TREATMENT OF SYNCHRONOUS HAIRY CELL LEUKAEMIA AND DIFFUSE LARGE B CELL LYMPHOMA IN A PATIENT WITH SEVERE HYPERCALCEMIA AND EXTENSIVE OSTEOLYTIC LESIONS

Introduction: Although secondary malignancies usually occur at different times after HCL treatment, (simultaneous) occurrence of HCL and other malignancies at the same time is very rare. Synchronous hairy cell leukemia (HCL) and diffuse large B cell lymphoma (DLBCL) has not been described so far. Case report: We report a 62-years old female patient who presented with intense constitutional symptoms, hypercalcaemia, pancytopenia and osteolytic destruction of the left shoulder joint. Immunohistochemical analysis of the bone marrow revealed presence of two populations: a population of HCL cells and a population of DLBCL cells with the expression of c-myc and bcl-2 ("double expressor" DLBCL) and high proliferative activity (Ki-67 + cells>90%). FISH analysis showed amplification of the bcl-2 gene. In addition, BRAF V600E mutation was detected. After intensive treatment with immunochemotherapy, radiotherapy and bisphosphonates patient achieved complete remission, lasting for more than two years. Conclusion: As the association of hairy cell leukemia and lymphoma is a very rare, diagnosis of synchronous occurrence of two lymphoproliferative diseases is diagnostic and therapeutic challenge. It remains unclear whether DLBC and HCL are derived from two different malignant clones or DLBCL developed by transformation of HCL as the result of clonal evolution of B-cell clone.


Introduction
Hairy cell leukemia (HCL) is uncommon type of hematological malignancy which constitutes 2% of all leukemias. Prognosis of HCL has considerable improved thanks to new effective chemotherapeutic agents. However, literature data showed that HCL patients have higher risk of developing second malignancies than the general population. In some studies second malignancies were the primary cause of death in patients with HCL 1 .
Although secondary malignancies usually occur at different times after HCl treatment, occurrence of HCL and other malignancies at the same time is very rare. It has been reported the simultaneous occurrence of HCL and several other lymphoproliferative diseases (follicular lymphoma 2 , T cell lymphoma 3 , B-cell chronic lymphocytic leukemia 4 , multiple myeloma 5 ). However, no one described simultaneous HCL and diffuse large cell B-cell lymphoma (DLBCL) so far.

Case report
We present a 62-year-old female patient who admitted to our hospital in August 2018 with fatigue, fever, weight loss (15kg/two months) and left shoulder pain. Physical examination showed poor general condition (ECOG 3), fever 38˚C, pallor of the skin and weakness of the left hand. Skeletal radiography showed osteolytic lesions in glenoid region of scapula, whilst chest X-ray showed consolidation in the area of the left lower lobe of the lung.. CT 5 of thorax showed non-homogeneous consolidation in S3 zone of the left lung with a negative bronchogram and hilar lymphadenopathy. Blood counts showed pancytopenia (Hb 74g/L, Plt 84x10 9 /L, WBC 3.8x10 9 /L with 48% neutrophiles, 44% lymphocytes, 6% monocytes, 2% eosinophiles and 3 erythroblasts/100 leukocytes in differential count).

Discussion
Presented patient is the first reported case of synchronous hairy cell leukemia and diffuse large B cell lymphoma. The patient also had very uncommon clinical presentation since the association of osteolytic lesions and hypercalcaemia are extremely rare initial symptoms of lymphoma (approximately 2%) 6 . Hypercalcemia in malignancies can be mediated by a number of different mechanisms. PTH-like substances (parathyroid hormone-related protein) secreted by malignant cells, secreting other cytokines that activate osteoclasts, ectopic activity of 1-alpha-hydroxylase and the production of 1,25dihydroxycholecalciferol as well as the excessive production of PTH are some of well characterized mechanisms of hypercalcemia 7 . Hypercalcemia of malignancy is the most often related with PTHrP 8 , but in some cases is associated with extensive bone metastases which was the case in our patient. It was previously considered that hypercalcemia is a result of direct destruction of bone by metastases. However, it was found that hypercalcemia is consequence of the release of local cytokines from the tumor cells, which activate osteoclasts and stimulate bone resorption, usually through RANK/RANKL 9 .
Patients with hypercalcemia of malignancy have limited survival of several months, thus it is considered a marker of poor prognosis 7 . It is not clear whether this poor prognosis is 7 related to the advanced stage of malignancy associated hypercalcemia or it is just a simply marker of underlying cancer. Our patient has our patient had numerous osteolytic lesions and advanced disease, but despite this, owing to optimal therapy, a complete therapeutic response was achieved. As the association of hairy cell leukemia and lymphoma is a very rare, diagnosis of synchronous occurrence of two lymphoproliferative diseases is diagnostic and therapeutic challenge. Establishing adequate diagnosis in cases of double malignancies is particularly important because it allows the implementation of optimal therapeutic approach which is usually directed to more aggressive disease. Such an approach resulted in complete remission of disease in our patient. It is important to emphasize that our patient achieved complete clinical remission after treatment with immune-chemotherapy (i.e. rituximab-