Summary
Neurofibromatosis type 1 (NF1) is an autosomal dominant multisystem syndrome caused
by mutations in the neurofibromin 1 (NF1) gene that encodes for the protein neurofibromin acting as a tumour suppressor. Neurofibromin
functions primarily as a GTPase-activating protein for the Ras family of oncogenes,
which activates many signalling pathways for cell proliferation and differentiation;
without neurofibromin, Ras is constitutively activated, thereby turning on many downstream
signalling pathways related to oncogenesis. Patients with NF1 have a well known predisposition
for certain types of malignancies including malignant peripheral nerve sheath tumours,
gliomas, and breast cancers, as well as a potential association of NF1 with lymphoproliferative
disorders such as lymphomas. In this article, we review the pathophysiology and tumourigenesis
of NF1, previously reported cases of cutaneous lymphomas in NF1 patients along with
our case demonstration of a NF1-associated scalp B-cell lymphoma, and NF1-associated
extra cutaneous lymphomas. The diagnosis of lymphomas particularly cutaneous lymphomas
may be difficult in NF1 patients as they often have skin lesions and/or cutaneous/subcutaneous
nodules or tumours like neurofibromas, which raises the possibility of underdiagnosed
cutaneous lymphomas in NF1 patients. We also comprehensively discuss the association
between NF1 and lymphomas. In summary, most studies support a potential association
between NF1 and lymphomas. Further investigation is needed to clarify the association
between NF1 and lymphomas in order to bring clinical awareness of possibly underdiagnosed
NF1-associated lymphomas and individualised management of NF1 patients to practice.
Key words
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to PathologyAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Impacts of NF1 gene mutations and genetic modifiers in neurofibromatosis type 1.Front Neurol. 2021; 12704639
- An update on the central nervous system manifestations of neurofibromatosis type 1.Acta Neuropathol. 2020; 139: 625-641
- Distinctive cancer associations in patients with neurofibromatosis type 1.J Clin Oncol. 2016; 34: 1978-1986
- Neurofibromatosis type 1.J Am Acad Dermatol. 2009; 61: 1-14
- Tumour microenvironment and neurofibromatosis type I: connecting the GAPs.Oncogene. 2007; 26: 4609-4616
- An epidemiological, clinical and genetic survey of neurofibromatosis type 1 in children under sixteen years of age.Ulster Med J. 2008; 77: 160-163
- Sporadic and familial variants in NF1: an explanation of the wide variability in neurocognitive phenotype?.Front Neurol. 2020; 11: 368
- Mortality in neurofibromatosis 1: an analysis using U.S. death certificates.Am J Hum Genet. 2001; 68: 1110-1118
- Primary cutaneous follicular helper T-cell lymphoma in a patient with neurofibromatosis type 1: case report and review of the literature.Am J Dermatopathol. 2017; 39: 134-139
- Risk of benign tumours of nervous system, and of malignant neoplasms, in people with neurofibromatosis: population-based record-linkage study.Br J Cancer. 2013; 108: 193-198
- Neurofibromatosis and childhood leukaemia/lymphoma: a population-based UKCCSG study.Br J Cancer. 1994; 70: 969-972
- Akt- or MEK- mediated mTOR inhibition suppresses Nf1 optic glioma growth.Neuro Oncol. 2015; 17: 843-853
- NF1 mutations are recurrent in adult acute myeloid leukemia and confer poor outcome.Leukemia. 2018; 32: 2536-2545
- Coincidental expression of classic Hodgkin lymphoma and neurofibromatosis type 1 and literature review.J Pediatr Hematol Oncol. 2021; 43 (e535–8)
