Gaucher disease and cancer incidence: a study from the Gaucher Registry

Vous trouverez des articles traitant du même sujet dans la catégorie "Cancer et Maladie de Gaucher"

Liens utiles à la fin des catégories.

Ghislaine SURREL

maladies-lysosomales-subscribe@yahoogroupes.fr

                                                                                                                                         

Blood, 15 June 2005, Vol. 105, No. 12, pp. 4569-4572.
Prepublished online as a Blood First Edition Paper on February 17, 2005; DOI 10.1182/blood-2004-12-4672.             

CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS

Gaucher disease and cancer incidence: a study from the Gaucher Registry

Barry E. Rosenbloom, Neal J. Weinreb, Ari Zimran, Katherine A. Kacena, Joel Charrow, and Elizabeth Ward

From the Tower Hematology Oncology Medical Group, Beverly Hills, CA; the University Research Foundation for Lysosomal Storage Diseases, Coral Springs, FL; the Department of Medicine, Shaare Zedek Medical Center, Jerusalem, Israel; Genzyme Corporation, Cambridge, MA; the Division of Genetics, Children's Memorial Hospital, Department of Pediatrics, Feinberg School of Medicine of Northwestern University, Chicago, IL; and the American Cancer Society, Atlanta, GA.

	Abstract

Patients with Gaucher disease (GD) are alleged to be at an increased risk of malignant disorders, possibly due to potential chronic stimulation of the immune system and lymphoproliferation associated with storage of glucocerebroside in tissue macrophages. Because previous reports of increased risk of malignancy in GD may have been affected by small patient numbers and ascertainment bias, 2742 patients with GD from the International Gaucher Registry were studied. The number of cancers identified among patients in the registry was compared with that expected in the US population of similar attained age and sex. The majority of patients were young or middle-aged adults at the time of last follow-up, with only 14% older than age 60. There were 10 patients with multiple myeloma, yielding an estimated relative risk of 5.9 (95% confidence interval [95% CI]: 2.8, 10.8). The relative risk of cancer overall was 0.79 (95% CI: 0.67, 0.94), and the subgroups for cancers of the breast, prostate, colon and rectum, lung, and hematologic malignancies other than myeloma did not yield statistically significant higher risks. This study suggests that, in general, patients with Gaucher disease are not at highly increased risk of cancer, at least during early and middle age. However, there appears to be a significantly higher risk of multiple myeloma of which physicians should be aware when caring for these patients. (Blood. 2005;105:4569-4572)

	Introduction

Gaucher disease, caused by an inherited deficiency of glucocerebrosidase, is the most prevalent lysosomal storage disease worldwide. Because of an excessive accumulation of glucocerebroside in macrophages, progressive hepatosplenomegaly, anemia, thrombocytopenia, and bone involvement commonly occur.¹ It has been reported that the incidence of malignant disorders is increased in patients with Gaucher disease.^2,3 If this conclusion is accurate, the ramifications for patients and their physicians is quite significant and may imply a causal relationship, possibly due to some chronic stimulation of the immune system.⁴ 

The Gaucher Registry is a database that, as of September 30, 2003, has information on nearly 3000 patients with Gaucher disease of all types.⁵ More than 90% have type I disease and form the basis of this retrospective review of the incidence of cancer in patients with Gaucher disease. The majority of these patients are receiving enzyme replacement therapy (ERT) with imiglucerase for injection (Cerezyme; Genzyme, Cambridge, MA),⁶ but untreated patients are also included. 

	Materials and methods

Gaucher Registry

The Gaucher Registry tracks outcomes of routine clinical practice for patients with GD from more than 40 countries, regardless of severity and treatment status. All patients (or for those younger than 18 years of age, their parents or guardians) gave consent to participate in the Gaucher Registry at the time of enrollment. All physicians following patients with Gaucher disease are encouraged to submit clinical data on their patients to the registry. The study protocol was approved by institutional review boards at all sites. Data submissions are checked and queried regarding completeness and apparent errors but are not validated by review of either medical or pathologic records. 

Analytical methods

The Gaucher Registry data were reviewed for cancer occurrence by analyzing both adverse events and concurrent illnesses. The standard method of analysis for studies in which cancer incidence is followed in a defined population over time is a life table approach in which patients are followed from the time they enter the population (in this case, enter the registry) until their date of cancer diagnosis or death. Expected cases are derived from age-, sex-, and race-specific person-years at risk and incidence rates. However, in the Gaucher Registry, although age at first and last follow-up into the registry is known, the age at cancer diagnosis is unknown for most cases; therefore, the life table method cannot be used. 

