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Case series and literature review of skeletal tumors and their incidence in the Gaucher disease population

Year: 2016

Type: article

Abstract: An Ashkenazi Jewish male first presented at age 40 with persistent bone pain and a tender mass on his right leg.This patient was the subject of a prior case report in 1995 [1].He had onset of persistent bone pain and splenomegaly at age 5 years and at age 10 suffered from avascular osteonecrosis of the right femur.At age 15 years, he suffered from recurrent avascular necrosis of right femur and right humerus.Diagnosis of Gaucher Disease (GD) Type 1 was made on bone marrow biopsy, later confirmed by low leucocyte acid b-glucosidase activity and the finding of homozygosity for N370S mutation in GBA gene.He underwent osteotomy of his right hip at age 18.At age 25 years, the patient suffered from infectious mononucleosis resulting in massive splenomegaly and splenic rupture that necessitated emergency splenectomy.Subsequently, he underwent right hip replacement.At his presentation with right leg mass, the mass and bone pain had been present for the previous 6 months and had worsened until the patient could no longer continue his daily activities.At this time in 1992, enzyme replacement therapy had not yet become the standard of care for GD.Gaucher disease, an autosomal recessive disorder, is a prototype inborn error of metabolism due to biallelic mutations in GBA1 that results in deficiency of lysosomal acid b-glucocerebrosidase, a key enzyme in the degradation pathway of membrane glycosphingolipids [2].GD displays a heterogeneous clinical presentation affecting multiple organs with major skeletal involvement based on the accumulation of glucocerebroside-laden macrophages, eponymously known as Gaucher cells [3].The accumulation of primary substrate leads to generation of bioactive lipids that cause immune activation and chronic metabolic inflammation [4,5].Bone disease was more common and more severe in asplenic patients with GD [2].In fact, asplenia is a major independent risk factor for avascular osteonecrosis [6].Plain radiographs of tibia showed typical bony lesions of Gaucher disease including osteopenia, extensive bone marrow infarcts, and lytic lesions.In addition, there was a focal mass concerning for a malignant tumor.The tibia was resected and replaced with intercalary allograft, soleus muscle flap, and split thickness skin graft.Subsequently, infectious complications necessitated an above knee amputation.On gross examination, the tumor measured 4 3 4 3 3 cm and was focally friable and hemorrhagic.The tumor was dispersed in sheets and cords within a hyalinized basophilic background.Intensely eosinophilic nucleoli, abundant cytoplasm, and cytoplasmic vacuoles with red blood cells were present.The extraosseous segment showed increasing atypia with primitive anastomosing split like vascular spaces.The bone marrow was extensively necrotic and demonstrated infiltration by Gaucher cells.By immunohistochemistry, the cells stained positive for keratin, factor VIII antigen, Ulex europaeus agglutinin, and vimentin [1].The cells demonstrated a high nuclear cytoplasmic ratio with striking euchromatin and large nucleoli.The cytoplasm was rich in ribosomes and rough endoplasmic reticulum interspersed with a mitochondria, filaments, and lipid droplets by electron microscopy [1].The patient was diagnosed with malignant epithelioid hemangioendothelioma.There is an increased cancer risk in GD, especially increased risk of hematologic malignancies [7] but there is uncertainty about whether the risk of solid organ malignancies is increased.DeFost et al. found in their study that GD patients also harbor an increased risk of solid tumors particularly hepatocellular carcinoma [8].In analysis of cancer-related deaths in GD patients in the era before enzyme replacement therapy became the standard of care, Weinreb and Lee found markedly increased risk of several solid tumors including sarcomas, hepatocellular carcinoma, and renal cell carcinoma [9].On a priori grounds, GD is primarily a bone marrow disease, hence as predicted hematological cancer risk is markedly elevated.Moreover, the primary target of GD is the skeleton suggesting that primary bone malignancies may also be increased.After above knee amputation, he commenced enzyme replacement therapy initially with placental enzyme, Alglucerase in 1992 (age 40) and switched to recombinant macrophage-targeted ERT, Imiglucerase in 1994 (age 42).In 2009, he switched to Velaglucerase due to

Source: American Journal of Hematology

DOI: 10.1002/ajh.24398