Chronic Myeloid Leukemia Arising in a Patient of Neurofibromatosis Type 1

Abstract

Neurofibromatosis type 1 (NF1) represents a major risk factor for development of malignancies, particularly malignant peripheral nerve sheath tumors (MPNST), optic gliomas, other gliomas, and leukemia. We report an unusual case of chronic myeloid leukemia (CML), developed in a patient of NF1. A 40-year-old Indian male, clinically manifesting NF1 since his childhood, presented with huge splenomegaly. Patient also had a large tumor mass arising in a café-au-lait spot on lower back with rapid growth in last 6 months. Excision of this tumor was done, and it turned out to be a diffuse neurofibroma histologically. Peripheral smear was also done in view of splenomegaly, which showed features of chronic myeloid leukemia. CML rarely co-exists with NF1, and there are a very few reports of such cases. It is important to be aware of the possibility that not only the malignant change in benign PNST is more common in these patients, but also other malignancies like CNS tumors and hematolymphoid neoplasm do occur with increased frequency.

What was known?

• Neurofibromatosis type 1 is an autosomal dominant disorder, cardinal feature being development of neurofibromas.

• Association of Neurofibromatosis I with other malignancies.

Introduction

Neurofibromatosis type 1 (NF1) or von Recklinghausen's disease is an autosomal dominant disorder, the cardinal feature of which is the development of multiple peripheral nerve sheath tumors called neurofibromas.[1] Other characteristics include pigmentory changes in the skin, skeletal anomalies, and learning disabilities.[2] It is well-known that malignant tumors of the nervous system, such as malignant peripheral nerve sheath tumors, gliomas, or astrocytomas, often co-exist with NF1 or NF2. Malignant tumors unrelated to nervous system rarely co-exist with neurofibromatosis 1 or 2, and most of such reports were cases with malignant lymphoma.[3] There are only few cases of chronic myeloid leukemia co-existing with NF1 reported. In pediatric patients, juvenile chronic myeloid leukemia is reported occurring with NF1.[4] Here, we report a case of chronic myeloid leukemia associated with neurofibromatosis 1.

Case Report

A 40-year-old Indian man presented with pain and fullness in left hypochondrium. On palpation, a huge splenomegaly was detected. Ultrasonography of abdomen revealed enlargement of spleen. However, no space occupying or enhancing lesion or no free fluid was seen. Peripheral smear examination showed mild anisocytosis and hypochromia in RBCs. WBCs showed leukocytosis with many immature forms coming in peripheral circulation. Total leukocyte count was more than 1.5 lac/mm³. The differential count was, myeloblast and promeylocyte - 8%, myelocyte and metamyelocyte - 50%, band forms and neutrophils - 30%, basophils - 8%, and lymphocytes - 4% [Figure 1]. Platelets showed moderate thrombocytosis. Considering all these features in peripheral blood smear along with presence of splenomegaly, a diagnosis of chronic myeloid leukemia (chronic phase) was given.

Figure 1.

Peripheral smear showing features of chronic myeloid leukemia (Leishman stain, ×1000)

Patient also complained of presence of a huge mass in his lower back region. The mass was present since 15-20 years, which was of smaller size initially, but it has grown rapidly to reach the present size in last 6 months. He had multiple café-au-lait spots and small swellings over trunk and limbs.

On examination, the tumor was arising in lower lumbar region of back and extending up to gluteal region. Overlying skin showed a café-au-lait spot [Figure 2]. This tumor was excised completely and sent for histopathological examination. Grossly, the tumor measured 30 cm × 12 cm × 10 cm with overlying skin flap showing black discoloration. Cut surface showed a whitish, firm, glistening mass with a cyst of 9 cm diameter containing hemorrhagic fluid [Figure 3]. Sections were taken from representative areas, processed, and stained with hematoxyline and eosin for histological diagnosis.

Figure 2.

Tumor mass in lower lumbar region with a café-au-lait spot in overlying skin

Figure 3.

Cut surface of tumor showing whitish, firm glistening areas and a large cyst containing hemorrhagic fluid

Microscopically, tumor was composed of spindle cells having short, fusiform, and rounded nuclei with inapparent cytoplasm and sheets of laminated bodies i.e., Wagner-Meissner corpuscles [Figure 4] in a fine fibrillary collagenous matrix. The tumor also infiltrated subcutaneous fat and encircled the adnexal structures without compressing them [Figure 5]. The diagnosis of diffuse neurofibroma was made on the basis of these classical histological features.

Figure 4.

Photomicrograph of Wagner-Meissner corpuscles in a fine fibrillary collagenous matrix (H and E, ×400)

Figure 5.

Photomicrograph of tumor mass showing features of diffuse neurofibroma (H and E, ×40)

In view of presence of multiple café-au-lait spots and swellings all over the body, excisional biopsy of two more swellings was done, the histology of which showed classical features of usual type of neurofibroma. Hence, the diagnosis of NF1 was confirmed. However, mutational analysis of NF-1 gene and FISH analysis for BCR/ABL translocation (Philadelphia chromosome) for chronic myeloid leukemia (CML) could not be done, as these facilities are not available in our center.

