Kiuru, Maija

Li, Yueju

Meyer, Summer

Rauen, Katherine A

Vaughn, Alexandra

English

eScholarship - University of California

UC DavisDermatologyTitleThe association between juvenile xanthogranulomas in neurofibromatosis type 1 patients and the development of leukemia: A systematic reviewPermalinkhttps://escholarship.org/uc/item/8x99z6nmAuthorsMeyer, SummerVaughn, AlexandraLi, Yuejuet al.Publication Date2022Data AvailabilityThe data associated with this publication are not available for this reason: N/AeScholarship.org Powered by the California Digital LibraryUniversity of CaliforniaAIMS▪ Among the 78 patients with NF1 and JXG, 23% (18/78) developed leukemia, and more specifically, 19% (15/78) developed JMML, which is more than what has been reported in NF1 patients alone.▪ Significant male predominance (93%), Table 1 ▪ Majority of patients had a family history of NF1 (67%)▪ JMML is the most common subtype (83%) compared to other groups▪ Earlier onset of JXGs (0.8 years) and leukemia (1.8 years), Table 1 ▪ JXGs precede onset of leukemia and JMML▪ Majority of pts had multiple JXGs, regardless of Group ▪ JXGs had a predilection for the face, scalp and neck in all groups, as well as the trunk in Group 3CONCLUSIONS▪ Our findings suggest that the NF1 patients with JXGs have an increased risk of developing JMML and leukemia, especially in males with a family history of NF1. ▪ The onset of JXGs, leukemia, and JMML tended to occur at earlier ages in those with the triple association compared to other groups. After age 6, the risk of developing JMML continues to decline with age. Thus, screening at an early age might be beneficial.▪ Currently, there are no guidelines specifically for pts with NF1 and JXGs ▪ Although the triple association remains rare, closer surveillance and screening of male patients with familial NF1 and JXGs lesions may be reasonable, particularly at early ages. INTRODUCTIONSummer Meyer BS1, Alexandra Vaughn MD1, Yueju Li PhD2, Katherine A. Rauen MD PhD3, Maija Kiuru MD PhD1,4The association between juvenile xanthogranulomas in neurofibromatosis type 1 patients and the development of leukemia: A systematic reviewOur objectives in performing this systematic review are to: (1) clarify the relationship between NF1, JXGs, and JMMLand identify patients that may benefit from additional screening, and (2) describe the clinical characteristics of JXGs arising in NF1.METHODS▪ Articles were included if they were peer-reviewed human studies, in English, and discussed one or more association between NF1, JXG, and/or JMML with individual patient data▪ Articles were screened according to Figure 1. ▪ Included: 65 articles, 181 individual patients▪ Patients were grouped (1-4) by association: ▪ Neurofibromatosis type 1 (NF1) is an inherited tumor syndrome caused by heterozygous germline mutations in the NF1 gene, occurring in approximately 1/2600 individuals.2▪ A subset of patients with neurofibromatosis type 1 (NF1) develop juvenile xanthogranulomas (JXGs), a non-Langerhans cell histiocytosis, and some of these patients also develop juvenile myelomonocytic leukemia (JMML). Yet, these associations are poorly delineated. ▪ JXG is a benign proliferation of non-Langerhans cells histiocytes characterized by small yellow/brown papulonodules ranging from 1-20 mm in size. 3▪ JMML is a mixed myeloproliferative-myelodysplastic disorder that affects children, most often before age 6.4▪ The first and only systematic review on this described the risk of developing JMML 20 to 30 times higher in patients with NF1 with JXG lesions compared to those without JXG. 1▪ Since then, mostly isolated case reports have either refuted or confirmed this triple association. EligibilityIncludedScreeningIdentificationRecords identified through PubMed database search (n= 347)Records screened against title and abstract(n= 273)Full-text articles assessed for eligibility(n= 112)Studies included in final review(n= 65)Records excluded(n= 161)Full-text articles excluded (n= 44)Non-human and