In this analysis, the numbers of selected cancers expected in the registry population was estimated by calculating cumulative lifetime probability of having developed the cancers by attained age. Attained age was defined in this analysis as the date of last registry follow-up or the date of diagnosis of cancer when known. The registry population was assigned to mutually exclusive 5-year age- and sex-specific subgroups. The probability of having developed cancer was calculated using DevCAN (Probability of Developing or Dying from Cancer), publicly available SEER (Surveillance, Epidemiology, and End Results) software (National Cancer Institute, Bethesda, MD), which allowed the calculation of the probability of developing cancers by specific attained ages. The number of cancers expected in this cohort were summed over all age groups and compared with the numbers observed in the patients in the registry. The standardized mortality ratio (SMR) relative risk (RR) was calculated by dividing the observed mortality by the expected mortality. For observed counts equal to 20, 95% confidence intervals (CIs) for the SMR were computed by using exact methods for the Poisson distribution. For observed counts greater than 20, an asymptotic method based on the log transformations was used.⁷ 

	Results

At the time of this analysis, there were 2742 patients in the registry. As shown in Table 1, the age distribution in the Gaucher Registry population in fact closely approximates the world standard population.⁸ Since the population age distributions are similar, and the Gaucher populations are stratified by age and sex to compare cancer rates, there should be no bias introduced as a result of difference in the population structure itself. Approximately 92% of the patients were type 1, 1% was type 2, 5% were type 3, and for 2% no type was identified by the participating physician. More than 80% of the patients had received ERT. The median age at last follow-up was in the third decade. There were 126 patients for whom at least one cancer event was reported (Table 2). One patient had 2 events of cancer reported. About 65% of all reported cancers occurred in patients older than 50 years of age. Cancer events were disproportionately greater in patients from the United States and in patients of Ashkenazi Jewish ethnicity. This observation is attributable to overrepresentation of older patients in the United States and Ashkenazi Jewish subpopulations. Cancer incidence was similar in patients ever treated with ERT (104 of 2241, 4.6%) and those never treated with ERT (22 of 495, 4.4%).

 

Age, y	Gaucher Registry, no. (%)*	World standardized population per 100 000 (%)
0-14	703 (25.6)	31 000 (31)
15-44	1288 (47)	43 000 (43)
45-54	334 (12.2)	11 000 (11)
55-64	207 (7.5)	8 000 (8)
65+	210 (7.7)	7 000 (7)

^* N = 2742.

Table 1.. Age distribution in the Gaucher Registry population (with age at last follow-up known) and in the World Standardized Population

 

Variable	No. all registry patients (%)	No. patients with any cancer (%)	No. patients with myeloma (%)
All patients	2742 (100)	126 (100)	10 (100)
Disease type
Type 1	2510 (91.5)	124 (98)	10 (100)
Type 2	27 (1.0)	0 (0)	0 (0)
Type 3	144 (5.3)	0 (0)	0 (0)
Unreported	61 (2.2)	2 (2)	0 (0)
ERT status at last follow-up
Never on ERT	495 (18.1)	22 (17.5)	3 (30)
Ever on ERT	2241 (81.7)	104 (82.5)	7 (70)
Unknown	6 (0.2)	0 (0)	0 (0)
Age distribution at last follow-up, y
0-10	426 (15.5)	0 (0)	0 (0)
11-20	503 (18.3)	5 (4.0)	0 (0)
21-30	404 (14.7)	3 (2.4)	0 (0)
31-40	435 (15.9)	14 (11.1)	0 (0)
41-50	416 (15.2)	22 (17.5)	0 (0)
51-60	263 (9.6)	21 (16.7)	1 (10)
61-70	154 (5.6)	24 (19.0)	4 (40)
71+	141 (5.1)	37 (29.4)	5 (50)
Geographic region
United States	1327 (48.4)	99 (78.6)	5 (50)
Americas (including Canada)	441 (16.1)	6 (4.8)	0 (0)
Europe	725 (26.4)	17 (13.5)	5 (50)
Middle East	158 (5.8)	2 (1.6)	0 (0)
Asia, Pacific, South Africa	91 (3.3)	2 (1.6)	0 (0)
Ethnicity
Caucasian, non-Jewish	623 (22.7)	17 (13.5)	1 (10)
African American/Caribbean	84 (3.1)	2 (1.6)	0 (0)
Hispanic	171 (6.2)	1 (0.8)	0 (0)
Jewish, Ashkenazi	636 (23.2)	58 (46.0)	3 (30)
Jewish, Sephardi	6 (0.2)	1 (0.8)	0 (0)
American Indian	24 (0.9)	0	0 (0)
Asian	25 (0.9)	0	0 (0)
Arab	39 (1.4)	0	0 (0)
Multiethnic, non-Jewish	29 (1.1)	0	0 (0)
Unreported	1092 (39.8)	47 (37.3)	6 (60)

