Paraneoplastic Leukemoid Reaction in Solid Tumors

REVIEW ARTICLE Paraneoplastic Leukemoid Reaction in Solid Tumors Subhankar Chakraborty, MD, PhD,* Brent Keenportz, MD,w Suzette Woodward, MD,w Jay Anderson, MD,z and David Colan, MDz Abstract: Leukemoid reaction is defined as leucocytosis >50,000/mL. When it occurs in association with a malignancy, and infection or leukemia has been ruled out, it is termed as paraneoplastic leukemoid reaction. A patient presented with fatigue, generalized weakness, and abdominal distension and was incidentally noted to have a white blood cell count of 139,000/mL. Leukemia was ruled out by peripheral smear and flow cytometry. Computed tomography–guided biopsy of thickened omentum revealed poorly differentiated metastatic carcinoma. He died 3 days after admission with a peak white blood cell count of 180,000/mL. Previous reports and pathophysiology of paraneoplastic leukemoid reaction are reviewed. Key Words: leukemoid, paraneoplastic, cytokine, carcinoma, cytokine (Am J Clin Oncol 2015;38:326–330) L eukemoid reaction is defined as a white blood cell count (WBC) more than 50,000/mL with predominance of neutrophil precursors. Although it can occur in severe infection, it can also present as a paraneoplastic syndrome in patients with a variety of cancers. Lung, esophageal, nasopharyngeal and laryngeal, gastric, cholangiocarcinoma, melanoma, multiple myeloma, bladder, kidney, prostate, and hepatocellular carcinomas have all been reported to be associated with this condition. The underlying mechanism appears to be the production of growth factors such as granulocyte macrophage colonystimulating factor (GM-CSF), granulocyte CSF (G-CSF), and interleukins (IL-3 and IL-6) that are produced by the tumor cells. We present the case of a 64-year-old man who was admitted with increasing fatigue, generalized weakness, and progressive abdominal distension. He was noted to have a marked leukemoid reaction and subsequently diagnosed with poorly differentiated carcinoma with peritoneal carcinomatosis. We reviewed the literature to present other reported cases of leukemoid reaction in association with solid tumors and discuss potential causative mechanisms. CASE A 64-year-old male patient presented to the emergency department complaining of progressive generalized weakness for the last 10 days. He also complained of anorexia, early satiety, generalized abdominal pain, abdominal distension, dark brown-colored urine, decreased urinary frequency, and progressive dyspnea on exertion. While the urinary symptoms had begun about 3 days prior, his other From the *Department of Internal Medicine, University of Nebraska Medical Center, Omaha; wDepartment of Pathology, Saint Francis Medical Center; and zInternal Medical Associates of Grand Island, Grand Island, NE. The authors declare no conflicts of interest. Reprints: Subhankar Chakraborty, MD, PhD, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE- 681982055. E-mail: schakra@unmc.edu. Copyright r 2013 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0277-3732/15/3803-0326 DOI: 10.1097/COC.0b013e3182a530dd 326 | www.amjclinicaloncology.com symptoms had been progressively worsening for the last 4 months. He also reported that he had not had a bowel movement for the last 1 week. He had a 100 pack-year smoking history and was a current smoker. Examination at the time of admission was significant for tachycardia (118/min), hypoxia (90% on 2 L/min oxygen), and tachypnea (22/min). He appeared dehydrated. There was significant abdominal distension with hypoactive bowel sounds. Multiple skin lesions suggestive of scabies were noted over the abdominal wall. Symmetrical lower extremity weakness was noted bilaterally, and reflexes were brisk. His WBC count was markedly elevated at 139,000/ mL, with 56% segmented neutrophils, 42% band forms, 2% lymphocytes, and no eosinophils or basophils. His hemoglobin level was 15.3 g/dL and platelet count was 246,000/mL. Other significant abnormal laboratory examinations revealed a sodium level of 132 mEQ/L (normal 136 to 145 mEQl/L), potassium level of 5.2 mEQ/L (3.5 to 5.1 mEQ/L), creatinine level of 3.55 mg/dL (0.6 to 1.3 mg/dL), and calcium level of 12.8 mg/dL (8.5 to 10.1 mg/dL). Alkaline phosphatase level was elevated at 436 U/L (50 to 136 U/L) together with bilirubin (1.4 mg/dL; range, 0.2 to 1.0 mg/dL). Aspartate aminotransferase and alanine aminotransferase levels, however, were normal. A computed tomography scan of the chest, abdomen, and the pelvis without contrast revealed a 1.3-cm spiculated mass in the right upper lobe adjacent to the trachea suspicious for malignancy (Fig. 1A). In the abdomen, there was diffuse omental caking suggestive of peritoneal carcinomatosis (Fig. 1B). There were also ascites and splenomegaly. An abdominal ultrasound revealed a 6.2-cm hypoechoic mass in the left lobe of the liver and a 16-cm spleen. Paracentisis revealed a