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Second neoplasms in patients with chronic lymphocytic leukemia

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Second malignancies occur with increased frequency in patients with chronic lymphocytic leukemia (CLL) regardless of treatment, but they may be more frequent and more aggressive after nucleoside analog therapy of CLL. In as many as 33% of patients with CLL who develop a second malignancy, a spontaneous remission of CLL precedes the diagnosis of the second malignancy by months or years. Richter’s syndrome, whether manifested by anaplastic large cell lymphoma or Hodgkin’s disease, is not truly a second malignancy because the CLL clone appears to be involved. However, all other malignancies developing in patients with CLL appear to be derived from a different clone. CLL and the second malignancy may have a common viral etiology. Second malignancies in patients with CLL should be treated as they would be in patients without CLL.

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References and Recommended Reading

  1. Wiernik PH, Hu X, Ratech H, et al.: Non-Hodgkin’s lymphoma in women with breast cancer. Cancer J 2000, 6:336–342.

    PubMed  CAS  Google Scholar 

  2. Sakai T, Ogura Y, Narita J, et al.: Simultaneous early adenocarcinoma and mucosa-associated lymphoid tissue (MALT) lymphoma of the stomach associated with Helicobacter pylori infection. Gastric Cancer 2003, 6:191–196.

    Article  PubMed  Google Scholar 

  3. Dincol D, Arican A, Ensari A, et al.: Concurrent occurrence of three neoplasms including non-Hodgkin’s lymphoma, renal cell carcinoma and leiomyoma in the same kidney. Med Oncol 1999, 16:134–138.

    PubMed  CAS  Google Scholar 

  4. Padmanabhan V, Trainer TD: Synchronous adenocarcinoma and mantle cell lymphoma of the colon. Arch Pathol Lab Med 2003, 127:E64-E66.

    PubMed  Google Scholar 

  5. McKenna DB, Stockton D, Brewster DH, Doherty VR: Evidence for an association between cutaneous malignant melanoma and lymphoid malignancy: a population-based retrospective cohort study in Scotland. Br J Cancer 2003, 88:74–78.

    Article  PubMed  CAS  Google Scholar 

  6. Etkind P, Du J, Khan A, et al.: Mouse mammary tumor virus-like ENV gene sequences in human breast tumors and in a lymphoma of a breast cancer patient. Clin Cancer Res 2000, 6:1273–1278.

    PubMed  CAS  Google Scholar 

  7. Rohwedder A, Philips B, Malfetano J, et al.: Vulvar malignant melanoma associated with human papillomavirus DNA: report of two cases and review of literature. Am J Dermatopathol 2002, 24:230–240.

    Article  PubMed  Google Scholar 

  8. Kamel D, Turpeenniemi-Hujanen T, Vahakangas K, et al.: Proliferating cell nuclear antigen but not p53 or human papilloma virus DNA correlates with advanced clinical stage in renal cell carcinoma. Histopathology 1994, 25:339–347.

    Article  PubMed  CAS  Google Scholar 

  9. Manusow D, Weinerman BH: Subsequent neoplasia in chronic lymphocytic leukemia. JAMA 1975, 232:267–269.

    Article  PubMed  CAS  Google Scholar 

  10. Greene MH, Hoover RN, Fraumeni JF Jr: Subsequent cancer in patients with chronic lymphocytic leukemia: a possible immunologic mechanism. J Natl Cancer Inst 1978, 61:337–340.

    PubMed  CAS  Google Scholar 

  11. Santoro A, Rilke F, Franchi F, Monfardini S: Primary malignant neoplasms associated with chronic lymphocytic leukemia. Tumori 1980, 66:431–437.

    PubMed  CAS  Google Scholar 

  12. Harvey EB, Brinton LA: Second cancer following cancer of the breast in Connecticut 1935–82. Natl Cancer Inst Monogr 1985, 68:99–112.

    PubMed  CAS  Google Scholar 

  13. Davis JW, Weiss NS, Armstrong BK: Second cancers in patients with chronic lymphocytic leukemia. J Natl Cancer Inst 1987, 78:91–94.

