I N D I A N J O U R N A L O F P A T H O L O G Y A N D M I C R O B I O L O G Y - 5 6 ( 4 ) , O C T O B E R - D E C E M B E R 2 0 1 3 453

Case R

eport

ABSTRACT

The coexistence of chronic myeloid leukaemia(CML) and chronic lymphocytic leukemia(CLL) has been reported occasionally in literature, with only seven cases of simultaneous occurrence of these two diseases. We present here a case of 57 yr male patient where a complete blood count and differential done using volume conductivity scatter (VCS) technology suggested a diagnosis of CML with CLL. It was further confi rmed by immunophneotyping and cytogenetic analysis. The patient was started on tyrosine kinase inhibitor, 400 mg once daily. Four months after the treatment, patient is doing fi ne with a count of 22 × 109/L and 64% lymphocytes.

KEY WORDS: Chronic lymphocytic leukemia, chronic myeloid leukemia, immunophenotype, cytogentics, volume conductivity scatter

Simultaneous occurrence of chronic myeloid leukemia and chronic lymphocytic leukemia: Report of an unusual caseKhaliqur Rahman, Seena George1, Sriyash Mangal2, Anurag MehtaDepartment of Hematology, Sanjay Gandhi Post Graduate Institute of medical sciences, Lucknow, 1Departments of Pathology, Rajiv Gandhi Cancer Institute & Research Centre, Rohini, New Delhi, 2Department of Biotechnolocy, Amity University, Noida, India

Address for correspondence:Dr. Khaliqur Rahman, Assistant Professor, Department of Hematology, Sanjay Gandhi Post Graduate Institute of medical sciences, Lucknow - 226 014. E-mail: drkhaliq81@gmail.com

INTRODUCTION

The coexistence of chronic myeloid leukemia (CML) and chronic lymphocytic leukemia (CLL) is an uncommon event with only 21 cases reported in literature until date.[1-20] These two diseases can occur either sequentially, or simultaneously as in the present case. High risk of developing a second malignancy associated with an immune modulation and associated therapeutic regimen, have been proposed as the cause for sequential development of these diseases. For simultaneous occurrence, a possibility of common stem cell origin for these two diseases has been suggested. The first investigation to be done in these cases is a complete blood count (CBC) with differential leukocyte count (DLC). Automated analyzers can indicate the presence of a proliferative neoplasm with a suggestion of myeloid or lymphoid origin. In addition, they can very well predict the morphology of the neoplastic cells. We present here a case of 57-year-old male patient who presented to us with a weakness and an abdominal discomfort. CBC done with the automated analyzer using VCS technology for differential suggested a proliferative neoplasm with both myeloid and lymphoid component. Morphological examination of peripheral smears and bone marrow along with immunophenotypic finding and cytogenetic analysis confirmed the simultaneous occurrence of CML and CLL in this case.

CASE REPORT

We report a case of a 57-year-old male, diabetic, normotensive patient presented to us with the complaint of weakness and an abdominal discomfort for 15 days. On examination, pallor was present but no icterus. Splenomegaly was seen, which was 3 cm below the costal margin. No lymphadenopathy or any other significant findings were

noted. CBC done with automated analyzer using VCS technology for the differential count showed a hemoglobin of 102 g/L, total leukocyte count of 131 109/L, platelet count of 436 109/L. DLC given by the analyzer was polymorphs-66.7, lymphocytes-26.6, monocytes-3.0, basophil-2.2, eosinophil-0.5. The mean volume of lymphocytes was lower than that of the control group (60 vs. 78$) with little variation in size, as indicated by slightly higher standard deviation of volume index (SDVI). Similarly, the mean volume of neutrophils was also increased (172.8 vs. 149.2$) with very high SDVI, indicating the presence of the whole spectrum of immature myeloid cells. Analyzing all these findings, we concluded that we were dealing with a proliferative disorder which was both myeloid as well as lymphoid and showed the presence of myeloid precursor, basophils and small sized lymphoid cells. Peripheral smear shows the presence of leukocytosis with the shift to left and basophilia. Lymphocytosis was also noted,

$Mean volume of lymphocytes and neutrophils were evaluated using the values from age and gender matched 30 healthy blood donors.

Access this article onlineWebsite: www.ijpmonline.orgPMID: xxxxxxxxx (when available)DOI: 10.4103/0377-4929.125369Quick Response Code:

[Downloaded free from http://www.ijpmonline.org on Tuesday, February 10, 2015, IP: 115.111.224.207]  ||  Click here to download free Android application for this journal

Rahman, et al.: Simultaneous occurrence of CML and CLL

I N D I A N J O U R N A L O F P A T H O L O G Y A N D M I C R O B I O L O G Y - 5 6 ( 4 ) , O C T O B E R - D E C E M B E R 2 0 1 3454

After an extensive search, only 21 cases with a concurrent occurrence of CML and CLL could be found in the literature. Most of the cases have CLL preceding CML (n = 11) with an interval between the two diseases ranging from 2 months to 84 months.

