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| Year : 2008 | Volume
: 51
| Issue : 4 | Page : 548-550 |
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| Abnormal chromatin clumping in leucocytes of Ph positive Chronic Myeloid Leukemia cases - extending the morphological spectrum |
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Amit Kumar Adhya1, Jasmina Ahluwalia1, Neelam Varma1, Reena Das1, Subhash Varma2
1 Department of Hematology, Postgraduate Institute of Medical Education and Research, Chandigarh 160 012, Union Territory, India
2 Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh 160 012, Union Territory, India
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 Abstract | | |
The syndrome of abnormal chromatin clumping is largely a morphological entity characterized by exaggerated chromatin clumping seen in the neutrophils. According to the recent World Health Organization (WHO) classification, it is categorized as a variant of atypical chronic myeloid leukemia (aCML) or Ph-negative CML. Most of the cases reported in literature have been negative for the Ph chromosome or the BCR-ABL gene. Till date, Ph positivity has been demonstrated in just one case. We report two more Ph-positive CML cases with abnormal chromatin clumping in neutrophils. To the best of our knowledge, this is only the second time in literature that such cases have been described. These two unusual cases go on to extend the morphological spectrum of granulocytic changes seen in Ph-positive CML. Keywords: Abnormal chromatin clumping, chronic myeloid leukemia
How to cite this article:
Adhya AK, Ahluwalia J, Varma N, Das R, Varma S. Abnormal chromatin clumping in leucocytes of Ph positive Chronic Myeloid Leukemia cases - extending the morphological spectrum. Indian J Pathol Microbiol 2008;51:548-50 |
How to cite this URL:
Adhya AK, Ahluwalia J, Varma N, Das R, Varma S. Abnormal chromatin clumping in leucocytes of Ph positive Chronic Myeloid Leukemia cases - extending the morphological spectrum. Indian J Pathol Microbiol [serial online] 2008 [cited 2023 Nov 29];51:548-50. Available from: https://www.ijpmonline.org/text.asp?2008/51/4/548/43758 |
| Introduction | |  |
The syndrome of abnormal chromatin clumping is largely a morphological entity characterized by exaggerated chromatin clumping seen in neutrophils. It has not found a proper place in the classification system of hematopoietic malignancies since its first description by Gustke, et al. [1] largely because of the overlap between features of both myeloproliferative and myelodysplastic disorders. Some authors consider it a subtype of myelodysplastic syndrome (MDS) with features of myeloproliferative syndrome (MPD). Some categorize it as atypical chronic myeloid leukemia (aCML) or Ph-negative chronic myeloid leukemia (CML). However, a final diagnosis can not be made on the basis of morphology alone. Most of the cases reported in literature have been negative for the Ph chromosome or the BCR-ABL gene. Till date, Ph positivity has been demonstrated in just one case reported earlier from our department. [2] We report two more cases with abnormal chromatin clumping in neutrophils and Ph positivity. To the best of our knowledge, this is only the second time that such cases have been reported.
| Case Reports | | |
Case 1
A 75-year-old female presented with a 6-month history of abdominal distention and abdominal pain. A physical examination revealed moderate pallor and massive splenomegaly (15 cm below the left costal margin) along with cervical, axillary, and inguinal lymphadenopathy. There was no history of fever, recurrent infections, or bleeds.
Her hemoglobin level was 58 gm/L, her total leucocyte count (TLC) was 70.7x10 9 /L, and her platelet count was 139x10 9 /L. The differential leucocyte count (DLC) in the peripheral blood was 4% blasts, 11% myelocytes, 20% metamyelocytes, 46% polymorphs, and 19% lymphocytes. Eosinophilia or basophilia was lacking. There were 2 nucleated RBCs/ 100 white blood cells (WBCs).
The neutrophils showed exaggerated chromatin clumping [Figure 1], hypolobation, hypogranularity, and a Pelger Huet-like anomaly. The abnormal chromatin clumping was noted in the metamyelocytes and the myelocytes as well.