    PubMed  CAS  Google Scholar 

  14. Bertoldero G, Scribano G, Podda L, et al.: Occurrence of second neoplasms in chronic lymphocytic leukemia: experience at Padua Hospital between 1979 and 1991. Ann Hematol 1994, 69:195–198.

    Article  PubMed  CAS  Google Scholar 

  15. Suzuki K, Maekawa I, Mikuni C, et al.: Prognosis in 75 cases of chronic lymphocytic leukemia and second malignancies. Rinsho Ketsueki 1997, 38:740–744.

    PubMed  CAS  Google Scholar 

  16. Hisada M, Biggar RJ, Greene MH, et al.: Solid tumors after chronic lymphocytic leukemia. Blood 2001, 98:1979–1981.

    Article  PubMed  CAS  Google Scholar 

  17. Duggan DB, Petroni GR, Johnson JL, et al.: Randomized comparison of ABVD and MOPP/ABV hybrid for the treatment of advanced Hodgkin’s disease: report of an intergroup trial. J Clin Oncol 2003, 21:607–614.

    Article  PubMed  CAS  Google Scholar 

  18. Smith RE: Risk for the development of treatmentrelated acute myelocytic leukemia and myelodysplastic syndrome among patients with breast cancer: review of the literature and the National Surgical Adjuvant Breast and Bowel Project experience. Clin Breast Cancer 2003, 4:273–279.

    PubMed  CAS  Google Scholar 

  19. Keating MJ, O’Brien S, Lerner S, et al.: Long-term follow-up of patients with chronic lymphocytic leukemia (CLL) receiving fludarabine regimens as initial therapy. Blood 1998, 92:1165–1171.

    PubMed  CAS  Google Scholar 

  20. Cheson BD, Vena DA, Barrett J, Freidlin B: Second malignancies as a consequence of nucleoside analog therapy for chronic lymphoid leukemias. J Clin Oncol 1999, 17:2454–2460.

    PubMed  CAS  Google Scholar 

  21. Cohen Y, Da’as N, Libster D, et al.: Large-cell transformation of chronic lymphocytic leukemia and follicular lymphoma during or soon after treatment with fludarabine-rituximab-containing regimens: natural history-or therapy-related complication? Eur J Haematol 2002, 68:80–83.

    Article  PubMed  CAS  Google Scholar 

  22. Morrison VA, Rai KR, Peterson BL, et al.: Therapy-related myeloid leukemias are observed in patients with chronic lymphocytic leukemia after treatment with fludarabine and chlorambucil: results of an intergroup study, Cancer and Leukemia Group B 9011. J Clin Oncol 2002, 20:3878–3884.

    Article  PubMed  Google Scholar 

  23. Lai R, Arber DA, Brynes RK, et al.: Untreated chronic lymphocytic leukemia concurrent with or followed by acute myelogenous leukemia or myelodysplastic syndrome: a report of five cases and review of the literature. Am J Clin Pathol 1999, 111:373–378.

    PubMed  CAS  Google Scholar 

  24. Barresi GM, Albitar M, O’Brien SM: Acute myeloid leukemia, inversion 16, occurring in a patient with chronic lymphocytic leukemia. Leuk Lymphoma 2000, 38:621–625.

    PubMed  CAS  Google Scholar 

  25. Miller MK, Strauchen JA, Nichols KT, Phelps RG: Concurrent chronic lymphocytic leukemia cutis and acute myelogenous leukemia cutis in a patient with untreated CLL. Am J Dermatopathol 2001, 23:334–340.

    Article  PubMed  CAS  Google Scholar 

  26. Raz I, Polliack A: Coexistence of myelomonocytic leukemia and monoclonal gammopathy or myeloma: simultaneous presentation in three patients. Cancer 1984, 53:83–85.

    Article  PubMed  CAS  Google Scholar 

  27. Ornellas De Souza MH, de Souza Fernandez T, Diamond HR, et al.: Cytogenetic and immunophenotypic evidence of independent clonal origin of concomitant chronic lymphocytic leukaemia and acute myeloid leukaemia. Eur J Haematol 2001, 66:281–283.