Cases with simultaneous are less frequent (n = 7). Three cases of CLL following CML by duration ranging from 20 to 74 months have been reported. A brief account of these cases has been mentioned in [Table 1].

The present case has leukocytosis at presentation with 30% of lymphocytes and shift to left. Automated analyzer with VCS technology for the differential count directed us to perform ancillary investigation to prove the co-existence of these two diseases. CML was the obvious finding, but the nature of lymphocytosis was to be determined. VCS parameters of a low mean volume with a slightly higher SDVI suggested the neoplastic nature of the lymphocytes. As suggested by Silva et al.[25] these findings favor a CLL over reactive lymphocytosis. Peripheral smear, bone marrow aspirate, bone marrow biopsy, immunophenotypic evaluation and cytogenetic

which was of small size and showed the presence of hyper-condensed chromatin. Bone marrow examination showed the presence of hypercellular packed particles with cellular trails. There was myeloid preponderance, shift to left and basophilia with a myeloid erythroid ratio of 30:1. Micromegakaryocytes were seen along with occasional sea blue histiocytes. An additional finding was the presence of approximately 30% small-sized atypical lymphoid cells with hyper-condensed chromatin. Bone marrow biopsy showed a hypercellular marrow with 95% of cellularity showing myeloid and megakaryocytic preponderance. Two CD20 positive lymphoid nodules were noted [Figure 1]. Immunophenotypic analysis by flow cytometry was performed on peripheral blood which showed the presence of 31% lymphoid cells with co expression of CD19, CD5, CD23 and FMC 7 negativity [Figure 2]. Conventional karyotype done on bone marrow sample showed t(9;22)(q34;q11), Philadelphia positive.

Based on all the above findings, a final diagnosis of concurrent CML and CLL was made. Patient was started on a tyrosine kinase inhibitor (imatinib) in a dose of 400 mg OD. Patient is on regular follow-up and is doing fine with a count of 22 109/L and 64% lymphocytes.

DISCUSSION

Coexistence of myeloproliferative and lymphoproliferative disorders in the same patient is uncommon. Even rare is the concordant occurrence of CML and CLL which can be found as isolated case reports in the literature.[1-20] Leukemogenic effect of therapy and an impaired immune response in cases of CLL have been suggested as the possible risk factors for development of second malignancy.[21] Although the second malignancy is usually a non-hematological one, association with other hematological neoplasm has also been reported. On the other hand, patients with CML have a natural history of developing a blast crisis and are rarely associated with the development of a second malignancy. However, it has also been documented that BCR-ABL transformed cells secrete cytokines like IL3 which increases the production of B lymphoid cells from human CD34+/CD38 progenitor cells and in turn may lead to the development of CLL.[22]

These probable explanations do not hold true for the cases where these two chronic neoplasms have occurred simultaneously without any prior history of one or the other disease. In such a situation, the concordant occurrence can either be a coincidental finding, or it can be presumed that these neoplasms originate from a unique stem cell capable of differentiating into two different cell lines. Molecular studies aimed at ascertaining such a possibility are scarce and have found the separate origins of these two diseases. BCR/ABL rearrangement could be detected in granulocytic component only, but not in the mononuclear cell fraction, probably composed mainly of CLL cells. On the contrary, characteristic band corresponding to a monoclonal lymphoid population after JH rearrangement analysis could be seen in the lymphoid-enriched cellular component, but not in the myeloid fraction.[2,23,24]

Figure 1: Leishman stained peripheral smear – leukocytosis with shift to left , basophilia and lymphocytosis (a, ×20). Small sized atypical lymphoid cells with patchy hypercondensed chromati n (b, ×100). May-Grünwald Giemsa stained bone marrow aspirati on - hypercellular packed parti cles with cellular trails (c, ×2). Myeloid precursors along with similar small sized atypical lymphoid cells noted (d, ×100). H and E stained marrow biopsy - hypercellular marrow showing myeloid preponderance along with two lymphoid nodules (e, ×2). The nodule is positi ve for CD20 (f, ×2)

a b

c d

e f

[Downloaded free from http://www.ijpmonline.org on Tuesday, February 10, 2015, IP: 115.111.224.207]  ||  Click here to download free Android application for this journal

Rahman, et al.: Simultaneous occurrence of CML and CLL

I N D I A N J O U R N A L O F P A T H O L O G Y A N D M I C R O B I O L O G Y - 5 6 ( 4 ) , O C T O B E R - D E C E M B E R 2 0 1 3 455