- An unusual association between neurofibromatosis type 1 and diffuse B cell lymphoma.Case Rep Oncol Med. 2021; 5575957
- Cutaneous and systemic findings in mosaic neurofibromatosis type 1.Pediatr Dermatol. 2017; 34: 271-276
- T-cell lymphoma in a patient with neurofibromatosis type 1 and AIDS.Case Rep Oncol. 2017; 10: 161-168
- Primary effusion lymphoma-like lymphoma in a patient with neurofibromatosis type 1.Tokai J Exp Clin Med. 2016; 41: 123-129
- Neurofibromatosis type 1 and malignancy in childhood.Clin Genet. 2016; 89: 341-345
- Intra-abdominal ALK-positive anaplastic large cell lymphoma in a patient with neurofibromatosis type 1.Histopathology. 2016; 68: 752-754
- Severe hypercholesterolemia: a unique presentation of non-Hodgkin's lymphoma in a patient with neurofibromatosis type 1.Case Rep Gastrointest Med. 2014; 1579352
- Fdg-pet in two cases of neurofibromatosis type 1 and atypical malignancies.Curr Oncol Rep. 2014; 21: e345-e348
- Oncologic manifestations in children with neurofibromatosis type 1 in Turkey.Turk J Pediatr. 2013; 55: 266-270
- Malignancies in Chinese patients with neurofibromatosis type 1.Hong Kong Med J. 2013; 19: 42-49
- Diffuse large B cell lymphoma presenting as Horner’s syndrome in a patient diagnosed with neurofibromatosis type 1: a case report and review of the literature.J Med Case Rep. 2012; 6: 8
- A 21-year-old woman with multiple cancers and a new brain lesion.Neurology. 2012; 78: 743-749
- Central nervous system lymphoma occurring in a patient with neurofibromatosis type 1 (von Recklinghausen disease).Neurol Sci. 2012; 33: 1429-1433
- An unusual self-limited clonal Mott cell proliferation with lymphoplasmacytic lymphoma-like features in a child with the Wiskott-Aldrich syndrome and Von Recklinghausen's neurofibromatosis.Pathol Res Pract. 2010; 206: 467-471
- Gaucher or Pseudo-Gaucher? The challenge of several diseases colliding in a pediatric patient.Hum Pathol. 2008; 40: 594-598
- Neurofibromatosis type 1 associated with central nervous system lymphoma.Ophthalmic Genet. 2004; 25: 49-51
- Neurofibromatosis type 1 and multiple primary malignancies.Med Pediatr Oncol. 2003; 41: 568-569
- A case of non-Hodgkin's lymphoma in a patient with neurofibromatosis type 1.Korean J Intern Med. 2013; 18: 202-205
- Subcutaneous panniculitis-like T-cell lymphoma in type 1 neurofibromatosis: a case report.Acta Dermatovenerol Croat. 2014; 22: 145-149
- Diffuse large B-cell lymphoma arising in a patient with neurofibromatosis type I and in a patient with neurofibromatosis type II.Tohoku J Exp Med. 2006; 208: 169-176
- Cutaneous T-cell lymphoma in a patient with neurofibromatosis type 1.Cutis. 2003; 72: 27-30
- Neurofibromatosis type 1 and mycosis fungoides.Int J Dermatol. 2002; 41: 236-238
- Coexistence of late onset neurofibromatosis and cutaneous T cell lymphoma.J Am Acad Dermatol. 1990; 23: 932-934
- Burkitt lymphoma in a patient with neurofibromatosis and pheochromocytoma.JAMA. 1977; 237: 993-994
- Identification of the neurofibromatosis type 1 gene product.Proc Natl Acad Sci USA. 1991; 88: 9658-9662
- Regulated expression of neurofibromin in migrating neural crest cells of avian embryos.J Neurobiol. 1995; 27: 535-552
- The structure and function of the NF1 gene: molecular pathophysiology.in: Neurofibromatosis: Phenotype, Natural History and Pathogenesis. 3rd ed. Johns Hopkins University Press, Baltimore1999: 119-141
- Expression of the neurofibromatosis 1 (NF1) isoforms in developing and adult rat tissues.Cell Growth Differ. 1995; 6: 315-323
