Year : 2009 | Volume
: 52 | Issue : 2 | Page : 167--170
Acute leukemia / myelodysplastic syndrome as a sequelae of carcinoma breast: A report of five cases from north India
Prateek Bhatia1, Reena Das1, Jasmina Ahluwalia1, Pankaj Malhotra2, Neelam Varma1, S Varma2, SC Sharma3, Gurjeewan Garewal1,
1 Department of Haematology, PGIMER, Chandigarh, India
2 Department of Internal Medicine, PGIMER, Chandigarh, India
3 Department of Radiotherapy, PGIMER, Chandigarh, India
Department of Haematology, Postgraduate Institute of Medical Education and Research, Chandigarh - 160 012
A second malignant neoplasm has been found to be more frequent than might be expected from the general population rates. Therapy-related myelodysplastic syndrome and acute leukemia are dreaded long-term complications of five cases of hematological malignancies following treatment for successful breast cancer therapy (therapeutic drugs or radiotherapy). We encountered carcinoma from north India over a 7-year period from 1999 to 2005. The patients presented 2-5 years after treatment of breast carcinoma. Three patients underwent surgery and received chemoradiotherapy. One patient received chemotherapy after surgery. One patient underwent only surgery and after 3 years presented with acute myeloid leukemia and bone marrow metastasis of carcinoma of the breast. At the time of presentation, all the patients had either bicytopenia or pancytopenia. A close follow-up with complete blood cell counts of the patients who previously had carcinoma of the breast is suggested for early detection of hematological abnormalities. However, the poor prognosis, limited financial resources and poor health insurance coverage results in few patients and their family members opting for treatment.
|How to cite this article:|
Bhatia P, Das R, Ahluwalia J, Malhotra P, Varma N, Varma S, Sharma S C, Garewal G. Acute leukemia / myelodysplastic syndrome as a sequelae of carcinoma breast: A report of five cases from north India.Indian J Pathol Microbiol 2009;52:167-170
|How to cite this URL:|
Bhatia P, Das R, Ahluwalia J, Malhotra P, Varma N, Varma S, Sharma S C, Garewal G. Acute leukemia / myelodysplastic syndrome as a sequelae of carcinoma breast: A report of five cases from north India. Indian J Pathol Microbiol [serial online] 2009 [cited 2019 Aug 25 ];52:167-170
Available from: http://www.ijpmonline.org/text.asp?2009/52/2/167/48908
Therapy-related myelodysplastic syndrome (MDS) and acute leukemia (AL) are dreaded long-term complications of successful cancer therapy. The term secondary leukemia encompasses both forms of acute myeloid leukemia (AML) evolving from previous myelodysplasia and forms of AL developing after exposure to therapeutic drugs or radiotherapy (therapy related). Various reports estimate the secondary leukemias to be 10-30% of all AML and the incidence increases with age.  Therapy-related leukemias are a major problem in patients treated for hematological malignancies like Hodgkin's disease, non-Hodgkin's lymphoma, myeloma and polycythemia vera. Solid tumors like carcinoma of the breast, ovaries or testes have a higher propensity to develop secondary AML.  The type and duration of the cumulative dose of the chemotherapeutic drugs are determining factors in the development of therapy-related AML (t-AML). Radiotherapy, alkylating agents, nitrosureas and procarbazine appear to have the highest leukemogenic potential. , Distinct chromosomal abnormalities are noted with t-MDS/t-AML, especially those involving loss of all or part of chromosome 5 or 7 or both. 
We encountered five cases of infiltrating duct carcinoma (IDC) of the breast that had been treated with various modalities of therapy and developed a hematological malignancy on follow-up between 2 and 5 years after the primary diagnosis. This report is a case compilation from the departmental archives over a 7-year period from 1999 to 2005. The association of these hematological malignancies as a second cancer in treated patients with breast carcinoma is discussed in this report.
A 59-year-old female, presented with clinical features of fever with cough and expectoration for 3months, bleeding from the nose and generalized weakness of 1month duration in 2004. She was operated upon for IDC of the breast with modified radical mastectomy (TNM stage T 2 N 1 M 0 ) 3years back, in 2001. She had not received radiotherapy or chemotherapy after the surgery. Chest X-ray revealed bilateral hilar and mediastinal lymphadenopathy. Ultrasonography of the abdomen showed mild hepatosplenomegaly with no space-occupying lesion. Hemogram revealed pancytopenia with hemoglobin (Hb) of 74g/L, total leucocyte count (TLC) of 2.6 × 10 9 /L and platelet count (PC) of 98 × 10 9 /L. The bone marrow examination showed an aparticulate aspirate with cellular trails, myeloid:erythroid (M:E) ratio of 2.7:1 and mild megaloblastosis. Differential counts showed 30% blasts (myeloperoxidase positive [MPO +ve]) with evidence of trilineage dysplasia. In addition, few clusters of large cells resembling metastatic adenocarcinoma cells were noted. Bilateral trephine biopsies showed hypercellular marrow spaces. Forty percent of the spaces showed sheets of immature granulocytic cells including blasts [Figure 1] and rest of the spaces showed infiltration by metastatic adenocarcinoma with marked desmoplastic reaction and new bone formation [Figure 2]. A diagnosis of AML with trilineage dysplasia and metastatic adenocarcinoma was made [Table 1].