Figure 2: Immunophenotyping done using four color fl ow cytometry showed approximately 30% lymphoid cells to co express CD19, CD5, CD23 along with negati vity for FMC7, indicati ng them to be chronic lymphocyti c leukemia

Table 1: Pati ents with concordant CML and CLL, described in literature

Authors Age in years

Gender Interval between the diseases

Cases with simultaneous occurrence

Leoni et al.[1] 55 M Simultaneous

Maher et al.[2] 69 M Simultaneous

Crescenzi et al.[3] 64 M Simultaneous

Vilpo et al.[4] 58 M Simultaneous

Esteve et al.[5] 71 F Simultaneous

Mansat-De Mas et al.[6] 68 M Simultaneous

Katović et al.[7] 55 M Simultaneous

Present case (2012) 55 M Simultaneous

CML following CLL

Khojasteh et al.[8] 55 M 61 Months

Faguet et al.[9] 83 M 2 Months

Teichmann et al.[10] 47 M 72 Months

Whang-Peng et al.[11] 62 M 36 Months

Whang-Peng et al.[11] 74 M 24 Months

Schreiber et al.[12] 55 M 84 Months

Hashimi et al.[13] 82 F 60 Months

Nanjangud et al.[14] 43 M 73 Months

Mossafa et al.[15] 76 F 12 Months

Ramanarayanan et al.[16] 52 F 29 Months

Hatt ori et al.[17] 68 F 24 Months

CLL following CML

Salim et al.[18] 54 F 36 Months

Gargallo et al.[19] 88 F 20 Months

Bhagavathi et al.[20] 71 M 74 MonthsCML: Chronic myeloid leukemia; CLL: Chronic lymphocyti c leukemia

analysis proved this case as concurrent CML and CLL. Patient was started on 400 mg OD imatinib with regular follow-up. 4 months after the treatment, patient is doing fine with a count of 22 109/L and 64% lymphocytes.

CONCLUSION

Our case is an addition to the scarce literature on concurrent occurrence of CML and CLL which can be either sequential or simultaneous. IPA, cytogenetic and molecular analysis of these cases has revealed a rare event of leukemogenesis caused by a biclonal evolution. In addition, our report points out the importance of automated CBC analyzer with VCS parameter in preliminary diagnosis where this rare possibility can be suggested and ancillary investigation advised for further work-up.

REFERENCES

1. Leoni F, Ferrini PR, Castoldi GL, Pata M, Del Prete GF, Tomasi P. Simultaneous occurrence of chronic granulocytic leukemia and chronic lymphoid leukemia. Haematologica 1987;72:253-6.

2. Maher VE, Gill L, Townes PL, Wallace JE, Savas L, Woda BA, et al. Simultaneous chronic lymphocytic le ukemia and chronic myelogenous leukemia. Evidence of a separate stem cell origin. Cancer 1993;71:1993-7.

3. Crescenzi B, Sacchi S, Marasca R, Temperani P, La Starza R, Matteucci C, et al. Distinct genomic events in the myeloid and lymphoid lineages in simultaneous presentation of chronic myeloid leukemia and B-chronic lymphocytic leukemia. Leukemia 2002;16:955-6.

[Downloaded free from http://www.ijpmonline.org on Tuesday, February 10, 2015, IP: 115.111.224.207]  ||  Click here to download free Android application for this journal

Rahman, et al.: Simultaneous occurrence of CML and CLL

I N D I A N J O U R N A L O F P A T H O L O G Y A N D M I C R O B I O L O G Y - 5 6 ( 4 ) , O C T O B E R - D E C E M B E R 2 0 1 3456

4. Vilpo JA, Klemi P, Lassila O, Schröder J, de la Chapelle A. Transformation in chronic granulocytic leukaemia. Different blast cell clones in different anatomical sites. Acta Haematol 1979;62:247-50.

5. Esteve J, Cervantes F, Rives S, Rozman M, Zarco MA, Montserrat E. Simultaneous occurrence of B-cell chronic lymphocytic leukemia and chronic myeloid leukemia with further evolution to lymphoid blast crisis. Haematologica 1997;82:596-9.

6. Mansat-De Mas V, Rigal-Huguet F, Cassar G, Kuhlein E, Laurent G, Dastugue N. 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 hybridisation. Leuk Lymphoma 2003;44:867-9.

7. Katović SK, Vasilj A, Maricević I, Carzavec D, Jurić SC. Simultaneous occurrence of chronic lymphocytic and chronic myeloid leukemia. Coll Antropol 2010;34:653-5.

8. Khojasteh A, Perry MC, Taylor HM. Chronic myelocytic leukemia developing as a second cancer in a patient with chronic lymphocytic leukemia. CA Cancer J Clin 1981;31:172-6.