The bone marrow aspirate, although aparticulate was cellular with a myeloid to erythroid ratio of 20:1. The maturing granulocytes showed frequent abnormal chromatin clumping in the neutrophils and less frequently in the myelocytic and metamyelocytic nuclei. There was a mild excess of blasts in the trephine biopsy, which showed granulocytic and megakaryocytic hyperplasia, along with attendant marrow fibrosis (Bauermeister Grade 3). Dysplastic features, other than the chromatin abnormality, were lacking. The leucocyte alkaline phosphatase (LAP) score was 12. Metaphase cytogenetics revealed Ph chromosome positivity. Hence, a final diagnosis of CML in chronic phase with myelofibrosis was made.
The patient was given supportive transfusions and advised therapy for CML, but did not report for the treatment and has been lost to follow-up.
Case 2
A 52-year-old male patient diagnosed with CML, on follow-up since 1995, was being treated with myleran. Over the past 2 months, a sudden drop occurred in his hemoglobin level (54 gm/L) and platelet count (17x109/L); however, his TLC was high (78.1x109/L). The counts did not improve after discontinuing the drug. The patient was given blood transfusions. His spleen was just palpable under the left costal margin and hepatomegaly was absent. Peripheral blood DLC was polymorphs 43%, lymphocytes 5%, eosinophils 4%, basophils 4%, blasts 8%, promyelocytes 6%, myelocytes 26%, and metamyelocytes 4%. The neutrophils showed exaggerated chromatin clumping, hypolobation, and hypogranularity. A Pelger Huet-like anomaly was seen. The abnormal chromatin clumping was noted in the metamyelocytes and the myelocytes as well. The leucocyte alkaline phospatase score was 164 (control 158).
The bone marrow was aparticulate but cellular with a normal myeloid to erythroid ratio. The DLC was similar to the peripheral blood. The neutrophils and myelocytes showed similar chromatin clumping. Metaphase cytogenetics revealed Ph positivity. A final diagnosis of CML in the chronic phase was made.
| Discussion | | |
Abnormal Chromatin Clumping (ACC) in leucocytes is a distinct morphological entity characterized by extremely exaggerated clumping of heterochromatin into large blocks separated by clear zones of euchromatin, mimicking nuclear fragmentation and associated with hypo segmentation of neutrophils. Ultrastructurally, heterochromatin is distributed in the form of predominant peripheral blocks, which often seem to cause the nuclear membrane to bulge out without being disrupted. The granules and other cytoplasmic structures appear normal. [3]
This chromatin abnormality distinguishes the cells from similar appearing Pelger Huet or pseudo Pelger Huet cells, the latter being a feature of MDS.
The typical features of classical CML were present in the first case: splenomegaly, granulocytic leucocytosis with an excess of myelocytes and metamyelocytes, granulocytic hyperplasia in the marrow and a low lukocyte alkaline phosphatase (LAP) score. There was a noticeable lack of basophilia or eosinophilia, otherwise commonly seen in CML and hence the final diagnosis of CML was made after the Ph chromosome was identified from the bone marrow aspirate metaphases. No additional cytogenetic abnormality was identified.
Abnormal chromatin clumping syndrome has been mentioned previously in association with non MDS or CML-MPD in two reports. Tertian, et al. [4] reported similar nuclear changes in a patient with Ph-negative (on conventional cytogenetic analysis) hematologically aCML, however rearrangement of BCR-ABL was detected by other means. The second case (Varma, et al. [2] ) was similar to the present cases, as the Ph chromosome was positive; however, the patient presented in the accelerated phase of the disease.
Dysgranulopoeisis has been reported as a morphological indicator of impending acceleration in patients with CML; [5] however, abnormal chromatin clumping is a distinctly rare finding.