Table 2.. Overview of available data from the Gaucher Registry

As shown in Table 3, the overall lifetime probability of developing cancer by attained age in this population was not greater than expected (relative risk, 0.79). This was also true for individual cancers, including breast cancer, prostate cancer, colorectal cancer, lung cancer, and all hematologic malignancies in aggregate, except multiple myeloma. The observed and expected incidence of myeloma was 10 and 1.7, respectively, with a relative risk of 5.9 (95% CI: 2.8, 10.8). With one exception, all patients with Gaucher disease with multiple myeloma were older than age 60, and the increase in myeloma incidence was observed in both US and European subpopulations (Table 2). Myeloma occurred in patients never treated with ERT (3 of 495, 0.6%) and in ERT-treated patients (7 of 2241, 0.3%).

	Observed, no.	Expected, no.	RR (95% CI)
All cancer*	126	159	0.79 (0.67, 0.94)
Multiple myeloma	10	1.7	5.9 (2.82, 10.82)
Breast cancer	15	33.2	0.45 (0.25, 0.75)
Prostate cancer	10	30.4	0.33 (0.16, 0.60)
Colorectal cancer	6	15.5	0.39 (0.14, 0.84)
Lung cancer	6	19.9	0.30 (0.11, 0.66)
Hematologic	19	15.6	1.23 (0.73, 1.90)

^* Includes nonmelanoma skin cancers, ovarian cancer, renal carcinoma, bladder cancer, hepatocellular cancer, ganglioneuroma, neurosarcoma, angiosarcoma, thyroid carcinoma, pancreatic cancer, testicular rhabdomyosarcoma, and carcinoid tumor.

Includes non-Hodgkin lymphoma (5), Hodgkin disease (1), acute myeloid leukemia (AML; 3), acute lymphoblastic leukemia (ALL; 1), chronic lymphocytic leukemia (CLL; 1), Waldenstrom macroglobulinemia (1), and unspecified (7)

Table 3.. Lifetime probability of cancer by attained age in patients (N = 2742) with Gaucher disease

	Discussion

In 1982, from a retrospectively collected population of 239 patients with type 1 Gaucher disease, Lee² reported a review of 35 deceased patients with Gaucher disease, 19 of whom (54%) had evident malignancies. He postulated that, in patients with milder variants of Gaucher disease in whom life expectancy in the pre-ERT era was considerably greater than in severely affected patients, the accumulated glucocerebroside somehow contributed in the causation of cancer.² Although detailed demographics for the 239 patients were not reported, assuming an age distribution similar to our study population (mean age, 33 years) resulting in 7887 risk-years, and an estimated cancer mortality for 1980 of 2 to 300 per 100 000,⁹ the predicted number of cancer deaths is 16 to 24. Thus, with the exception of multiple myeloma (3 of 19 deaths), the report of Lee² does not support a hypothesis that patients with type 1 Gaucher disease (GD) have an increased lifetime cancer risk. 

Shiran et al³ reported a 20.8% incidence of cancer among 48 patients with GD from their hematology clinic compared with a 6.8% incidence among healthy patients throughout their institution. There was a 14.7-fold increased risk of hematologic malignancies, including 2 patients with multiple myeloma. There are also numerous case reports of various malignancies reported in association with Gaucher disease.^10-45 Notable is a striking incidence of multiple myeloma in these reports.^{10,15,16,19,20,30,34,36,38,42} 

In the large population of patients with Gaucher disease presented in our report, the overall incidence of malignancy is 3.6%, about half the incidence reported by Shiran et al.³ For hematologic malignancies other than multiple myeloma, the collective incidence is 0.9%, which is far less than the 10.4% incidence in the study of Shiran et al.³ The relative risk for developing hematologic malignancies is slightly increased, but this result is not statistically significant, and it also assumes that the 7 cases of hematologic malignancy reported as "unspecified" are indeed properly classified. Additionally, the one case of Waldenstrom macroglobulinemia might appropriately be better grouped with patients with myeloma. 