A 61-year-old female, presented with weakness, easy fatigability, and progressive pallor for 1 month and petechial bleeds of 4 days duration in the year 2004. Four years back (2001), she had been operated upon for IDC followed by eight courses of chemotherapy, i.e. Cyclophosphamide, Methotrexate and 5-Flurouracil (CMF) and 6 weeks of radiotherapy (30 Gray chest and 40Gray to lymph nodes). On physical examination, moderate pallor, petechial spots and mild hepatomegaly was found. Hemogram showed bicytopenia with Hb of 68g/L, TLC of 7 × 10 9 /L and PC of 23 × 10 9 /L. A bone marrow examination revealed hypercellular particles, M:E ratio of 6:1, 14% myeloblasts (MPO +ve), hypogranular polymorphs, Pelger-Huet anomaly, abnormal chromatin clumping with ring neutrophils and many micromegakaryocytes. The final diagnosis was t-MDS (refractory anemia with excess of blasts according to the FAB classification)[Table 1]. The patient was managed palliatively after diagnosis and was lost to follow-up 6 months later.
A 50-year-old female, presented with progressive pallor, weakness and low-grade fever for 4 months duration in the year 1999. She had been operated upon for IDC 5 years back (1994) followed by 6 weeks of radiotherapy. Physical examination revealed pallor, sternal tenderness and purpura. The liver was palpable 4 cm below the right costal margin and the spleen was palpable 2 cm below the left costal margin. Hemogram showed Hb of 48g/L, TLC of 110 × 10 9 /L and PC of 43 × 10 9 /L. The peripheral smear showed 93% blasts and 2n red blood cells (RBCs)/100 white blood cells (WBCs) smear. A bone marrow examination revealed hypercellular particles, M:E ratio of 200:1 and 97% blasts, which were MPO -ve and block positive for periodic acid Schiff. The Bennett's score was acute lymphoblastic leukemia (ALL-L1). The trephine biopsy showed sheets of immature cells with increased reticulin of 2-3+ and focal myelofibrosis. A flow cytometric work-up for the case was not performed at that time as the complete set up for the same was not available in our department. However, our present policy is to perform a complete flow cytometric evaluation for all MPO -ve ALs. A diagnosis of t-ALL-L1 was made [Table 1].
A 40-year-old female, presented with progressive pallor and petechial bleeds for 1 month in our department in year 1999 for hematological evaluation. Two years back (1997), she had undergone radical mastectomy with axillary clearance for infiltrating ductal carcinoma. Radiotherapy and chemotherapy with Cyclophosphamide and Methotrexate was administered, including hormonal treatment with tamoxifen. Present hemogram showed anemia (Hb 38/L), thrombocytopenia (PC 17 × 10 9 /L) and a TLC of 14.1 × 10 9 /L with 82% blasts. Bone marrow showed Auer rods in the blasts and MPO positivity. A diagnosis of AML-M2 was made [Table 1].
A 78-year-old female and was a known case of infiltrating ductal carcinoma, diagnosed in the year 2002. She underwent radical mastectomy and received standard CMF chemotherapy regimen and radiotherapy. Three years later in 2005 she presented with pallor and was detected to be anemic, with an Hb of 69gm/L. The PC was 257 × 10 9 /L and TLC was 23.3 × 10 9 /L. There were 6% blasts in the periphery, with 42% monocytic cells and 2-3% nRBCs/100 WBC. Bone marrow was hypercellular and both myeloid and monocytic blasts could be identified to make a diagnosis of myelomonocytic leukemia (AML-M4) [Table 1]. She succumbed to her illness in 2 weeks time before a specific treatment could be instituted.
A second malignant neoplasm has been found to be more frequent than might be expected from the general population rates, particularly after a first cancer in childhood.  The latency to develop t-MDS/t-leukemia is longer after alkylating agents (3-8 years) and shorter after topoisomerase II inhibitors (2-3 years). The increased incidence of t-MDS/t-AL is possibly due to the longer survival of treated cancer patients, more intensive chemotherapy and greater awareness of the association. The general outcome of t-MDS/t-AML is worse than the primary MDS/AML.
Most of the cases of carcinoma of the breast followed by AL/MDS reported in the literature are following chemotherapy and radiotherapy, but our first case did not receive chemoradiotherapy. , Also, this case presented simultaneously with metastatic carcinoma and AML with trilineage dysplasia. Therefore, the AML was not therapy related and possibly reflects an increased susceptibility of patients with malignancy to develop a second cancer.  A study by Pagano et al . in 2001 found 27% (10/37) patients of secondary AML after carcinoma of the breast where surgical debridement was the only therapy offered for carcinoma of the breast.  This also reiterates the fact that these patients have a higher propensity to develop a second malignancy.