    Article  Google Scholar 

  28. Salim R, Wang L, Lin K, Clark RE: Chronic lymphocytic leukaemia developing in the course of chronic myeloid leukemia. Leuk Lymphoma 2002, 43:2225–2227.

    PubMed  CAS  Google Scholar 

  29. Mansat-De Mas V, Rigal-Huguet F, Cassar G, et al.: Chronic myeloid leukemia associated with B-cell chronic lymphocytic leukemia: evidence of two separate clones as shown by combined cell-sorting and fluorescence in situ hybridization. Leuk Lymphoma 2003, 44:867–869.

    Article  CAS  Google Scholar 

  30. Yahata N, Iwase O, Tauchi T, et al.: Chronic lymphocytic leukemia complicated by plasmacytoma originating from different clones. Leuk Lymphoma 2000, 39:203–207.

    PubMed  CAS  Google Scholar 

  31. Patriarca F, Gaidano G, Capello D, et al.: Occurrence of multiple myeloma after fludarabine treatment of chronic lymphocytic leukemia: evidence of a biclonal derivation and clinical response to autologous stem cell transplantation. Haematologica 2000, 85:982–985.

    PubMed  CAS  Google Scholar 

  32. Chang H, Wechalekar A, Li L, Reece D: Molecular cytogenetic abnormalities in patients with concurrent chronic lymphocytic leukemia and multiple myeloma shown by interphase fluorescence in situ hybridization: evidence of distinct clonal origin. Cancer Genet Cytogenet 2004, 148:44–48.

    Article  PubMed  CAS  Google Scholar 

  33. Barton JC: Thalidomide and dexamethasone therapy of myeloma in a patient with previously untreated Bchronic lymphocytic leukemia. Am J Hematol 2003, 74:205–207.

    Article  PubMed  Google Scholar 

  34. Makower D, Venkatraj U, Dutcher JP, Wiernik PH: Occurrence of myeloma in a chronic lymphocytic leukemia patient after response to differentiation therapy with interleukin-4. Leuk Lymphoma 1996, 23:617–619.

    PubMed  CAS  Google Scholar 

  35. Larsen CR, Hansen PB, Clausen NT: Aggressive growth of epithelial carcinomas following treatment with nucleoside analogues. Am J Hematol 2002, 70:48–50. This is one of many studies that raises the question whether second tumors occur in patients with CLL more often after nucleoside analog therapy and whether these tumors are more aggressive after nucleoside therapy for CLL.

    Article  PubMed  Google Scholar 

  36. Hartley BE, Searle AE, Breach NM, et al.: Aggressive cutaneous squamous cell carcinoma of the head and neck in patients with chronic lymphocytic leukaemia. J Laryngol Otol 1996, 110:694–695.

    PubMed  CAS  Google Scholar 

  37. Hsu CW, Krevsky B, Sigman LM, Thomas RM: Rapid progression of Barrett’s esophagus to metastatic esophageal carcinoma in a patient with chronic lymphocytic leukemia. J Clin Gastroenterol 1998, 27:261–264.

    Article  PubMed  CAS  Google Scholar 

  38. Nakamura N, Abe M: Richter syndrome in B-cell chronic lymphocytic leukemia. Pathol Int 2003, 53:195–203.

    Article  PubMed  CAS  Google Scholar 

  39. Schmidt HH, Sill H, Eibl M, et al.: Hodgkin’s disease developing after spontaneous remission of chronic lymphocytic leukemia. Ann Hematol 1995, 71:247–252.

    PubMed  CAS  Google Scholar 

  40. Gopal AK, Schuetze SM, Maloney DG, Weiden PL: Large cell non-Hodgkin’s lymphoma and Hodgkin’s disease arising synchronously in a patient with chronic lymphocytic leukemia: importance of immunochemistry. Blood 1999, 94:2537.