- The sec14 homology module of neurofibromin binds cellular glycerophospholipids: mass spectrometry and structure of a lipid complex.J Mol Biol. 2007; 366: 551-562
- Structural differences in the minimal catalytic domains of the GTPase-activating proteins p120GAP and neurofibromin.J Biol Chem. 1996; 271: 16409-16415
- The NF1 locus encodes a protein functionally related to mammalian GAP and yeast IRA proteins.Cell. 1990; 63: 851-859
- Differential regulation of rasGAP and neurofibromatosis gene product activities.Nature. 1991; 351: 576-579
- The GAP-related domain of the neurofibromatosis type 1 gene product interacts with ras p21.Cell. 1990; 63: 843-849
- A cytoplasmic protein stimulates normal N-ras p21 GTPase, but does not affect oncogenic mutants.Science. 1987; 238: 542-545
- The catalytic domain of the neurofibromatosis type 1 gene product stimulates ras GTPase and complements ira mutants of S. cerevisiae.Cell. 1990; 63: 835-841
- Preclinical in vivo evaluation of rapamycin in human malignant peripheral nerve sheath explant xenograft.Int J Cancer. 2010; 126: 563-571
- The NF1 tumour suppressor critically regulates TSC2 and mTOR.Proc Natl Acad Sci USA. 2005; 102: 8573-8578
- Clinical and molecular aspects of RAS related disorders.J Med Genet. 2008; 45: 695-703
- The RASopathies: developmental syndromes of Ras/MAPK pathway dysregulation.Curr Opin Genet Dev. 2009; 19: 230-236
- The primacy of NF1 loss as the driver of tumourigenesis in neurofibromatosis type 1-associated plexiform neurofibromas.Oncogene. 2017; 36: 3168
- Neurofibromatosis type 1-associated tumours: their somatic mutational spectrum and pathogenesis.Hum Genomics. 2011; 5: 623-690
- Toward a survey of somatic mutation of the NF1 gene in benign neurofibromas of patients with neurofibromatosis type 1.Am J Hum Genet. 2000; 66: 393-401
- A search for evidence of somatic mutations in the NF1 gene.J Med Genet. 2000; 37: 44-49
- Identification of NF1 mutations in both alleles of a dermal neurofibroma.Nat Genet. 1996; 14: 110-112
- Schwann cells harbor the somatic NF1 mutation in neurofibromas: evidence of two different Schwann cell subpopulations.Hum Mol Genet. 2000; 9: 3055-3064
- Penetrance of von Recklinghausen neurofibromatosis: a distinction between predecessors and descendants.Am J Hum Genet. 1998; 42: 284-289
- The use of next-generation sequencing in molecular diagnosis of neurofibromatosis type 1: a validation study.Genet Test Mol Biomarkers. 2014; 18: 722-735
- Pathophysiology of neurofibromatosis type 1.Ann Intern Med. 2006; 144: 842-849
- Exhaustive mutation analysis of the NF1 gene allows identification of 95% of mutations and reveals a high frequency of unusual splicing defects.Hum Mutat. 2000; 15: 541-555
- Clinical characteristics and NF1 gene mutation analysis of three successive generations in three different Indian families with neurofibromatosis type 1 and peripheral nerve sheath tumours.J Clin Neurosci. 2018; 53: 62-68
- Neurofibromatosis type 1: from genotype to phenotype.J Med Genet. 2012; 49: 483-489
- From peas to disease: modifier genes, network resilience, and the genetics of health.Am J Hum Genet. 2017; 101: 177-191
- The clinical and diagnostic implications of mosaicism in the neurofibromatoses.Neurology. 2001; 56: 1433-1443
- Neurofibromatosis type 1 due to germ-line mosaicism in a clinically normal father.N Engl J Med. 1994; 331: 1403-1407
- Gonosomal mosaicism for a nonsense mutation (R1947X) in the NF1 gene in segmental neurofibromatosis type 1.J Invest Dermatol. 2005; 125: 463-466
- Neurofibromatosis type 1 in a child of a parent with segmental neurofibromatosis (NF-5).Neurofibromatosis. 1989; 2: 244-245
