasm or lobulated nuclei, indicating atypical monocytes or small lymphocytes. Cell suspensions prepared from this skin tissue were stained positively for CD1a and S-100, which were specific findings for LCH; however, CD207 (langerin) was negative. On the other hand, CD68 and lysozyme, which were specific for JMML, were positive, while myeloperoxidase was negative (Fig. 1b–f). Thus, microscopic findings were not typical for either LCH or JMML. Electron microscopy for the detection of Birbeck granules was not performed. In addition, in vitro cultures of the patient’s bone marrow cells revealed spontaneous proliferation of monocyte colonies with no growth factor and extremely high proliferation of the colonies with GM-CSF. A somatic NRAS mutation [GGT(Gly) ? GAT(Asp)] at codon 13 was revealed by polymerase chain reaction in two separate blood samples. Ultimately, the patient was diagnosed as JMML. Since the diagnosis of JMML was confirmed about one and half months after admission, the patient received the chemotherapy for LCH at first. The patient was treated by vincristine, Ara-C, and prednisolone for 1 month. The leukocytosis was improved, whereas the skin eruptions and
JMML with LCH-like cutaneous lesion
391
Fig. 1 Clinical and histological findings. Multiple erythematous plaques of less than 0.3 cm in diameter were observed on the patient’s chest (a). Histopathological invasion of atypical mononuclear cells around vessels was observed throughout the dermis. Some of these had lobulated or coffee bean-like nuclei (arrows) (H&E; low 950; high 91000) (b). CD1a (?) (c), S-100 (?) (d), CD68 (?) (e), and lysozyme (?) (f) cells were scattered throughout the dermis (9400). CD207 (g) and myeloperoxidase (h) were not stained (9400)
hepatosplenomegaly were not improved after the treatment. After the diagnosis was confirmed as JMML, 6-mercaptopurine (6MP) was administered as a maintenance therapy while the patient awaited a stem cell transplantation. The WBC count was controlled at 8–15 9 109/L, and minor infections (e.g., otitis media and bronchitis) had been controlled by oral antibiotics. The eczema had been resolved 2 months after 6MP had started, but the hepatosplenomegaly was not improved during maintenance therapy. Nine months after the first visit, a stem cell transplantation from an HLA
full-matched unrelated donor was performed, and this graft was accepted. The cutaneous lesions and hepatosplenomegaly had been improved at the time of discharge.
3 Discussion In this case report, we described an infant who showed hepatosplenomegaly, anemia, repetitive otitis media, and skin lesions. Clinical findings of this case showed several
123
392
common features for both JMML and LCH (i.e., hepatosplenomegaly, cutaneous lesion, pulmonary infiltration, anemia, thrombocytopenia, and fever). Meanwhile, leukocytosis with monocytosis, peripheral blast cells, and an elevation of HbF were specific findings for JMML. Ultimately, this patient was diagnosed with JMML. A somatic NRAS point mutation was detected by a polymerase chain reaction test, which is now widely performed practice for the molecular pathogenesis of JMML [4]. Objectively, JMML is related to organ infiltration, such as the liver and spleen, and other frequent infiltration sites are the skin and lungs. Skin lesions are reported to appear in 36–48% of patients [2, 3], and most of them have been reported as reactive lesions, referred to as ‘‘leukemids’’, neurofibromatosis, and xanthogranuloma [10, 11]. On the other hand, several cases with leukemic skin infiltration have been reported [12, 13]. In these case reports, leukemic cells were positive for CD14, CD36, CD68, lysozyme, myeloperoxidase, and XIIIa by immunohistochemical studies. In one JMML case, immunoreactivity for the S-100 protein, which occurs in antigen-presenting cells, including indeterminate cells, interdigitating reticulum cells, Langerhans’ cells, and veiled cells, was a characteristic finding [14]. In our case, CD68, lysozyme, and S-100 were positive in immunohistochemical findings, while myeloperoxidase was negative. A clear detection of cutaneous infiltration of leukemic cells was regarded as the most definite diagnosis. However, the constricted shaped nuclei and the positivity for S-100 and for CD1a antigen apparently pointed to LCH [15]. Meanwhile, in view of the lack of expression of CD207 (langerin), an LCH diagnosis was incomplete in this case [16, 17]. Consensus has yet to be reached as to whether such events should be categorized as part of the spectrum of LCH, or whether they should be clearly classified as an LCH-like event of JMML. Some authors have argued that indeterminate cell histiocytosis (ICH) is considered a dedifferentiated type of the LCH family, but others argue that it is an unrelated disease [18]. In ICH, S-100 and CD1a antigen are present, and CD207 (langerin) is absent. This phenomenon accounts for the lack of Birbeck granules because their structure is generated by the endocytic receptor langerin [19]. The controversial discussion about the categorization of ‘incomplete’ LCH-like disease is mainly consequent of the lack of clarity surrounding the pathogenesis of LCH. Whether LCH is reactive or neoplastic is under-debated, and several characteristics, such as spontaneous recovery from the disease [20] and clonality of lesional LCH [21], provide apparently contradictory evidence. The benign nature of its proliferating cells and its typical inflammatory infiltrates indicate that LCH may be an inflammatory disease. In addition, dysregulational expression of inflammatory