    PubMed  CAS  Google Scholar 

  41. Adiga GU, Abebe L, Wiernik PH: Partially successful treatment of a patient with chronic lymphocytic leukemia and Hodgkin’s disease: case report and literature review. Am J Hematol 2003, 72:267–273. This is a fairly comprehensive review of Hodgkin’s disease occurring in patients with CLL. It demonstrates the influence of one disease on the other disease, in which Hodgkin’s disease developing in patients with CLL is more easily treated if the CLL is quiescent as opposed to active.

    Article  PubMed  Google Scholar 

  42. Naranjo TA, Matutes EI, Martinez JJ, et al.: Prolymphocytic leukaemia and Hodgkin’s disease. Eur J Haematol 2002, 69:182–184.

    Article  PubMed  Google Scholar 

  43. Robak T, Szmigelska-Kaplon A, Smolewski P, et al.: Hodgkin’s type of Richter’s syndrome in familial chronic lymphocytic leukemia treated with cladribine and cyclophosphamide. Leuk Lymphoma 2003, 44:859–866.

    Article  PubMed  CAS  Google Scholar 

  44. Alliot C, Tabuteau S, Desablens B: Hodgkin’s disease variant of Richter’s syndrome: complete remission of both malignancies after 14 years. Hematology 2003, 8:229–231.

    Article  PubMed  Google Scholar 

  45. Kyasa MJ, Hazlett L, Parrish RS, et al.: Veterans with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) have a markedly increased rate of second malignancy, which is the most common cause of death. Leuk Lymphoma 2004, 45:507–513. This study, despite some minor flaws, demonstrates conclusively that second malignancy occurs with greater than expected frequency in patients with CLL. It also demonstrates the seriousness of the problem.

    Article  PubMed  Google Scholar 

  46. Smith KJ, Germain M, Skelton H: Bowen’s disease (squamous cell carcinoma in situ) in immunosuppressed patients treated with imiquimod 5% cream and a cox inhibitor, sulindac: potential applications for this combination of immunotherapy. Dermatol Surg 2001, 27:143–146.

    Article  PubMed  CAS  Google Scholar 

  47. Nouri K, O’Connell C, Rivas MP: Imiquimod for the treatment of Bowen’s disease and invasive squamous cell carcinoma. Drugs Dermatol 2003, 2:669–673. This study demonstrates an important new treatment for this uncommon but serious complication of CLL.

    Google Scholar 

  48. Salim A, Leman JA, McColl JH, et al.: Randomized comparison of photodynamic therapy with topical fluorouracil in Bowen’s disease. Br J Dermatol 2003, 148:539–543.

    Article  PubMed  CAS  Google Scholar 

  49. Ziprin P, Smith S, Salerno G, Rosin RD: Two cases of Merkel cell tumour arising in patients with chronic lymphocytic leukaemia. Br J Dermatol 2000, 142:525–528.

    Article  PubMed  CAS  Google Scholar 

  50. Vlad R, Woodlock TJ: Merkel cell carcinoma after chronic lymphocytic leukemia: case report and literature review. Am J Clin Oncol 2003, 26:531–534.

    Article  PubMed  Google Scholar 

  51. Levi F, Randimbison L, Te VC, La Vecchia C: Non-Hodgkin’s lymphomas, chronic lymphocytic leukaemias and skin cancers. Br J Cancer 1996, 74:1847–1850.

    PubMed  CAS  Google Scholar 

  52. Ramsay HM, Fryer A, Strange RC, Smith AG: Multiple basal cell carcinomas in a patient with acute myeloid leukaemia and chronic lymphocytic leukaemia. Clin Exp Dermatol 1999, 24:281–282.

    Article  PubMed  CAS  Google Scholar 

  53. Weimar VM, Ceilley RI, Goeken JA: Aggressive biologic behavior of basal-and squamous-cell cancer in patients with chronic lymphocytic leukemia or chronic lymphocytic lymphoma. J Dermatol Surg Oncol 1979, 5:609–614.

    PubMed  CAS  Google Scholar 

  54. Mehrany K, Byrd DR, Roenigk RK, et al.: Lymphocytic infiltrates and subclinical epithelial tumor extension in patients with chronic leukemia and solid-organ transplantation. Dermatol Surg 2003, 29:129–134.

