Case series and literature review of skeletal tumors and their incidence in the Gaucher disease population
Authors: Vagishwari Murugesan, Andrew Lischuk, Andrew Haims, Richard Lackman, John S. Brooks, Henry Mankin, Pramod K. Mistry
Journal: American Journal of Hematology (2016)

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 β-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 β-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 × 4 × 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 vimentin1. 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 microscopy1. 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 shortage of Imiglucerase. Evaluation in 2016 revealed evidence of old AVNs in the head of the humerus and vertebrae in addition to stable osteoporosis and chitotriosidase levels. There has been no recurrence of the epithelioid hemangioendothelioma for 20 years. Table 1 and Fig. 3 depict the timeline of events for the patient. This report emphasizes the importance of careful evaluation to rule out malignancies as well as timely surgical resection and optimal enzyme replacement therapy all of which likely contribute to improve outcomes. A 55-year-old male with Gaucher disease type 1 presented in 2008 with worsening of left pelvic/hip pain. This patient is included in a recent case series of angiosarcomas arising in chronic hematomas due to miscellaneous causes10. The patient was diagnosed at 26 years of age when he presented with avascular necrosis of left hip. His GBA1 genotype was N370S/IVS + 2 mutations. He had left hip replacement at age 27 which was revised at age 33 years (Fig. 1A). In 1991, at the age of 38, he presented with a large pelvic mass 15–17 cm extending from the mid-thigh to above the acetabular dome, medially displacing the pelvic structures. This was diagnosed to be a Gaucheroma. During surgical resection, over 1 l of blood and a large organized clot was removed. Histologically the lesion comprised numerous Gaucher cells embedded within an organized hematoma (Fig. 2A). He had started on enzyme replacement therapy in 1991 and achieved remission of hematological parameters and reversal of hepatosplenomegaly. Radiological features of disease in patient 2. (A) Frontal radiograph of the pelvis from 1991 (age 38 years) shows revision left hip arthroplasty with bone graft along the proximal diaphyseal metaphyseal junction. (B) Frontal pelvic radiograph in 1999 (age 46): there is interval resorption of the proximal aspect of the bone graft with erosive changes extending into the inferior pubic ramus. Soft tissue mass extends medially into the pelvis (white arrows). (C) MRI Imaging in 2005 (age 52): STIR imaging sequence performed to reduce metal artifact from the hip prosthesis shows a large and heterogeneous mass with predominantly high signal intensity extending into the left hemipelvis causing mass effect on the rectum. Incidentally noted is a bone infarct along the left iliac wing (white arrow). (D) MR imaging in 2005 (age 52): postcontrast images reveal thick, nodular peripheral enhancement (white arrow) with nonenhancing soft tissue centrally. Imaging findings are nonspecific, but given the increase in size over time and aggressive appearing enhancement, biopsy was recommended. Histopathology of Patient 2. (A) Gaucheroma with Gaucher cells embedded in an organized hematoma at 38 years of age. (B) Hematoma at 55 years of age: The cyst wall surrounding most of the hematoma was composed of dense collagen (10×). (C) Angiosarcoma, epithelioid type. The tumor cells have abundant cytoplasm, oval large nuclei with nucleoli, and form irregular vascular channels (center) (400×). (D) Sheets of Gaucher histiocytes (bottom, small arrows) are present within the bone, and are infiltrated by scattered angiosarcoma cells (long arrows), which form one blood-filled vascular channel (top center) (400×). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] Glucocerebroside-laden macrophages, Gaucher cells accumulate in the bone marrow in GD resulting in variable rate of progressive infiltration over time, displacement of marrow elements and eventually increased pressure induced by this process can contribute to the occlusion of microcirculation leading to necrosis and bone infarcts 11. Moreover, bioactive lipids arising from alternative metabolic pathways of glucosylceramide, lead to osteoblast dysfunction, may further contribute to AVN, as osteoblasts are believed to support angiogenesis in the bone marrow 12. He received variable doses of ERT but his compliance to therapy was erratic. At his first evaluation in our clinic in 1999, the patient continued to show extensive skeletal involvement and interval osteonecrosis of the right hip. He had also developed a painful lesion in his left hemipelvis in the same region of previous Gaucheroma (Fig. 1B). Magnetic resonance imaging (MRI) showed an 8 × 10 cm lesion located adjacent to the left acetabulum and extending into the pelvis causing destruction of the left ischium and pubis. It was concluded to be a remnant of the prior Gaucheroma with component of cystic hematoma. Majority of patients with GD1 have skeletal manifestations ranging from osteopenia, bone marrow infiltration, infarction, avascular necrosis, pathological fractures, lytic lesions, and joint replacements 2, 3. Bone pain can be debilitating occurring in about two-thirds of patients and bone crisis in one-third of the patients 2. About a quarter of the patients have bone infarction and avascular necrosis 2. Therefore, the bone marrow and the skeleton is the primary target of GD. At age 52 in 2005, MRI scans showed further enlargement of the left pelvic lesion. It was described as a large heterogeneous lobulated mass measuring 11.9 × 10.3 × 13.7 cm arising from the left ischial tuberosity and exerting a mass effect leading to medial deviation of the rectum, urethra, and bladder (Fig. 1C,D). Positron emission tomography scan showed a large moderately intense uptake with hyper metabolism consistent with Gaucheroma. Over the next year, the mass enlarged further and magnetic resonance imaging