The patient received chemotherapy for CML and went in remission after 6 months. This patient is alive and without any recurrence at 1-year of follow-up after treatment.

Discussion

Neurofibromatosis is divided broadly into 3 categories: (a) von Recklinghausen's neurofibromatosis or NF-1, (b) bilateral acoustic neuroma (NF-2), and (c) all other neurofibromatosis, including alternate or atypical forms of the disease. NF-1 comprises about 90% of all cases. It is an autosomal dominant inherited disorder with a high rate of penetrance affecting about 1 in 4000 people.[2,5]

Neurofibromatosis type 1 has been recognized as a clinical entity for more than a century, but it is only since the NF1 gene was identified in 1990 that we have begun to understand the pathophysiology of the disorder. It is clear that NF1 has tumor suppressor function, which is involved in the formation of neurofibromas, and that it also has other important functions in the pathogenesis of non-tumor manifestations.[5]

The NF1 gene is located on the proximal long arm of chromosome 17 and is thought to be a kind of tumor suppressor gene. Neurofibromin - a product of the NF1 gene - has an important role in the activation of ras protein and in controlling the proliferation and differentiation of cells. The absence of neurofibromin predisposes to tumor formation. As a result, people with NF1 are at increased risk for the development of malignancies such as leukemia, rhabdomyosarcoma, optic glioma, and brain tumors. However, the relationship of NF1 with CML has not been clarified.[6] As per a recent report published of a adult Ghanaian patient of NF1 developing CML, the authors have kept the possibility of a synergistic action between the absence of neurofibromin and the presence of the tyrosine kinase activity of the BCR/ABL gene in the development of CML in these patients.[7]

Sorensen, et al.[3] reported 57 malignant tumors in 212 patients with neurofibromatosis. There were 21 central nervous system malignancies, 6 peripheral nervous sarcomas, and 57 other cancers or sarcomas. The relative frequencies of tumors differed markedly from those in the general population. In addition to PNSTs and sarcomas, individuals with NF1 are also at higher risk for developing hematological malignancies like lymphoma, multiple myeloma, acute myeloid leukemia, chronic lymphoid leukemia, juvenile chronic myelomonocytic leukemia, and myelodysplastic syndrome.[6]

The triple association of leukemia, xanthomatous skin lesions, and neurofibromatosis 1 was first described by Royer, et al. in 1958. Most of the leukemias in this study were of the juvenile chronic myelogenous type (JCML).[4] Jang, et al. described a 7-year-old male child with xanthoma, NF 1, and chronic myelomonocytic leukemia with positive family history of NF1 in mother. They suggested that the presence of xanthomas and NF1 in a young child should raise awareness of the possible development of JCML, especially in patients with family history of NF1.[4]

Bader, et al.[8] reported an increased proportion of non-lymphocytic leukemia among children with NF1 and leukemia. Siller, et al.[9] conducted a population-based study and found an increased relative risk of chronic myelomonocytic leukemia, acute lymphoblastic leukemia, and non-Hodgkin's lymphoma in NF1 population. Juvenile xanthogranuloma (JXG), cutaneous nodules consisting of histiocytes, is found with increased frequency in children with NF1 and also has been correlated with risk of chronic myelogenous leukemia (JCML) in the general population.[8,9,10]

Review of literature shows that most of such cases reported are in children with NF1 and JCML. However, to date, there has been only one case reported to the best of our knowledge of an adult patient with NF1 developing CML. Hence, our case is a second rare case in literature showing association of NF1 and CML in an adult patient.

Leukemic cells from NF1 patients have loss of heterozygosity for NF1 gene, but do not have activating Ras mutations in contrast with many non-NF1-associated myeloid malignancies. Increased levels of Ras-GTP are found in the NF1-associated leukemias, and the leukemic cells show hypersensitivity to GM-CSF and other cytokines.[8] Eighteen cases of co-existence of neurofibromatosis and malignant lymphoma have been reported.[11]

Malignancy is an important component of NF1 phenotype and one of the few life-threatening complications. Furthermore, the natural history of malignancy in patients of NF1 is often different from that of similar tumor types in the general population. Treatment of malignant condition is another therapeutic target. Early diagnosis is particularly problematic since tumors usually arise from pre-existing benign lesions, and individuals with NF1 are accustomed to having lesions, for which they do not seek care. Our patient responded to chemotherapy and doing well without any relapse in 1-year follow-up.

Conclusion

There is no cure for neurofibromatosis; treatment consists of amelioration of clinical symptoms. It is recommended that thorough clinical examination at diagnosis and during routine follow-up should be done. Although malignancies are rare in NF1, there is an increased incidence of sarcomas and leukemias, especially in childhood. When malignancies are detected, NF1 patients should be evaluated and treated in the same manner as other patients. As NF1 patients also have an increased incidence of second malignancies, they must have long-term follow-up.

What is new?

The association of NF-I with hematolymphoid malignancies is known most of the cases reported JCML in children. However only one case of NF-I developing CML in Adult is reported till date