For solid tumors in our patient population, the cumulative probability of developing cancer by attained age is actually less than expected. Because our study methodology relies on the SEER database as applied to a population with a US component of only 48.4%, our calculations of expected cancer incidence may be inaccurate. However, the majority of patients in the registry come from economically developed countries, where cancer patterns are generally similar to those in the United States.⁴⁶ the application of US data worldwide may partly explain why the observed incidence of cancer in our patients was less than expected. However, even using country-specific cancer incidences, save for myeloma, the relative cancer risk is not increased.  Consequently,

The statistical methodology of this report assumes that the registry is likely to have identified all cancer cases whether they occurred before or after entry into the registry. This method possibly may underestimate the relative risk of cancer in these patients, because complete identification by the registry of all cancers is improbable. In addition, the registry population is young, with few patients having reached the ages of 60 and older, when cancer rates are highest in the general population. The study might have failed to detect some cancers occurring at young ages because any such patients from earlier cohorts would not have survived long enough to be enrolled when the Gaucher Registry was initiated in 1991. However, this is unlikely to be an important bias since the literature review reveals only very rare reports of malignancy in children or young adults with GD.^24,27 

In contradistinction to all other malignancies, the incidence of multiple myeloma in patients with type 1 Gaucher disease is almost 6 times higher than expected. The association of Gaucher disease with polyclonal and monoclonal gammopathies has previously been reported.^{16,19,34,36,38,42,47} It has been theorized that persistent and progressive glucocerebroside storage may cause chronic stimulation of the immune system and consequent lymphoproliferation.⁴ However, the inflammatory response in Gaucher disease may in fact be independent of glucocerebroside deposition, as systemic inflammation is reported in glucocerebrosidase-deficient mice who demonstrate minimal storage of glucosyl ceramide.⁴⁸ Ferritin release from Gaucher cells has been implicated in reducing T-cell function and immunoglobulin M (IgM) release from B cells.⁴⁹ Interleukin 6 (IL-6) is a significant putative signal transduction cytokine in multiple myeloma,⁵⁰ and IL-6 levels are increased in some patients with Gaucher disease.⁵¹ Although recent histochemical analysis of GD splenic tissue suggests that classic Gaucher cells most closely resemble anti-inflammatory alternatively activated macrophages and do not produce typical proinflammatory molecules, there is nonetheless variable expression of IL-6 by Gaucher cells which also appear to induce a vigorous inflammatory response in surrounding classically activated red pulp macrophages.⁵² 

In conclusion, on the basis of this large database, the incidence of solid tumors and hematologic malignancies does not appear to be significantly increased in patients with Gaucher disease followed through early to middle age, except for multiple myeloma. This information should serve to alleviate inordinate fear of cancer in patients with Gaucher disease and their families that is attributable to frequent citation of the earlier literature on patient-accessible internet sites. Regarding the increased incidence of multiple myeloma, treating physicians should be cognizant of this finding and monitor patients with Gaucher disease accordingly. We recommend a baseline serum immunoelectrophoresis with initial diagnosis, at time of first evaluation, or prior to initiation of ERT, if such treatment is indicated. Abnormal results should be investigated following standard hematologic protocols. For patients with normal baseline results, we recommend serial follow-up at 1- to 2-year intervals, particularly in patients older than 50 years of age. Polyclonal gammopathies, which appear unrelated to emergence of monoclonal gammopathy and myeloma, are commonly identified in patients with type 1 Gaucher disease and often decrease in conjunction with the overall response to ERT.⁵³ Because myeloma occurs predominantly in elderly patients with Gaucher disease, long-term follow-up of patients in whom treatment is started in childhood or young adulthood is necessary to determine whether the increased incidence of monoclonal gammopathy and multiple myeloma in Gaucher disease will decrease with enzyme replacement therapy. 

	Acknowledgements

We thank the patients with Gaucher disease along with their physicians and health care personnel who submit data to the registry, and the US Regional Coordinators of the International Collaborative Gaucher Group (ICGG) for their review of the manuscript. 

	Footnotes

Submitted December  7, 2004; accepted February  5, 2005.

Prepublished online as Blood First Edition Paper, February 17, 2005; DOI 10.1182/blood-2004-12-4672. 