- What is segmental neurofibromatosis?.Br J Dermatol. 1994; 130: 106-110
- A prospective study of neurofibromatosis type 1 cancer incidence in the UK.Br J Cancer. 2006; 95: 233-238
- Mortality in neurofibromatosis 1: in North West England: an assessment of actuarial survival in a region of the UK since 1989.Eur J Hum Genet. 2011; 19: 1187-1191
- Lymphoproliferative malignancies in patients with neurofibromatosis 1.Orphanet J Rare Dis. 2021; 16: 230
- The role of the immune system in neurofibromatosis type 1-associated nervous system tumours.CNS Oncol. 2017; 6: 45-60
- Dual biological effects of the cytokines interleukin-10 and interferon-gamma.Cancer Immunol Immunother. 2011; 60: 1529-1541
- Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumour microenvironment is driven by CD8(+) T cells.Sci Transl Med. 2013; 5: 200
- Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation.J Exp Med. 2000; 192: 1027-1034
- The human mast cell: an overview.Methods Mol Biol. 2016; 315: 13-34
- TNF signaling drives myeloid-derived suppressor cell accumulation.J Clin Invest. 2012; 122: 4094-4104
- The c-kit receptor, stem cell factor, and mast cells. What each is teaching us about the others.Am J Pathol. 1993; 142: 965-974
- Neurofibroma-associated macrophages play roles in tumour growth and response to pharmacological inhibition.Acta Neuropathol. 2013; 125: 159-168
- Contributions of inflammation and tumour microenvironment to neurofibroma tumourigenesis.J Clin Invest. 2018; 128: 2848-2861
- The ultrastructure of schwannoma and neurofibroma of the peripheral nerves.Ital J Orthop Traumatol. 1991; 17: 237-246
- Angiogenic and invasive properties of neurofibroma Schwann cells.J Cell Biol. 1990; 111: 645-653
- Ultrastructure of benign peripheral nerve sheath tumours.Cancer. 1966; 19: 699-709
- 100 protein in soft-tissue tumours derived from Schwann cells and melanocytes.Am J Pathol. 1982; 106: 261-268
- Loss of NF1 allele in Schwann cells but not in fibroblasts derived from an NF1-associated neurofibroma.Genes Chromosomes Cancer. 1999; 24: 283-285
- Nf1+/− mast cells induce neurofibroma like phenotypes through secreted TGF-beta signaling.Hum Mol Genet. 2006; 15: 2421-2437
- Neurofibromatosis Type 1 and tumourigenesis: molecular mechanisms and therapeutic implications.Neurosurg Focus. 2010; 28: E8
- A neurogenic tumour containing a low-grade malignant peripheral nerve sheath tumour (MPNST) component with loss of p16 expression and homozygous deletion of CDKN2A/p16: a case report showing progression from a neurofibroma to a high-grade MPNST.Int J Clin Exp Pathol. 2015; 8: 5113-5120
- PTEN and NF1 inactivation in Schwann cells produces a severe phenotype in the peripheral nervous system that promotes the development and malignant progression of peripheral nerve sheath tumours.Cancer Res. 2012; 72: 3405-3413
- Mouse models of tumour development in neurofibromatosis type 1.Science. 1999; 286: 2172-2176
- TORC1 is essential for NF1-associated malignancies.Curr Biol. 2008; 18: 56-62
- Ral overactivation in malignant peripheral nerve sheath tumours.Mol Cell Biol. 2009; 29: 3964-3974
- Proteasomal and genetic inactivation of the NF1 tumour suppressor in gliomagenesis.Cancer Cell. 2009; 16: 44-54
- An integrated genomic analysis of human glioblastoma multiforme.Science. 2008; 321: 1807-1812
- Microarray analyses reveal regional astrocyte heterogeneity with implications for neurofibromatosis type 1 (NF1)-regulated glial proliferation.OPAC. 2009; 57: 1239-1249