123
S. Ozono et al.
cytokines such as IL-17A has been reported [22]. On the other hand, as a common genomic abnormality, which indicates neoplasia, the recurrent BARF mutation was found in 57% of LCH cases [23]. In terms of treatment strategies for this case, JMML is usually a rapidly progressing fatal disease if untreated. The probability of survival without allogeneic hematopoietic stem cell transplantation (HSCT) is less than 10% [9]. Nowadays, HSCT is the sole therapy for long-term remission of the disease. A preparative regimen with a busulfan-based protocol showed better 5-year survival than a total body irradiation-based regimen [24]. Mercaptopurine, given either as a single drug or in combination with low-dose cytarabine, is usually administered prior to HSCT to control WBC although it may not improve the prognosis [4]. In our case, allogeneic unrelated HSCT with a busulfan-based preparative regimen probably leads the disease into remission. In summary, this patient demonstrated features of both JMML and LCH in clinical manifestation and a skin biopsy. A somatic mutation analysis enabled us to diagnose the patient as JMML. The various cutaneous lesions, as part of a multisystem manifestation, often point to a precise diagnosis of JMML or LCH. Contrarily, these polymorphic lesions in infants may be misdiagnosed as a more common disease with broad spectrum. A pitfall should be carefully avoided through the assessment of physical examinations, laboratory findings, skin biopsies, and mutational analysis. The diagnostic criteria suggested by the International JMML Working Group in 1998 [25], as well as somatic mutational analysis of PTPN11, KRAS, and NRAS or NF1, and a clinical diagnosis of NF1 or monosomy 7, helped in making a definite diagnosis of JMML.
References 1. Baumann I, Bennett J, Niemeyer C, Thiele J, Shannon K. WHO classification of tumors of haematopoetic and lymphoid tissues. In: Steven H, Swerdlow E, Harris N, editors. Juvenile Myelomonocytic Leukaemia. Lyon: IARC; 2008. p. 82–844. 2. Niemeyer CM, Arico M, Basso G, Biondi A, Cantu Rajnoldi A, Creutzig U, et al. Chronic myelomonocytic leukemia in childhood: a retrospective analysis of 110 cases. European Working Group on Myelodysplastic Syndromes in Childhood (EWOGMDS). Blood. 1997;89:3534–43. 3. Arico` M, Biondi A, Pui CH. Juvenile myelomonocytic leukemia. Blood. 1997;90:479–88. 4. Yoshimi A, Kojima S, Hirano N. Juvenile myelomonocytic leukemia: epidemiology, etiopathogenesis, diagnosis, and management considerations. Paediatr Drugs. 2010;12:11–21. 5. Egeler RM, Nesbit ME. Langerhans cell histiocytosis and other disorders of monocyte-histiocyte lineage. Crit Rev Oncol. 1995; 18:9–35. 6. Favara BE, Feller AC, Pauli M, Jaffe ES, Weiss LM, Arico M, et al. Contemporary classification of histiocytic disorders. The
JMML with LCH-like cutaneous lesion
7.
8.
9.
10.
11.
12.
13.
14.
15.