An Inside Blood analysis of this article appears in the front of this issue. 

The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734. 

Reprints: Barry E. Rosenbloom, Tower Oncology, 9090 Wilshire Blvd, Ste 200, Beverly Hills, CA 90211; e-mail: rosenbloom@toweroncology.com.

	References

1. Beutler E, Grabowsli GA. Gaucher disease. In: Scriver CR, Valle D, Beudet A, Sly WS, eds. The Metabolic and Molecular Bases of Inherited Diseases. Vol III. New York, NY: McGraw-Hill; 2001: 3635-3668.
2. Lee RE. The pathology of Gaucher disease. In: Desnick RJ, Grabowski GA, eds. Gaucher Disease: A Century of Delineation and Research. New York, NY: Alan R. Liss; 1982: 177-217.
3. Shiran A, Brenner B, Laor A, et al. Increased risk of cancer in patients with Gaucher disease. Cancer. 1993;72: 219-224.[CrossRef][Medline] [Order article via Infotrieve]
4. Schoenfeld Y, Gallant LA, Shaklai M, et al, Gaucher's disease: a disease with chronic stimulation of the immune system. Arch Pathol Lab Med. 1982;106: 388-391.[Medline] [Order article via Infotrieve]
5. Charrow J, Andersson HC, Kaplan P, et al, The Gaucher Registry: demographic and disease characteristics in patients with Gaucher disease. Arch Int Med. 2000;160: 2835-2843.[Abstract/Free Full Text]
6. Barton NW, Brady RO, Dambrosia JM, et al. Replacement therapy for inherited enzyme deficiency-macrophage targeted glucocerebrosidase for Gaucher's disease. N Engl J Med. 1991;324: 1464-1470.[Abstract]
7. Mills JL, Schonberger LB, Wysowski DK, et al. Long-term mortality in the United States cohort of pituitary-derived growth hormone recipients. J Pediatr. 2004;144: 430-436.[CrossRef][Medline] [Order article via Infotrieve]
8. Doll R, Smith PG. Comparison between registries: age-standardized rates. In: Waterhouse JAH, Muir CS, Shanmugaratnam K, Powell J, Peacham D, Whelan S, eds. Cancer Incidence in Five Continents. Vol. 4. Lyon, France: IARC; 1982: 671-675.
9. Levi F, Lucchini F, Negri E, Boyle P, La Vecchia C. Cancer mortality in Europe, 1995-1999, and an overview of trends since 1960. Int J Cancer. 2004;110: 155-169.[CrossRef][Medline] [Order article via Infotrieve]
10. Pinkhas J, Djaldetti M, Yaron M. Coincidence of multiple myeloma with Gaucher's disease. Isr J Med Sci. 1965;1: 537-540.[Medline] [Order article via Infotrieve]
11. Sharer LR, Barondess JA, Silver RT, Gray GF. Association of Hodgkin disease and Gaucher disease. Arch Pathol. 1974;98: 376-378.[Medline] [Order article via Infotrieve]
12. Chang-Lo M, Yam LT, Rubenstone AI, Schwartz SO. Gaucher's disease associated with chronic lymphocytic leukaemia, gout and colon carcinoma. J Pathol. 1975;116: 203-207.[CrossRef][Medline] [Order article via Infotrieve]
13. Cho SY, Sastre M. Coexistence of Hodgkin's disease and Gaucher's disease. Am J Clin Pathol. 1976;65: 103-108.[Medline] [Order article via Infotrieve]
14. Tsung SH, Cotes E. Coexistence of bronchogenic carcinoma and Gaucher disease [letter]. Arch Pathol Lab Med. 1977;101: 56.[Medline] [Order article via Infotrieve]
15. Dikman SH, Goldstein N, Kahn T, Leon M, Weinreb NJ. Amyloidosis: an unusual complication of Gaucher's disease. Arch Pathol Lab Med. 1978;102: 460-462.[Medline] [Order article via Infotrieve]
16. Benjamin D, Joshua H, Djaldetti M, Hazaz B, Pinkhas J. Nonsecretory IgD-kappa multiple myeloma in a patient with Gaucher's disease. Scand J Haematol. 1979;22: 179-184.[Medline] [Order article via Infotrieve]
17. Krause JR, Bures C, Lee RE. Acute leukaemia and Gaucher's disease. Scand J Haematol. 1979;23: 115-118.[Medline][Order article via Infotrieve]