Synchronous adenocarcinoma of the breast with AL is the development of leukemia within 6 months of diagnosis of the primary malignancy.  Recently, a report from India described AML within a month of development of carcinoma of the breast.  Our first case also showed the presence of simultaneous malignancies (AML-M2 and metastatic adenocarcinoma) but because a preceding history of the primary tumor was 3 years, it did not strictly qualify for synchronous malignancies.
One of our patients with breast cancer who had been offered surgery and radiotherapy for the primary malignancy developed ALL-L1. A study using the GIMEMA archive of adult leukemia from 1992 to 1996 found 200 patients with leukemia as the second malignancy. 2.3% of all ALL and 6% of all AML were diagnosed as second malignancy. Pagano et al, in 2001, found 40 cases of leukemias after carcinoma of the breast and only three patients (7.5%) were ALL, showing that the frequency of ALL is much lower than that of AML. In our report also ALL was only one out of five (20%). It has been shown that the prognosis of secondary ALL is better than that of secondary AML.
In the remaining three cases of t-MDS, AML-M2 and AML-M4, the hematological malignancy developed following surgery and chemoradiotherapy. Overall, the proportion of secondary AL is increasing due to multifactorial factors. Successful outcomes of primary malignancies with combination chemoradiotherapy and surgery have increased the disease-free survival and increased documented evidence shows that these individuals, for factors not clear yet, have an increased propensity to develop a secondary leukemia. Also, increased aging of the population may be responsible for the apparent rise in the cases of secondary leukemias. Predisposition to malignancy also remains a distinct possibility in these patients.
Reportable cytogenetic plates were not available in the cases included in the study although samples were taken. Unfortunately, at that time we did not have the resources for fluorescent in situ hybridization analysis. In two of the cases, the cytogenetic material was unsatisfactory due to associated bone marrow fibrosis. However, all the cases were morphologically satisfactory on evaluation.
We are unable to offer any comment on the response to conventional therapy to the patients with a second hematological malignancy because we do not have follow-up of the patients (except one who died soon after the diagnosis) as the patients opted not to be treated due to the high cost of therapy and poor prognosis. Also, because treatment in India is predominantly not under any insurance scheme and is not paid by the government, the financial constraints are considerable. According to the literature, most of the studies have shown that secondary leukemias are prognostically poor and difficult to treat.
This report of five cases of hematological malignancies following treatment for breast carcinoma from north India confirms the relative rarity of ALL after carcinoma of the breast and depicts the diverse spectrum of hematological malignancies in these cases. A close hematological follow-up of the patients on treatment with carcinoma of the breast is required for early detection and management. Optimum management for such patients is a constraint in our country due to the prohibitively high cost of treatment and poor prognosis of hematological malignancies following carcinoma of the breast.
|1||Leone G, Mele L, Pulsoni A, Equitani F, Pagano L. The incidence of secondary leukaemias. Haematologica 1999;84:937-45.|
|2||Carey RW, Holland JF, Sheehe P, Graham S. Association of cancer of breast and acute myelocyteic leukaemia. Cancer 1967;20:1080-8.|
|3||Thirmann MJ, Larson RA. Therapy-related myeloid leukaemia. Hematol Oncol Clin N Am 1996;2:293-317.|
|4||Kantarjian HM, Keating MJ. Therapy-related leukaemia and myelodysplastic syndrome. Semin Oncol 1987;14:435-43.|
|5||Smith SM, Beau MM, Huo D, Karrison T, Sobecks RM, Anastasi J, et al . Clinical-cytogenetic associations in 306 patients with therapy-related myelodysplasia and myeloid leukemia: The University of Chicago series. Blood 2003;102:43-52.|
|6||Mike V, Meadows AT, D'Angio GJ. Incidence of second malignant neoplasms in children: Results of an international study. Lancet 1982;2:1326-31.|
|7||Ershler WB, Robins HI, Davis HL, Hafez GR, Meisner LF, Dahlberg S, et al . Emergence of acute non-lymphocytic leukaemia in breast cancer patients. Am J Med Sci 1982;284:23-31.|
|8||Samdja J, Krulik M, Genot JY, Audebert AA, Debray J. Hematologic and cytogenetic study of two cases of acute leukaemia associated with breast cancer. Cancer Genet Cytogenet 1983;9:185-96.|
|9||Pagano L, Pulsoni A, Mele L, Tosti ME, Cerri R, Visani G, et al . Acute myeloid leukaemia in patients previously diagnosed with breast cancer: Experience of the GIMEMA group. Ann Oncol 2001;12:203-7.|
|10||Rosner F, Carey RW, Zarrabi MH. Breast cancer and acute leukaemia: Report of 24 cases and review of the literature. Am J Hematol 1978;4:151-72.|
|11||Mishra PP, Mahapatra M, Choudhry VP, Saxena R, Pati H, Dixit A, et al . Synchronous occurrence of breast carcinoma and acute myeloid leukaemia: Case report and review of literature. Ann Hematol 2004;83:541-3.|