non-English studies removed by PubMed filter(n= 74)Figure 1. Preferred Reporting Items for Systematic Reviews and MetaAnalysis (PRISMA) flow diagram.Groups (Dx) No. of patients1 (NF1 and JXG) 562 (NF1 and leukemia) 983 (NF1, JXG, and leukemia) 184 (JXG and leukemia) 9Subtype Group 2 Group 3 Group 4JMML 43% (42/98) 83% (15/18) 55% (5/9) AML 18% (18/98) 5% (1/18) 11% (1/9) ALL 16% (16/18) - 22% (2/9) CML 11% (11/98) 11% (2/18) -ATLL - - 11% (1/9) CEL 1% (1/98) - -NM 10% (10/98) - -Total 98 18 9RESULTSSex, n (%) Median age (yrs), (range) FHx , n (%)Groups Males M-F ratio Presentation Leukemia dx JMML dx JXG onset Follow up FHx of NF1Maternal NF1 transmissionM-P ratio1 19 (54.3) 1.2:1 1.5 (0-28) - - 1.5 (0.21-23) 4 (0-10) 9 (31.0) 6 (75.0) 32 63 (66.3) 2.0:1 3.7 (0.2-75) 3.5 (0.1-75) 2.5 (0.2-7) - 3 (0-17.8) 33 (61.1) 19 (61.3) 1.93 14 (93.3) 14:1 0.8 (0-0.8) 1.8 (0.3-7.5) 1.8 (0.3-4.5) 0.8 (0.1- 4.4) 3 (0.2-7.9) 8 (66.7) 4 (57.1) 1.34 5 (55.6) 1.3:1 2 (0.1-23) 2.5 (0.5-68) 2.2 (0.5-2.5) 1 (0.1-65) 1.3 (0.9-3.5) 0 (0.0) 0  (0.0) -Table 1. Patient characteristics.  JXG lesions, median (cm), (range) n (%)Groups Size Number Multiple lesions1 0.3 (0.3-1.5) 2.9 (1-50) 48 (90.6)2 - - -3 0.5 (0.2-0.6) 6.5 (1-100) 13 (86.7)4 0.6 (0.4-1.3) 26 (1-100) 6 (85.7)p-value 0.43 0.013* 0.89Table 2. Leukemia subtypes by groups. While JMML makes up majority of leukemia cases across all groups, this was most significant in Group 3, p = 0.0172.Table 3. Size and number of JXG lesions between groups. Group 4 had significantly more lesions. Majority of patients had multiple lesions regardless of leukemia or NF1 diagnosis, and there was no significant difference in the number of lesions. Location 1 3 4N % N % N %Face 24 70.6 8 61.5 5 62.5Scalp/neck 26 76.5 11 84.6 8 100Trunk 15 44.1 9 69.2 4 50Upper extremities 9 26.5 1 7.7 4 50Lower extremities 6 17.6 3 23.1 5 62.5Eyes 2 5.9 1 7.7 0 0Genitals 0 0 0 0 0 0Cerebello-pontine angle 1 2.9 0 0 0 0TOTAL 34 100 13 100 8 100Table 4. Location of JXG lesions between groups. JXGs were most commonly located on the face, neck, and scalp in all groups, but also the trunk in Group 3 and the lower extremities in Group 4. GROUP 3: TRIPLE ASSOCIATION LIMITATIONS▪ Possible underdiagnoses of the triple association as most JXG lesions regress, potentially before they are diagnosed or the onset of leukemia and/or NF1 ▪ Length of follow up possibly not long enough for leukemia onset ▪ Small size of groups 3 and 4▪ Our observed frequencies of leukemia and JMML are likely inflated due to publication bias. Meaning our calculations are based on published studies, which are those that are rare and unlikely to represent the general population. REFERENCESDepartment of 1Dermatology, 2Public Health Sciences, 3Pediatrics, and 4Pathology & Laboratory Medicine, University of California Davis1. Zvulunov A, Barak Y, Metzker A. Juvenile xanthogranuloma, neurofibromatosis, and juvenile chronic myelogenous leukemia. World statistical analysis. Arch Dermatol. 1995;131(8):904-8. 2. Evans DG, Howard E, Giblin C, et al. Birth incidence and prevalence of tumor-prone syndromes: estimates from a UK family genetic register service. Am J Med Genet A. Feb 2010;152a(2):327-32. doi:10.1002/ajmg.a.331393. Janssen D, Harms D. Juvenile xanthogranuloma in childhood and adolescence: a clinicopathologic study of 129 patients from the kielpediatric tumor registry. Am J Surg Pathol. Jan 2005;29(1):21-8. doi:10.1097/01.pas.0000147395.01229.064. Gupta AK, Meena JP, Chopra A, Tanwar P, Seth R. Juvenile myelomonocytic leukemia-A comprehensive review and recent advances in management. Am J Blood Res. 2021;11(1):1-21. 

The association between juvenile xanthogranulomas in neurofibromatosis type 1 patients and the development of leukemia: A systematic review

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The association between juvenile xanthogranulomas in neurofibromatosis type 1 patients and the development of leukemia: A systematic review

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