18. Bruckstein AH, Karanas A, Dire JJ. Gaucher's disease associated with Hodgkin's disease. Am J Med. 1980;68: 610-613.[CrossRef][Medline] [Order article via Infotrieve]
19. Ruestow PC, Levinson DJ Catchatourian R, et al. Coexistence of IgA myeloma and Gaucher's disease. Arch Int Med. 1980;140: 1115-1116.[Abstract/Free Full Text]
20. Garfinkel D, Sidi Y, Ben-Bassat M, Salomon F, Hazaz B, Pinkhas J. Coexistence of Gaucher's disease and multiple myeloma. Arch Intern Med. 1982;142: 2229-2230.[Abstract/Free Full Text]
21. Lyons JC, Scheithauer BW, Ginsburg WW. Gaucher's disease and glioblastoma multiforme in two siblings: a clinicopathologic study. J Neuropathol Exp Neurol. 1982;41: 45-53.[Medline] [Order article via Infotrieve]
22. Mark T, Dominguez C, Rywlin AM. Gaucher's disease associated with chronic lymphocytic leukemia. South Med J. 1982;75: 361-363.[Medline] [Order article via Infotrieve]
23. Shinar E, Gershon ZL, Leiserowitz R, Matzner Y, Yatziv S, Polliack A. Coexistence of Gaucher Disease and Philadelphia positive chronic granulocytic leukemia. Am J Hematol. 1982;12: 199-202.[Medline] [Order article via Infotrieve]
24. Kojiro M, Kage M, Abe H, Imamura M, Shiraishi K, Mizoguchi M. Association of dysgerminoma and Gaucher's disease. Cancer. 1983;51: 712-715.[CrossRef][Medline] [Order article via Infotrieve]
25. Watanabe M, Yanagisawa M, Sonobe S, et al. An adult form of Gaucher's disease with a huge tumour formation of the right tibia. Int Orthop. 1984;8: 195-202.[CrossRef][Medline] [Order article via Infotrieve]
26. Fox H, McCarthy P, Andre-Schwartz J, et al. Gaucher's disease and chronic lymphocytic leukemia: possible pathogenetic link between Gaucher's disease and B-cell proliferations? Cancer. 1984;54: 312-314.[CrossRef][Medline][Order article via Infotrieve]
27. Burstein Y, Recchavi G, Rausen AR, et al. Association of Gaucher's disease and lymphoid malignancy in 2 children. Scand J Haematol. 1985:35: 445-447.[Medline] [Order article via Infotrieve]
28. Kaufman S, Rozenfelkd V, Yona R, et al. Gaucher's disease associated with chronic lymphocytic leukemia. Clin Lab Haematol. 1986;8: 321-324.[Medline] [Order article via Infotrieve]
29. Corbett GM, Darbyshire PJ, Besley GT, et al. Adult Gaucher disease in association with acute leukemia. Postgrad Med J. 1987;63: 899-900.[Abstract/Free Full Text]
30. Gal R, Gukovsky-Oren S, Floru S, Djaldetti M, Kessler E. Sequential appearance of breast carcinoma, multiple myeloma and Gaucher's disease. Haematologica. 1988;73: 63-65.[Medline] [Order article via Infotrieve]
31. Goodman S. Nodular sclerosing Hodgkin's disease in association with Gaucher's disease. Clin Radiol. 1988;39: 326-327.[Medline] [Order article via Infotrieve]
32. Paulson JA, Marti GE, Fink JK, et al. Richter's transformation of lymphoma complicating Gaucher's disease. Haematol Pathol. 1989;3: 91-96.
33. Breiden-Langen CM, Buchsel R, Brambs HJ, Oehlert M, Matern S. Coincidence of Gaucher disease with primary hepatocellular carcinoma [in German]. Leber Magen Darm. 1991;21: 126-130.[Medline] [Order article via Infotrieve]
34. Airo R, Gabusi G, Guidini M. Gaucher's disease associated with monoclonal gammopathy of undetermined significance: a case report. Haematologica. 1993:78: 129-131.[Medline] [Order article via Infotrieve]
35. Marsh RD, Killeen RB Jr, Agaliotis D. Gaucher's disease associated with chronic lymphocytic leukemia. South Med J. 1993;86: 473-475.[CrossRef][Medline] [Order article via Infotrieve]
36. Shvidel L, Hurwitz N, Shtalrid M, et al. Complex IgA gammopathy in Gaucher's disease. Leuk Lymphoma. 1995;20: 165-168.[Medline] [Order article via Infotrieve]