    Article  PubMed  Google Scholar 

  55. McKenna DB, Doherty VR, McLaren KM, Hunter JA: Malignant melanoma and lymphoproliferative malignancy: is there a shared aetiology? Br J Dermatol 2000, 143:171–173.

    Article  PubMed  CAS  Google Scholar 

  56. Cahill RA, McGreal G, Neary P, Redmond HP: Synchronous high-risk melanoma and lymphoid neoplasia. Melanoma Res 2001, 11:517–522.

    Article  PubMed  CAS  Google Scholar 

  57. Schmid-Wendtner MH, Lebeau A, Sander CA, et al.: Lymphadenopathy detected by ultrasound examination as first diagnostic hint of chronic lymphocytic leukaemia in a patient with melanoma. Eur Acad Dermatol Venereol 2002, 16:491–493.

    Article  CAS  Google Scholar 

  58. McKenna DB, Stockton D, Brewster DH, Doherty VR: Evidence for an association between cutaneous malignant melanoma and lymphoid malignancy: a population-based retrospective cohort study in Scotland. Br J Cancer 2003, 88:74–78.

    Article  PubMed  CAS  Google Scholar 

  59. Konits PH, Aisner J, Whitacre M, Wiernik PH: Lung cancer as a complication of prolonged survival in patients with lymphoma. Med Pediatr Oncol 1982, 10:331–338.

    Article  PubMed  CAS  Google Scholar 

  60. Travis LB, Gospodarowicz M, Curtis RE, et al.: Lung cancer following chemotherapy and radiotherapy for Hodgkin’s disease. J Natl Cancer Inst 2002, 94:182–192.

    PubMed  Google Scholar 

  61. Gilbert ES, Stovall M, Gospodarowicz M, et al.: Lung cancer after treatment for Hodgkin’s disease: focus on radiation effects. Radiat Res 2003, 159:161–173. This study suggests that the lung cancer that occurs in patients with Hodgkin’s disease is radiation induced.

    Article  PubMed  CAS  Google Scholar 

  62. De Benedetti VM, Travis LB, Welsh JA, et al.: p53 mutations in lung cancer following radiation therapy for Hodgkin’s disease. Cancer Epidemiol Biomarkers Prev 1996, 5:93–98.

    PubMed  CAS  Google Scholar 

  63. Parekh K, Rusch V, Kris M: The clinical course of lung carcinoma in patients with chronic lymphocytic leukemia. Cancer 1999, 86:1720–1723.

    Article  PubMed  CAS  Google Scholar 

  64. Potti A, Ganti AK, Koch M, et al.: Identification of HER-2/neu overexpression and the clinical course of lung carcinoma in non-smokers with chronic lymphocytic leukemia. Lung Cancer 2001, 34:227–232.

    Article  PubMed  CAS  Google Scholar 

  65. Davis JW, Weiss NS, Armstrong BK: Second cancers in patients with chronic lymphocytic leukemia. J Natl Cancer Inst 1987, 78:91–94.

    PubMed  CAS  Google Scholar 

  66. Thomas R, Ribeiro I, Shepherd P, et al.: Spontaneous clinical regression in chronic lymphocytic leukaemia. Br J Haematol 2002, 116:341–345.

    PubMed  Google Scholar 

  67. Wiernik PH: Spontaneous regression of hematologic cancers. Natl Cancer Inst Monogr 1976, 44:35–38.

    PubMed  CAS  Google Scholar 

  68. Robak T, Blonski JZ, Gora-Tybor J, et al.: Second malignancies and Richter’s syndrome in patients with chronic lymphocytic leukaemia treated with cladribine. Eur J Cancer 2004, 40:383–389.

    Article  PubMed  CAS  Google Scholar 

  69. Mellemgaard A, Geisler CH, Storm HH: Risk of kidney cancer and other second solid malignancies in patients with chronic lymphocytic leukemia. Eur J Haematol 1994, 53:218–222.

