Secondary Haematological Cancers in Adults: A Single Centre Experience

Introduction: Advances in early detection and treatment mean that more and more people are surviving cancer today. Increased long-term survival seen in patients with solid and hematologic cancers achieved as a result of aggressive chemo radiotherapy has come at a price. Some cancer survivors may develop a new, unrelated cancer later. This is called a second cancer. Reasons for second cancers are varied. Field cancerization, shared environment, familial syndromes, Radiation and Chemotherapy are among the few risk factors affecting the risk of secondary cancers. Therapy-related acute myeloid leukaemia and secondary non-Hodgkin lymphoma has been frequently documented in these patient cohorts. We aim to study the prevalence as well as analyse the factors involved in secondary haematological cancers in our subset of patients. Methods: This Cross sectional descriptive study was taken up in Apollo Institute of Medical Sciences and Research, Hyderabad. This is a 5 year observational study. We analysed all patients presenting to the Department of pathology, Apollo Hospitals during the period 2010 to 2015. Results: Total 4 cases of Second cancers were documented in our study. Out of which 2 cases were acute myeloid leukaemias and both of them had history of treatment with alkylating agents. The other 2 cases were diagnosed to have secondary Multiple myeloma. Of the patient presenting with multiple myeloma one of them had history of prior Renal cell carcinoma Conclusion: Assessment of the risk of second leukaemia should become part of any therapeutic plan for cancer patients. Chemo is known to be a greater risk factor then radiation. Avoidance of drugs with more leukemogenic potential will reduce the occurrence of second leukaemias. It is also important to understand the possibility of a correlation between renal cell carcinoma and multiple myeloma. Field cancerization and increased cytokine expression probably could play an important role in these second cancers.


Introduction
Advances in early detection and treatment mean that more people are surviving cancer today. Increased long term survival seen in patients with solid and hematologic cancers -as a result of aggressive chemo-radiotherapy has come at a price. Some cancer survivors may develop a new unrelated cancer later -called as second cancer. Second cancer is a second neoplasm which differs anatomically, histologically and genetically from the primary neoplasm. Second primary cancers have become an increasingly important concern in oncology during the last two decades, as they now comprise the sixth most common group of malignancies after skin, prostate, breast, lung, and colorectal cancers. [1,2] Survivors of all cancers are living for longer periods, partly because of the more frequent use of effective therapy. The formerly unacceptable toxicities of therapy are more readily controlled with better supportive care. Other reasons for an increase in multiple cancers include fewer competing causes of mortality and consequently more naturally occurring cancers in an increasingly aging population. prevalence of second cancer risk factors, including primary cancer treatments, environmental and lifestyle exposures, and genetic susceptibility. Further research is needed to quantify second cancer risks associated with specific etiologic factors and to identify the patients at highest risk of developing a second cancer to target prevention and screening efforts. Being a tertiary centre, we regularly encounter quite a variety of Haematological cancers. We intend to review and analyse the cases of haematological cancer registered in the last five years in our centre and study the prevalence as well as analyse the factors involved in secondary haematological cancers in our subset of patients.      acute Myelogenous leukaemia (AML). Sometimes, MDS occurs first, and then turns into AML. Acute lymphocytic leukaemia (ALL) has also been linked to chemo. Chemo is known to be a greater risk factor than radiation therapy in causing leukaemia. Alkylating agents, nitrosureas and procarbazine appear to have the highest leukemogenic potential. [6,8]  One of the patient who developed AML-M5 received Alkylating agent (Cyclophosphamide) and another Patient who developed MDS which progressed to AML-M4 received Cisplatin based chemotherapy. Alkylating agents are chemo drugs that interfere with a cell's DNA in a certain way. These drugs can sometimes cause AML and MDS. Often MDS develops first, which then progresses to AML. Alkylating agents related leukaemias are similar to post MDS leukaemia's with preleukemic phase and tri lineage dysplasia. 5 and 7 chromosomal cytogenetic abnormalities are seen, with a poor prognosis. The risk gets higher with higher drug doses, longer treatment time, and higher dose-intensity (more drugs given over a short period of time). Studies have shown that leukaemia risk begins to rise about 2 years after treatment with alkylating agents, becomes highest after 5 to 10 years, and then declines. Unfortunately, MDS and leukaemia that develop after treatment with alkylating agents tend to be hard to treat and have a poor outcome with a median survival of 8 months. [2,3,6,8] The chemo drugs cisplatin and carboplatin are not alkylating agents, but they attack cancer cells in much the same way. These drugs seem to increase the risk of leukaemia (mainly AML), too, but the risk is not as great as with the alkylating agents. This leukaemia is hard to treat and tends to have a poor outcome, much like the leukaemia linked to the alkylating agents. The risk of leukaemia rises as the amount of drug used gets higher. The risk of developing leukaemia increases even more if radiation is given along with cisplatin or carboplatin. Both the patients in our study had poor outcomes with early mortality. [2,3,6,8] The class of chemo drugs called topoisomerase II inhibitors stop cells from being able to repair DNA. These drugs can also cause leukaemia, mainly AML. Leukaemia develops sooner after treatment with these drugs than the leukaemia from alkylating agents. Most cases are found within 2 or 3 years of treatment and without MDS occurring first. Balanced translocations involving chromosome 11 q23 are usually seen. Leukaemia from topoisomerase II inhibitors tends to respond to better to treatment and has a better outlook than the leukaemia from alkylating agents. Drugs called anthracyclines are also topoisomerase II inhibitors. Anthracyclines are less likely to cause leukaemia than the other topoisomerase II inhibitors. [6,8] Most kinds of leukaemia, including AML, CML and ALL can be caused by past radiation exposure. Myelodysplastic syndrome (MDS), a bone marrow cancer that can turn into acute leukaemia, has also been linked to past radiation exposure. The risk of these diseases after radiation treatment depends on a number of factors such as:

Materials and Methods
1. How much of the bone marrow was exposed to radiation 2. The amount of radiation that reached the bone marrow 3. The radiation dose rate (how much was given in each dose, how long it took to give the dose, and how often it was given) The person's age when they were treated with radiation does not seem to be a risk factor. Most often, these cancers develop within several years of radiation treatment, peaking at 5 to 9 years after exposure. [2,3,6,8] None of the patients in our study had an history of prior radiotherapy. This could be due to the referral bias.
Multiple myeloma is a hematologic disorder characterized by monoclonal proliferation of plasma cells in the bone marrow that secrete immunoglobulin's. For the diagnosis of myeloma it is necessary to detect >10 % plasma cells in bone marrow or tissue biopsy. Its incidence is approximately 3-4/100.000 and responsible for about 1% of all malignancy related deaths. Not uncommonly www.pacificejournals.com/apalm eISSN: 2349-6983; pISSN: 2394-6466 this is seen as a second cancer. [9,10] In the present study two cases (2/4-50%) were diagnosed to have secondary Multiple myelomas.
One patient developed Multiple myeloma after chemotherapy for Breast carcinoma (Alkylating agent, Cyclophosphamide). In the literature there are reports of Multiple myeloma cases secondary to chemotherapy and it has long been recognized. [9,10,11] Marinopoulos et al reported a case of M.M after chemotherapy for non small cell lung cancer (cisplatin based). [11] Radiotherapy and alkylating agents used in the treatment of carcinoma breast pose the risk of myelodysplasia and secondary leukaemia's. Plasma cell dyscrasias, plasmacytoma and multiple myeloma have rarely been reported in the literature coexisting with carcinoma breast. [10] Multiple myeloma was reported in 5 out of 443 second neoplasms after treatment for Breast cancer in a study by Levi F et al. [7] Another developed M.M after partial nephrectomy for papillary renal cell carcinoma, with history of neither Radiation nor Chemotherapy. These tumours may represent coincidence of two not so uncommon tumours in elderly population or may show a true association. [13] Number of case reports and a small case series has hypothesized an association between renal cell carcinoma (RCC), and multiple myeloma (MM). [14,15,16,17] This hypothesis has been confirmed in a large population-based study from the USA and the association is supposed to be bidirectional, pointing to shared risk factors rather than treatment related factors. Patients with RCC have higher relative risk of developing MM during follow-up and vice versa. [18] Although not necessarily specific to this association, certain genetic risk factors may be shared between renal cell carcinoma and multiple myeloma that contribute to the observed bidirectional association. For example, c-met oncogene mutations are well recognized in hereditary papillary renal cell carcinoma. [19,20] Hereditary papillary renal cell carcinoma is most often observed in older age, an attribute that is consistent with multiple myeloma incidences. More importantly, c-met expression was recently implicated in myeloma cell proliferation through feedback loops with interleukin-6, an inflammatory cytokine that has a critical role in the development and growth of myeloma cells. [20] Therefore, c-met expression may be a candidate for elucidating the association between renal cell carcinoma and multiple myeloma.
Lifestyle-related risk factors such as obesity may also contribute to the observed association. Obesity is a strong risk factor for renal cell carcinoma and has modest but consistent effects on multiple myeloma incidences. [21,22] Furthermore, obesity is characterized by marked changes in adipose tissue, such as increased number and size of adipocytes. Adipose tissue is a major source of inflammatory mediators, particularly interleukin-6. [23] Therefore, obesity may facilitate the creation of a microenvironment that supports the development of renal cell carcinoma and multiple myeloma. [23,24,25] Shared environmental risk factors are another factor which plays important role in second cancers. Sometimes the second cancer isn't nearby, but is still linked to the same cancer-causing agent. Lifestyle factors, such as smoking, alcohol, exercise, sun exposure, and diet, clearly play individual roles in a long list of cancers, such as those of the head and neck, lung, bladder, skin and gastrointestinal tract, which are often seen as secondary cancers following treatment for a primary neoplasm. Environmental risk factors continue to raise the probability for a new cancer after the diagnosis and treatment of an initial malignancy. [2,3,5,26] For some cancers, having that cancer means you are at an increased risk of getting another cancer in the same organ or nearby. This may be because the whole organ (and sometimes nearby organs and tissues) were exposed to the same cancer-causing agents that led to the first cancer. This means that the entire area could already have early changes that can lead to cancer. This is called field cancerization. Although cancer survivors often reduce their exposures, the effects of earlier exposure can continue to influence their risks for years. Individuals with a genetic predisposition to multiple neoplasm's are another group at risk. Polymorphisms for metabolizing enzymes are another potentially critical category of etiologic factors that cannot yet be evaluated. [26] Conclusion Assessment of risk of secondary leukemia should be a part of therapeutic plan for cancer patients. Chemotherapy is a greater risk factor than radiation. Avoidance of drugs with more leukomegenic potential will be beneficial. Correlation between Renal cell carcinoma and Multiple myeloma needs to be further studied. Shared risk factors, Field cancerisation and increased cytokine expression could probably play an important role in these cancers.