37. Kenan S, Abdelwahab IF, Hermann G, et al. Osteoblastoma of the humerus associated with type I Gaucher's disease: a case report. J Bone Joint Surg Br. 1996:78: 702-705
38. Brady K, Corash L, Bhargava V. Multiple myeloma arising from monoclonal gammopathy of undetermined significance in a patient with Gaucher's disease. Arch Pathol Lab Med. 1997;121: 1108-1111.[Medline] [Order article via Infotrieve]
39. Perales M, Cervantes F, Cobo F, et al. Non-Hodgkin's lymphoma associated with Gaucher's disease. Leuk Lymphoma. 1998:31: 609-612.[Medline] [Order article via Infotrieve]
40. Petrides PE, leCoutre P, Muller-Hocker J, et al. Coincidence of Gaucher's disease due to a private mutation and Ph' positive chronic myeloid leukemia. Am J Hematol. 1998:59: 87-90.[CrossRef][Medline] [Order article via Infotrieve]
41. Erjavec Z, Hollak CE, de Vries EG. Hepatocellular carcinoma in a patient with Gaucher disease on enzyme supplementation therapy [letter]. Ann Oncol. 1999:10: 243.[Free Full Text]
42. Harder H, Eucker J, Zang C, et al. Coincidence of Gaucher's disease due to 1226G/1448C mutation and of an immunoglobulin G lambda multiple myeloma with Bence-Jones proteinuria. Ann Hematol. 2000;79: 640-643.[CrossRef][Medline] [Order article via Infotrieve]
43. Manz M, Riessen R, Poll L, et al. High-grade lymphoma mimicking bone crisis in Gaucher's disease. Br J Haematol. 2001;113: 191-193.[CrossRef][Medline] [Order article via Infotrieve]
44. Bohm P, Kunz W, Horny HP, et al. Adult Gaucher disease in association with primary malignant bone tumors. Cancer. 2001;91: 457-462.[CrossRef][Medline] [Order article via Infotrieve]
45. Haran MZ, Feldbereg E, Berrebi A. Incidental diagnosis of Gaucher's disease in an elderly patient with lymphoma. Leuk Lymphoma. 2001;40: 445-446.[Medline] [Order article via Infotrieve]
46. World Health Organization, International Agency for Cancer Research. Globocan 2002. http://www-depdb.iarc.fr/globocan/GLOBOframe.htm. Accessed January 11, 2005.
47. Marti GE, Ryan ET, Papadopoulos NM, et al. Polyclonal B-cell lymphocytosis and hypergammaglobulinemia in patients with Gaucher disease. Am J Hematol. 1988;29: 189-194.[Medline] [Order article via Infotrieve]
48. Mizukami H, Mi Y, Wada R, et al. Systemic inflammation in glucocerebrosidase deficient mice with minimal glucosylceramide storage. J Clin Invest. 2002;109: 1215-1221.[CrossRef][Medline] [Order article via Infotrieve]
49. Bassan R, Montanelli A, Barbui T. Interaction between a serum factor and T-lymphocytes in Gaucher disease. Am J Hematol. 1985;18: 381-384.[Medline] [Order article via Infotrieve]
50. Cheung WC, van Ness B, Distinct interleukin-6 signal transduction and death in B-cells or growth promotion and cell survival in myeloma cells. Leukemia. 2002;16: 1182-1188.[CrossRef][Medline] [Order article via Infotrieve]
51. Allen MJ, Myer BJ, Khokher AM, et al. Pro-inflammatory cytokines and the pathogenesis of Gaucher's disease: increased release of interleukin-6 and interleukin-10. QJM. 1997;90: 19-25.[Abstract/Free Full Text]
52. Boven LA, van Meurs M, Boot RG, et al. Gaucher cells demonstrate a distinct macrophage phenotype and resemble alternatively activated macrophages. Am J Clin Pathol. 2004;122: 359-369.[CrossRef][Medline][Order article via Infotrieve]
53. Brautbar A, Elstein D, Pines G, Abrahamov A, Zimran A. Effect of enzyme replacement therapy on gammopathies in Gaucher disease. Blood Cells Mol Dis. 2004;32: 214-217.[CrossRef][Medline] [Order article via Infotrieve]

http://bloodjournal.hematologylibrary.org/cgi/content/full/105/12/4569

---