showed a cystic lesion with a hemorrhagic component of 15 × 10 × 15 cm size with gadolinium contrast revealing a large central segment of liquefaction necrosis with a thick irregular enhancing rim. In addition, there was extensive signal abnormality within the left sacral wing and diffusely throughout the superior gluteus maximus muscle dorsal to the left iliac wing of uncertain significance. Assessment of the primary origin of the lesion was difficult because of the extensive metallic artifact in the region of the left hip and it was diagnosed as aneurysmal bone cyst arising in a cystic hematoma. Radiation therapy followed by multiple rounds of embolization was performed with only modest relief of symptoms. At age 55, patient was admitted to relieve symptoms due to compression to the pelvic organs. Initially limited debridement and later open excision was performed but the patient had continuous bleeding from the site. Finally, he underwent a left hemipelvectomy. Histopathology reports showed the growth of an epithelioid angiosarcoma (Fig. 2C,D) measuring 2 × 2 cm embedded within an organized chronic hematoma (Fig. 2B). Shortly thereafter, he developed metastatic disease in the lungs with pulmonary hemorrhage, pleura, liver, and spleen as well as skeletal metastatic disease. Patient was started on Paclitaxel but sadly passed away due to disseminated metastasis to pleura, lungs, liver, spleen, and bone. Table 1 and Fig. 3 illustrate that rare skeletal tumors occurred in the setting of severe skeletal manifestations of GD. Patient 2 despite starting enzyme replacement therapy suffered from suboptimal dosing for years resulting in continuous development of bone disease despite therapy; in addition, detailed repeated investigations of the Gaucheroma failed to reveal malignancy until advanced metastatic disease developed. Timeline of events for Patient 1 and 2. A review of current literature through Pubmed of associated musculoskeletal tumors with GD yielded individual case reports of leiomyosarcoma 13, pelvic sarcoma 14, hemangioendotheliosarcoma 8, angiosarcoma 15, and two cases of osteoblastoma 7, 16. Weinreb and Lee in their article report two cases of soft tissue sarcoma 9. The case report by Pins et al. 1 on epithelioid hemangioendothelioma and case series on angiosarcoma 10 were excluded from this because it describes the same patients in case 1 and case 2 of this report. Further details on each of these reports are outlined in Table 2. Adding the two patients in our report with epithelioid hemangioendothelioma and angiosarcoma to the pool of data aggregates a total of 10 reported cases of skeletal tumors in patients with GD. Four of the 10 cases (40%) were highly vascular tumors of the bone, which are tumors considered exceedingly rare in the general population. The mechanistic link between GD-related pathological bone remodeling to development of benign and malignant skeletal lesions is unclear. In general, several aspects of GD pathophysiology promote oncogenesis, such as increased glycosphingolipids, alternatively activated macrophages, and modifier genes 5. Epithelioid hemangioendothelioma has a well-defined genetic association, for example, with translocation and fusion of CAMTA1 and WWTR1 genes on chromosomes 1 and 3 [t(1; 3) (1p36.23; 3q25.1)] 17, 18. Both CAMTA1 and WWTR1 genes have been elucidated to be involved in oncogenesis in multiple studies 19, 20. Angiosarcomas are extremely rare and genetic associations have not been studied thoroughly. Even though angiosarcomas present with considerable genetic heterogeneity, Italiano et al. have reported an association with amplification of MYC oncogene 21. Burgert-Lon et al. also describe C-MYC staining in three of the five angiosarcoma patients 10. Further studies are required to see if there is evidence of association of GBA1 gene with CAMTA1, WWTR1, and MYC oncogenes. Similar association of GD with T cell lymphoblastic lymphoma has been described due to presence of MHS6 gene mutation 22. Complications of GD, particularly avascular necrosis and infarcts, provide fertile ground for sarcomatous degeneration. However bone infarcts are generally commonly associated with malignant fibrous histiocytomas and osteosarcomas 23. Domson et al. combining data from 57 non-GD patients reported that 69% of all tumors arising from bone infarcts were malignant fibrous histiocytomas, 17% were osteosarcomas, and 9% angiosarcomas 23. Given that as many as 43% of GD patients have avascular necrosis and bone infarctions 24, it is surprising that no cases of malignant fibrous histiocytoma or osteosarcoma have been reported in literature to our knowledge. Vascular tumors of the bone, in general, have a low incidence rate in the general population. Angiosarcomas are extremely rare and have been mentioned in only a handful of case reports and in small case series 25. They are more commonly associated with radiation therapy and lymphedema 17. In our case, patient 2 had radiation therapy for his enlarging chronic hematoma. Our 2 cases arose in a total GD population of approximately 400 patients that we have followed. Considering that there are at least 4 reported cases of occurrence of malignant vascular skeletal tumors in GD, which itself is a rare disease, suggests that the incidence of these tumors may be greatly increased. This raises interesting questions on whether the bioactive lipids and dysregulation of glycosphingolipid pathways in GD amplify risk of these malignancies. Our cases emphasize the importance of vigilance for skeletal lesions that are atypical in Gaucher disease or that become symptomatic and enlarge over time. Given the low number of cases and rarity of GD, it is difficult to delineate a cause–effect relation with GD and skeletal malignancies although the incidence of these tumors seems to be increased. Given the genetic associations of these vascular tumors, it would be interesting to perform whole exome sequencing to search for mutations in germline and tumor DNA in genes associated with these tumors. Early diagnosis and appropriate treatment should improve outcomes.