    Article  PubMed  CAS  Google Scholar 

  70. Linet MS, Van Natta ML, Brookmeyer R, et al.: Familial cancer history and chronic lymphocytic leukemia: a case-control study. Am J Epidemiol 1989, 130:655–664.

    PubMed  CAS  Google Scholar 

  71. Shousha S, Costello C, Luqmani YA, Sinnett HD: CD5 positive breast carcinoma in a patient with untreated chronic lymphocytic leukaemia: molecular studies of chromosome 13q. J Clin Pathol 1998, 51:862–864.

    Article  PubMed  CAS  Google Scholar 

  72. Rosen ST, Maciorowski Z, Wittlin F, et al.: Estrogen receptor analysis in chronic lymphocytic leukemia. Blood 1983, 62:996–999.

    PubMed  CAS  Google Scholar 

  73. Paietta E, Tudoriu CD, Goldstein M, et al.: Plasmacytoid blast crisis in B-cell chronic lymphocytic leukemia effect of estradiol on growth and differentiation in vitro. Leuk Res 1985, 9:19–29.

    Article  PubMed  CAS  Google Scholar 

  74. Melo N, Hobday C, Dowsett M, et al.: Oestrogen receptor (ER) analysis in B-cell chronic lymphocytic leukemia: correlation of biochemical and immunocytochemical methods. Leuk Res 1990, 14:949–952.

    Article  PubMed  CAS  Google Scholar 

  75. Hammarsund M, Corcoran MM, Wilson W, et al.: Characterization of a novel B-CLL candidate gene DLEU7, located in the 13q14 tumor suppressor locus. FEBS Lett 2004, 556:75–80.

    Article  PubMed  CAS  Google Scholar 

  76. Sossey-Alaoui K, Kitamura E, Head K, Cowell JK: Characterization of FAM10A4, a member of the ST13 tumor suppressor gene family that maps to the 13q14.3 region associated with B-cell leukemia, multiple myeloma, and prostate cancer. Genomics 2002, 80:5–7.

    Article  PubMed  CAS  Google Scholar 

  77. Ivanov DV, Tyazhelova TV, Lemonnier L, et al.: A new human gene KCNRG encoding potassium channel regulating protein is a cancer suppressor gene candidate located in 13q14.3. FEBS Lett 2003, 539:156–160.

    Article  PubMed  CAS  Google Scholar 

  78. Terris MK, Hausdorff J, Freiha FS: Hematolymphoid malignancies diagnosed at the time of radical prostatectomy. J Urol 1997, 158:1457–1459.

    Article  PubMed  CAS  Google Scholar 

  79. Weir EG, Epstein JI: Incidental small lymphocytic lymphoma/ chronic lymphocytic leukemia in pelvic lymph nodes excised at radical prostatectomy. Arch Pathol Lab Med 2003, 127:567–572. It is important to recognize that occult low-grade lymphoma or CLL may reside in nodes removed at radical prostatectomy, as they may in nodes removed at mastectomy.

    PubMed  Google Scholar 

  80. Narasimhan P, Amaral L: Lymphopenic response of patients presenting with chronic lymphocytic leukemia associated with carcinoma of the prostate to diethylstilbestrol: correlation of response to the in vitro synthesis of RNA by patient lymphocytes and its relationship to transcortin. Am J Hematol 1980, 8:369–375.

    Article  PubMed  CAS  Google Scholar 

  81. Teruya-Feldstein J, Greene J, Cohen L, et al.: Analysis of mismatch repair defects in the familial occurrence of lymphoma and colorectal cancer. Leuk Lymphoma 2002, 43:1619–1626.

    Article  PubMed  CAS  Google Scholar 

  82. Kaplan MH, Susin M, Pahwa SG, et al.: Neoplastic complications of HTLV-III infection: lymphomas and solid tumors. Am J Med 1987, 82:389–396.

    Article  PubMed  CAS  Google Scholar 

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Wiernik, P.H. Second neoplasms in patients with chronic lymphocytic leukemia. Curr. Treat. Options in Oncol. 5, 215–223 (2004). https://doi.org/10.1007/s11864-004-0013-7

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