- Optic nerve glioma in mice requires astrocyte Nf1 gene inactivation and Nf1 brain heterozygosity.Cancer Res. 2003; 63: 8573-8577
- Central nervous system tumours.in: WHO Classification of Tumours Series. 5th ed, vol. 6. International Agency for Research on Cancer, Lyon2021
- Neuronal NF1/RAS regulation of cyclic AMP requires atypical PKC activation.Hum Mol Genet. 2014; 23: 6712-6721
- Cyclic AMP suppression is sufficient to induce gliomagenesis in a mouse model of neurofibromatosis-1.Cancer Res. 2010; 70: 5717
- Breast cancer and other neoplasms in women with neurofibromatosis type 1: a retrospective review of cases in the Detroit metropolitan area.Am J Med Genet A. 2012; 158: 3061-3064
- Women with neurofibromatosis 1 are at a moderately increased risk of developing breast cancer and should be considered for early screening.J Med Genet. 2007; 44: 481-484
- Increased risk of breast cancer in women with NF1.Am J Med Genet A. 2012; 158A: 3056-3060
- Age-specific risk of breast cancer in women with neurofibromatosis type 1.Br J Cancer. 2015; 112: 1546-1548
- A transposon-based analysis reveals RASA1 is involved in triple-negative breast cancer.Cancer Res. 2017; 77: 1357-1368
- Comparative oncogenomics implicates the neurofibromin 1 gene (NF1) as a breast cancer driver.Genetics. 2012; 192: 385-396
- The NF1 gene revisited - from bench to bedside.Oncotarget. 2014; 15: 5873-5892
- A case of neurofibromatosis and breast cancer: loss of heterozygosity of NF1 in breast cancer.Cancer Genet Cytogenet. 2005; 156: 86-88
- Metaplastic breast cancer in a patient with neurofibromatosis.J Clin Imaging Sci. 2015; 5: 1-4
- Neurofibromatosis type 1 and childhood cancer.Cancer. 1993; 72: 2746-2754
- Preexisting conditions in pediatric ALL patients: spectrum, frequency and clinical impact.Eur J Med Genet. 2016; 59: 143-151
- Genome-wide single-nucleotide polymorphism analysis in juvenile myelomonocytic leukemia identifies uniparental disomy surrounding the NF1 locus in cases associated with neurofibromatosis but not in cases with mutant RAS or PTPN11.Oncogene. 2007; 26: 5816-5821
- Chronic lymphocytic leukemia associated with von Recklinghausen neurofibromatosis.Int J Hematol. 1991; 54: 441-442
- An unusual manifestation in a patient with neurofibromatosis type 1.G Ital Dermatol Venereol. 2016; 151: 129-130
- Acquired copy number alterations in adult acute myeloid leukemia genomes.Proc Natl Acad Sci USA. 2009; 106: 12950-12955
- NF1 inactivation in adult acute myelogenous leukemia.Clin Cancer Res. 2010; 16: 4135-4147
- Targeting Ras in myeloid leukemias.Clin Cancer Res. 2008; 14: 2249-2252
- NF1 mutations are recurrent in adult acute myeloid leukemia and confer poor outcome.Leukemia. 2018; 32: 2536-2545
- Xantholeucemie due nourisson et neurofibormatose de Recklinghausen.Ann Pediatr. 1958; 5: 260
- Neurofibromatosis and childhood leukemia.J Pediatr. 1978; 92: 925-929
- Comparison of cancer prevalence in patients with neurofibromatosis type 1 at an academic cancer center vs in the general population from 1985 to 2020.JAMA Netw Open. 2021; 4e210945
- Neurofibromin GTPase- activating protein-related domains restore normal growth in Nf1−/− cells.J Biol Chem. 2001; 276: 7240-7245
- NF1 deficiency causes Ras-mediated granulocyte/macrophage colony stimulating factor hypersensitivity and chronic myeloid leukemia.Nat Genet. 1996; 12: 137-143
- Nf1 regulates hematopoietic progenitor cell growth and ras signaling in response to multiple cytokines.J Exp Med. 1998; 187: 1893-1902
- Genetic analysis is consistent with the hypothesis that NF1 limits myeloid cell growth through p21ras.Blood. 1994; 84: 3435-3439