WHO Committee On Histiocytic/Reticulum Cell Proliferations. Reclassification Working Group of the Histiocyte Society. Med Pediatr Oncol. 1997;29:157–66. Satter EK, High WA. Langerhans cell histiocytosis: a review of the current recommendations of the Histiocyte Society. Pediatr Dermatol. 2008;25:291–5. Egeler RM, Neglia JP, Arico` M, Favara BE, Heitger A, Nesbit ME, et al. The relation of Langerhans cell histiocytosis to acute leukemia, lymphomas, and other solid tumors. The LCH-Malignancy Study Group of the Histiocyte Society. Hematology. 1998;12:369–78. Egeler RM, Neglia JP, Arico` M, Favara BE, Heitger A, Nesbit ME. Acute leukemia in association with Langerhans cell histiocytosis. Med Pediatr Oncol. 1994;23:81–5. Sires UI, Mallory SB, Hess JL, Keating JP, Bloomberg G, Dehner LP. Cutaneous presentation of juvenile chronic myelogenous leukemia: a diagnostic and therapeutic dilemma. Pediatr Dermatol. 1995;12:364–8. Cham E, Siegel D, Ruben BS. Cutaneous xanthogranulomas, hepatosplenomegaly, anemia, and thrombocytopenia as presenting signs of juvenile myelomonocytic leukemia. Am J Clin Dermatol. 2010;11:67–71. Matsumoto K, Miki J, Matsuzaki S, Koike K, Saida T. Skin infiltration of juvenile myelomonocytic leukemia. J Dermatol. 2004;31:748–51. Kitamura H, Kaneko T, Nakano H, Terui K, Ito E, Sawamura D. Juvenile myelomonocytic leukemia presenting multiple painful erythematous lesions diagnosed as Sweet’s syndrome. J Dermatol. 2008;35:368–70. Ng CS, Lam TK, Chan JK, Hui PK, Ng HK, Szeto SC, et al. Juvenile chronic myeloid leukemia. A malignancy of S-100 protein-positive histiocytes. Am J Clin Pathol. 1988;90:575–82. Querings K, Starz H, Balda BR. Clinical spectrum of cutaneous Langerhans’ cell histiocytosis mimicking various diseases. Acta Derm Venereol. 2006;86:39–43.
393 16. Chikwava K, Jaffe R. Langerin (CD207) staining in normal pediatric tissues, reactive lymph nodes, and childhood histiocytic disorders. Pediatr Dev Pathol. 2004;7:607–14. 17. Valladeau J, Dezutter-Dambuyant C, Saeland S. Langerin/CD207 sheds light on formation of Birbeck granules and their possible function in Langerhans cells. Immunol Res. 2003;28:93–107. 18. Ratzinger G, Burgdorf WH, Metze D, Zelger BG, Zelger B. Indeterminate cell histiocytosis: fact or fiction? J Cutan Pathol. 2005;32:552–60. 19. Kashihara-Sawami M, Horiguchi Y, Ikai K, Takigawa M, Ueda M, Hanaoka M, et al. Letterer-Siwe disease: immunopathologic study with a new monoclonal antibody. J Am Acad Dermatol. 1988;18:646–54. 20. Broadbent V, Pritchard J, Davies EG, Levinsky RJ, Heaf D, Atherton DJ, et al. Spontaneous remission of multi-system histiocytosis X. Lancet. 1984;1:253–4. 21. Yu RC, Chu C, Buluwela L, Chu AC. Clonal proliferation of Langerhans cells in Langerhans cell histiocytosis. Lancet. 1994;343:767–8. 22. Coury F, Annels N, Rivollier A, Olsson S, Santoro A, Speziani C, et al. Langerhans cell histiocytosis reveals a new IL-17Adependent pathway of dendritic cell fusion. Nat Med. 2008;14: 81–7. 23. Badalian-Very G, Vergilio JA, Degar BA, Macconaill LE, Brandner B, Calicchio ML, et al. Recurrent BRAF mutations in Langerhans cell histiocytosis. Blood. 2010;116:1825–7. 24. Locatelli F, Niemeyer C, Angelucci E, Bender-Go¨tze C, Burdach S, Ebell W, et al. Allogeneic bone marrow transplantation for chronic myelomonocytic leukemia in childhood: a report from the European Working Group on Myelodysplastic Syndrome in Childhood. J Clin Oncol. 1997;15:566–73. 25. Pinkel D. Differentiating juvenile myelomonocytic leukemia from infectious disease. Blood. 1998;91:365–7.
123
