Khusroo M Qureshi1, Arun K Raman2, Dongfeng Tan1, Marwan G Fa
1Department of Medicine, Roswell Park Cancer Institute; 2Department of Medicine, University at Buffalo School of Medicine and Biomedical Sciences. Buffalo, NY, USA
Received: 24 June 2006 Accepted: 24 August 2006
Context The presentation of pancreatic cancer with a leukemoid reaction is rare with no prior reports in the English language literature.Case report We report a case of advanced pancreatic cancer presenting with leukemoid reaction. Granulocyte colony-stimulating factor and granulocyte-macrophage colonystimulating factor levels were normal while interleukin-6 was elevated. The patient had no evidence of infection. The leukemoid reaction correlated with tumor response.Conclusion This is the first case report in the English literature of a leukemoid paraneoplastic syndrome in a patient withpancreatic cancer. A clear correlation between tumor response, serum carbohydrate antigen 19-9 levels and leukemoid reaction is documented
Interleukin-6; Leukemoid Reaction; Pancreatic Neoplasms
CA: carbohydrate antigen; GCSF: granulocyte colony-stimulating factor; GM-CSF: granulocyte-macrophage colonystimulating factor; IL: interleukin; LAP: leukocyte alkaline phosphatase
Although only 28,000 cases are diagnosed annually, pancreatic cancer is the fifth leading cause of cancer-death in the US. Symptoms upon diagnosis include abdominal pain (80%); anorexia (65%); weight loss (60%) and jaundice (50%). Paraneoplastic syndromes have been less commonly described. These include panniculitisarthritis- eosinophilia, dermatomyositis, recurrent Trousseau’s syndrome and Cushing’s syndrome
Leukemoid reaction refers to a reactive leukocytosis and has been described in response to inflammation, severe or disseminated infection, tissue destruction or other marrow stimulants. Leukemoid reactions have been described mainly in association with lung, gastrointestinal, genitourinary and head and neck cancers [1, 2, 3, 4, 5]. These reactions have been attributed to increased cytokine production. Cytokines implicated in this process include granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colonystimulating factor (G-CSF), interleukin 3 (IL- 3) and interleukin 6 (IL-6) [5, 6, 7, 8, 9, 10, 11].
Leukemoid reactions have rarely been described in association with pancreatic cancer. To our knowledge, this is the fourth case to be reported in literature. Furthermore, this is the only case described that shows an unequivocal tumor response and leukemoid reaction correlation.
A 47-year-old man presented with a history of 3.5 kg weight loss and pain in his right upper quadrant and shoulder of 2-month duration. Subsequent imaging studies revealed a mass in the body of the pancreas and metastatic disease to the liver. An ultrasound-guided biopsy of the liver was performed and confirmed a metastatic moderately to poorly differentiated adenocarcinoma of pancreatic origin. His initial WBC count was 30,300 cells/mm3 and his peripheral smear (Figure 1) showed marked granulocytosis without any bands, myelocytes, or metamyelocytes. His leukocyte alkaline phosphatase (LAP) score was 202 (reference range: 50-100) suggesting a non-malignant myeloproliferative process. Septic work-up, including chest X-ray, urine culture, and blood cultures was negative. GCSF and GM-CSG were within normal range while IL-6 level was elevated at 27 pg/mL (reference range: 0-12 pg/mL).
He was started on palliative chemotherapy with docetaxel and gemcitabine with initial resolution of leukemoid reaction. A correlation between CA19-9 response and white blood cell count (WBC) was noted (Figure 2). An initial decrease in his CA 19-9 levels was associated with normalization of WBC counts as well as disease stabilization on computerized tomography performed after 3 cycles of treatment (Figure 3). Of interest, he never developed any significant leukopenia despite the myelosuppressive nature of docetaxel and gemcitabine combination. As his CA 19-9 increased, his WBC increased despite ongoing chemotherapy. Radiological disease progression was documented after 6 cycles of chemotherapy at which point his WBC exceeded 60.3x109 (cells/L). Treatment was discontinued and he died shortly after. His total WBC prior to expiring exceeded 100x109 (cells/L).
Leukemoid reactions have been rarely described in association with pancreatic cancer. A review of the literature revealed only three other case reports of leukemoid reactions in pancreatic cancer and in two of those the patients expired shortly after diagnosis [12, 13, 14]. This case, to our knowledge, is the first case described in the English literature.
Leukemoid reactions in advanced malignancy are usually myelocytic although eosinophilia, basophilia or monocytosis may be seen. On the peripheral smear, orderly progressive granulocyte maturation is noted and there are usually no blasts or nucleated red cells. The leukemoid reaction is distinguished from chronic myelogenous leukemia by an increased leukocyte alkaline phosphatase, and generally, lack of thrombocytopenia. The mechanisms of cancer-associated leukemoid reactions are under study. There are various reports in the literature of elevations in GM-CSF, G-CSF, IL-3 or IL-6 in tumors of the nasopharynx, kidneys and bladder [5, 6, 7, 8, 9, 10, 11].
In this particular case, leukocytosis represented a true leukemoid reaction as suggested by the elevated LAP and lack of a left shift on the WBC differential. An infectious etiology is unlikely given the negative septic work-up. The paraneoplastic etiology is confirmed by the strong inverse correlation between tumor response and leukocytosis. It is highly likely that tumor progression and necrosis may be associated with an increase in inflammatory cytokine response resulting in leukocytosis. The possibility of a direct secretion of cytokines by the tumor leading to a leukemoid reaction is also a distinct possibility. Although some reports implicated G-CSF [7, 9, 15] or GMCSF [5, 6] in paraneoplastic leukemoid reactions, this is unlikely to be the case in our patient since his G-CSF and GM-CSF levels were within normal range. It is not clear that the moderate IL-6 elevation had a significant role in inducing the leukemoid reaction, but this remains a distinct possibility since this interleukin has been associated with leukemoid reactions [10, 11]. Other factors secreted directly by the tumor or related to an inflammatory process may also have had a contributory role. The identification of such factors may have prognostic as well as therapeutic implications.