- Molecular pathogenesis of Hodgkin lymphoma: past, present, future.Int J Mol Sci. 2020; 21: 6623
- Non-Hodgkin lymphoma.in: StatPearls. Treasure island. StatPearls Publishing, , FL2022
- Signaling pathways in lymphoma: pathogenesis and therapeutic targets.Future Oncol. 2013; 9: 1549-1571
- Aggressive lymphomas.N Engl J Med. 2010; 362: 1417-1429
- Mechanisms of B-cell lymphoma pathogenesis.Nat Rev Cancer. 2005; 5: 251-262
- B cell chronic lymphocytic leukemia: lessons learned from studies of the B cell antigen receptor.Annu Rev Immunol. 2003; 21: 841-894
- Molecular profiling of diffuse large B-cell lymphoma identifies robust subtypes including one characterized by host inflammatory response.Blood. 2005; 105: 1851-1861
- Chronic active B-cell-receptor signaling in diffuse large B-cell lymphoma.Nature. 2010; 463: 88-92
- Genomic imbalances including amplification of the tyrosine kinase gene JAK2 in CD30+ Hodgkin cells.Cancer Res. 2000; 60: 549-552
- Molecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favorable subgroup of diffuse large B cell lymphoma related to Hodgkin’s lymphoma.J Exp Med. 2003; 198: 851-862
- Molecular subtypes of diffuse large B-cell lymphoma arise by distinct genetic pathways.Proc Natl Acad Sci USA. 2008; 105: 13520-13525
- Signaling pathway and dysregulation of PD1 and its ligands in lymphoid malignancies.Biochim Biophys Acta. 2016; 1865: 58-71
- The PD-1 pathway in tolerance and autoimmunity.Immunol Rev. 2010; 236: 219-242
- Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma.Blood. 2010; 116: 3268-3277
- PD-L1 expression is characteristic of a subset of aggressive B-cell lymphomas and virus-associated malignancies.Clin Cancer Res. 2013; 19: 3462-3473
- High numbers of tumour-infiltrating programmed cell death 1-positive regulatory lymphocytes are associated with improved overall survival in follicular lymphoma.J Clin Oncol. 2009; 27: 1470-1476
- The PD-1/PD-L1 axis contributes to T-cell dysfunction in chronic lymphocytic leukemia.Haematologica. 2013; 98: 953-963
- Effector T cell subclasses associate with tumour burden in neurofibromatosis type 1 patients.Cancer Immunol Immunother. 2016; 65: 1113-1121
- Lymphoproliferative defects in mice lacking the expression of neurofibromin: functional and biochemical consequences of Nf1 deficiency in T-cell development and function.Blood. 2002; 100: 3656-3662
- Defective proliferative responses in B lymphocytes and thymocytes that lack neurofibromin.Mol Immunol. 2002; 38: 701-708
- Neurofibromin 1 impairs natural killer T-cell-dependent antitumour immunity against a T-cell lymphoma.Front Immunol. 2018; 8: 1901
- Positive and negative selection invoke distinct signaling pathways.J Exp Med. 1996; 184: 9-18
- Regulation of lipid signaling by diacylglycerol kinases during T cell development and function.Front Immunol. 2013; 4: 178
- Virus-induced inhibition of CD1d1-mediated antigen presentation: reciprocal regulation by p38 and ERK.J Immunol. 2005; 175: 4301-4308
- Anthrax lethal toxin impairs CD1d-mediated antigen presentation by targeting the ERK1/2 MAPK pathway.Infect Immun. 2010; 78: 1859-1863
- Consecutive glioblastoma and B cell non-Hodgkin’s lymphoma in a young child with von Recklinghausen’s neurofibromatosis.Med Pediatr Oncol. 1995; 24: 46-49
- Epidemiology of lymphomas.Curr Opin Oncol. 2000; 12: 383-394
Article info
Publication history
Published online: February 10, 2023
Accepted:
January 6,
2023
Received in revised form:
December 22,
2022
Received:
July 16,
2022
Identification
Copyright
© 2023 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.