This change has also been observed in the lymphocytes from the lymph node in a patient with MDS, with a postulation that the lymphoid cells also arose from a similar clone. Drug therapy with mycophenolate mofetil may be accompanied by abnormal chromatin clumping in granulocytes, which resolves after cessation of therapy. The exact pathogenetic mechanism is uncertain though, inhibition of guanosine nucleoside synthesis may be responsible. [6]
It has been generally agreed that the presence of ACC imparts a poorer survival rate to the disease. Most of the patients die of complications such as infection or hemorrhage. The reported survival ranges from 2 months to more than 29 months. The case of the patient with Ph-positive CML with ACC previously described was in the accelerated phase of the disease and survived for 3 months and ultimately succumbed to fulminant infections. [2] Our second case opted for treatment from another center and has been lost to follow up.
The risk of leukemic conversion has been reported variable in the literature and is considered to be around 30%. [3] Various cytogenetic anomalies have been reported in the literature including a partial deletion of chromosome 12, [3] trisomy 8, [7] deletion of chromosome 3, [8] and deletion of chromosome 14. [9]
Presently, it would be difficult to assess the impact of this unusual morphology on the course of the disease in patients with CML, due to the paucity of such patients and more cases need to be studied before its exact importance can be assessed. A final diagnosis ultimately rests on the cytogenetic/molecular genetic abnormalities detected in the appropriate hematological and morphological settings. Nevertheless, these unusual cases go on to extend the morphological spectrum of granulocytic changes seen in Ph-positive CML.
| References | | |
| 1. | Gustke SS, Becker GA, Garancis JC, Geimer NF, Pisciotta AV. Chromatin clumping in mature leucocyte: A hitherto unrecognized abnormality. Blood 1970;35:637-58.  [PUBMED] [FULLTEXT] |
| 2. | Varma N, Varma S, Movafagh A, Mittal O, Garewal G. Philadelphia chromosome positive chronic myelocytic leukemia with abnormal chromatin clumping (ACC) syndrome. Eur J Haematol 1993;5:50-1. |
| 3. | Felman P, Bryon PA, Genteilhomme O, Ffrench M, Charrin C, Espinouse D, et al. The syndrome of abnormal chromatin clumping in leucocytes: A myelodysplastic disorder with proliferative features? Br J Haematol 1988;70:49-54. |
| 4. | Tertian G, Misrahi M, Diallo D, Mielot F, Leonard C, Salmeron S, et al. Abnormal chromatin clumping in granulocytes in a case of Ph1-negative, BCR-ABL rearrangement positive, haematologically atypical chronic myeloid leukaemia (CML). Nouv Rev Fr Hematol 1995;37:245-7. [PUBMED] |
| 5. | Kvasnicka HM, Thiele J, Schmitt-Graeff A, Diehl V, Niederle N, Schaefer HE. Impact of bone marrow morphology on multivariate risk classification in chronic myelogenous leukemia. Acta Haematol 2003;109:53-6. [PUBMED] [FULLTEXT] |
| 6. | Daliphard S, Accard F, Delattre C, Toupance O, Guyot C, Mechinaud F, et al. Reversible abnormal chromatin clumping in granulocytes from six transplant patients treated with mycophenolate mofetil: A rare adverse effect mimicking abnormal chromatin clumping syndrome. Br J Haematol 2002;116:726-7. |
| 7. | Winter JN, Variakojis D, Gaynor ER, Larson RA, Miller KB. Low-dose cytosine arabinoside (Ara-C) therapy in the myelodysplastic syndromes and acute leukemia. Cancer 1985;56:443-9. |
| 8. | Brizard A, Huret JL, Lamotte F, Guilhot F, Benz-Lemoine E, Giraud C, et al. Three cases of myelodysplastic-myeloproliferative disorder with abnormal chromatin clumping in granulocytes. Br J Haematol 1989;72:294-5. [PUBMED] |
| 9. | Jaen A, Irriguible D, Milla F, Vallespi T, Torrabadella M, Abella E, et al. Abnormal chromatin clumping in leucocyte: A clue to a new subtype of myelodysplastic syndrome. Eur J Haematol 1990;45:209-14. |
Correspondence Address:
Neelam Varma
Department of Hematology, Postgraduate Institute of Medical Education and Research, Chandigarh 160 012, union territory
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/0377-4929.43758
[Figure 1] |
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