9. Faguet GB, Little T, Agee JF, Garver FA. Chronic lymphatic leukemia evolving into chronic myelocytic leukemia. Cancer 1983;52:1647-52.

10. Teichmann JV, Sieber G, Ludwig WD, Karow J, Ruehl H. Chronic myelocytic leukemia as a second neoplasia in the course of chronic lymphocytic leukemia. Case report and review of the literature. Leuk Res 1986;10:361-8.

11. Whang-Peng J, Gralnick HR, Johnson RE, Lee EC, Lear A. Chronic granulocytic leukemia (CGL) during the course of chronic lymphocytic leukemia (CLL): Correlation of blood, marrow, and spleen morphology and cytogenetics. Blood 1974;43:333-9.

12. Schreiber ZA, Axelrod MR, Abebe LS. Coexistence of chronic myelogenous leukemia and chronic lymphocytic leukemia. Cancer 1984;54:697-701.

13. Hashimi L, Al-Katib A, Mertelsmann R, Mohamed AN, Koziner B. Cytofluorometric detection of chronic myelocytic leukemia supervening in a patient with chronic lymphocytic leukemia. Am J Med 1986;80:269-75.

14. Nanjangud GJ, Saikia TK, Chopra H, Kadam PR, Advani SH. Development of Ph positive chronic myeloid leukemia in a patient with chronic lymphocytic leukemia treated with total body irradiation: A rare association. Leuk Lymphoma 1996;22:355-9.

15. Mossafa H, Fourcade C, Pulic M, Jary L, Cheze S, Szpiro-Tapia S, et al. Chronic lymphocytic leukemia associated with myelodysplastic syndrome and/or chronic myeloid leukemia: Evidence for independent

clonal chromosomal evolution. Leuk Lymphoma 2001;41:337-41.16. Ramanarayanan J, Dunford LM, Baer MR, Sait SN, Lawrence W,

McCarthy PL. Chronic myeloid leukemia after treatment of lymphoid malignancies: Response to imatinib mesylate and favorable outcomes in three patients. Leuk Res 2006;30:701-5.

17. Hattori H, Kuwayama M, Kotake T, Karasuno T. A case of chronic myeloid leukemia occurring during treatment for chronic lymphocytic leukemia. Gan To Kagaku Ryoho 2011;38:333-6.

18. Salim R, Wang L, Lin K, Clark RE. Chronic lymphocytic leukaemia developing in the course of chronic myeloid leukaemia. Leuk Lymphoma 2002;43:2225-7.

19. Gargallo P, Cacchione R, Chena C, Dupont J, Garay G, Riveros D, et al. Chronic lymphocytic leukemia developing in a patient with chronic myeloid leukemia: Evidence of distinct lineage-associated genomic events. Cancer Genet Cytogenet 2005;161:74-7.

20. Bhagavathi S, Borromeo V, Desai H, Crisan D. Case report and literature review: A rare patient with chronic myeloid leukemia and chronic lymphocytic leukemia. Ann Clin Lab Sci 2008;38:405-9.

21. Bartik MM, Welker D, Kay NE. Impairments in immune cell function in B cell chronic lymphocytic leukemia. Semin Oncol 1998;25:27-33.

22. Crooks GM, Hao QL, Petersen D, Barsky LW, Bockstoce D. IL-3 increases production of B lymphoid progenitors from human CD34+CD38- cells. J Immunol 2000;165:2382-9.

23. Browett PJ, Pattinson J, Pinkney J, Hoffbrand AV, Norton JD. Gene probe analysis demonstrates independent clonal evolution of co-existent chronic myeloid and chronic lymphocytic leukaemia. Eur J Haematol 1988;40:181-4.

24. Zollino M, Genuardi M, Tanci P, Mango G, Rumi C, Mancini R, et al. Chronic myelogenous leukemia in the course of chronic lymphocytic leukemia: Evidence for an independent clonal origin. Leuk Res 1991;15:269-73.

25. Silva M, Fourcade C, Fartoukh C, Lenormand B, Buchonnet G, Callat MP, et al. Lymphocyte volume and conductivity indices of the haematology analyser Coulter GEN.S in lymphoproliferative disorders and viral diseases. Clin Lab Haematol 2006;28:1-8.

How to cite this article: Rahman K, George S, Mangal S, Mehta A. Simultaneous occurrence of chronic myeloid leukemia and chronic lymphocytic leukemia: Report of an unusual case. Indian J Pathol Microbiol 2013;56:453-6.

Source of Support: Nil Confl ict of Interest: None declared.

[Downloaded free from http://www.ijpmonline.org on Tuesday, February 10, 2015, IP: 115.111.224.207]  ||  Click here to download free Android application for this journal