cloudy, amber-colored fluid with 28,694 red blood cells/mL and 9207 WBCs/mL (91% neutrophils, 8% lymphocytes, and 1% monocytes). The serum albumin ascites gradient was 0.3. Cultures of the ascites fluid were negative for any bacterial infection. Hepatitis serology was negative. Serum parathyroid hormone level was elevated at 154 pg/mL (12 to 88 pg/mL). However, parathyroid hormone-related protein and free T4 levels were normal. The thyroid-stimulating hormone level was mildly elevated (4.34 mU/L; range, 0.36 to 3.74 mU/L). The total 25hydroxy vitamin D level was low at 10.2 ng/mL (24 to 80 ng/mL), whereas the 1,25-dihydroxy vitamin D level was normal. Fractionation of the alkaline phosphatase isoenzymes revealed that the percentage of heat-stable isoenzyme was 5%, which was suggestive of a predominantly bone isoenzyme contributing to the increased total enzyme level. A peripheral smear showed neutrophilia with band forms but no blasts (Figs. 2A, B). Ascites fluid cytology revealed a few atypical cells (Figs. 2C–E). Fine-needle biopsy of the omentum revealed poorly differentiated malignant cells that were positive for cytokeratin (CK) 7 but negative for CK20 or hepatocyte-specific antigen (Figs. 2F–H). Flow cytometry of the peripheral blood showed a marked increase in maturing granulocytes with a mild left shift, suggestive of a myeloproliferative disorder. Although initially stable, the patient deteriorated rapidly about 48 hours later, becoming rapidly hypoxic, tachycardic, hypotensive, and unresponsive. His leukocyte count peaked at 180,000/ mL, with a platelet count of 260,000/mL, whereas the red blood cell count remained unchanged. Despite resuscitation attempts, the patient died on day 3 of hospitalization of cardiorespiratory failure. The family declined an autopsy. Because of the small amount of tissue available, we could not pinpoint the primary tumor in this patient. However, on the basis of the CK staining pattern, CK7 positive CK20 negative, there were several candidates for a primary source including lung, mesothelial, pancreatobiliary, gallbladder, small bowel, squamous cell carcinomas, and thyroid tumors. The patient had elevated calcium levels together with elevated parathyroid hormone levels, low total vitamin D level, and American Journal of Clinical Oncology  Volume 38, Number 3, June 2015 Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. American Journal of Clinical Oncology  Volume 38, Number 3, June 2015 FIGURE 1. Noncontrast computed tomography scan of the chest and the abdomen showing (A) a 1.3-cm spiculated mass in the right upper lobe adjacent to the trachea (yellow arrow) and (B) omental caking suggestive of carcinomatosis. normal parathyroid hormone-related protein levels, suggesting a coexisting primary hyperparathyroidism and hypovitaminosis D. The elevated bone alkaline phosphatase levels suggest enhanced bone turnover from the hyperparathyroidism, whereas the elevated uric acid levels could be attributed to increased destruction of myeloid precursors and rapid turnover of cancer cells (supported by high lactate dehydrogenase). Omental caking (Fig. 1B) is a feature of advanced malignancy. This radiologic sign is caused by infiltration of the omental fat by malignant cells either from a primary tumor of the omentum or metastases from the stomach, pancreas, colon, and bladder cancer and sometimes from malignant melanoma. DISCUSSION Paraneoplastic syndromes (PNS) are defined as effects distant from the site of the primary tumor that are produced by substances released from tumor cells but not due to direct tissue invasion by the primary tumor or its metastases. Several categories of PNS exist including cutaneous, hematologic, rheumatologic, endocrine, neurologic, and ocular manifestations. A paraneoplastic leukemoid reaction (PLR) is a hematologic PNS that has been defined in the literature as leucocytosis >20,000 to 50,000/mL and described in association with different solid tumors. Neutrophils are generally the Copyright r Leukemoid Reaction in Solid Tumors predominant white cell type in these cases. However, there have been case reports of PLR wherein the predominant cell types were eosinophils.1–3 PLR has also been reported in patients with tumor recurrence, suggesting that it is caused by tumor-released factors.4 In one case, PLR preceded the diagnosis of colorectal cancer by nearly 4 years and was initially misdiagnosed as chronic neutrophilic leukemia.5 Most reviewed studies have reported an association between elevated levels of a particular cytokine and leucocytosis. The levels of IL-1a, b, IL-3, G-CSF, GM-CSF, IL-6, and TNF-a have all been reported to be elevated in various solid tumors and suggested to contribute to an elevated leukocyte count.6 We reviewed the Medline database through PubMed for articles describing leukemoid reaction in association with solid tumors. Articles in English for which published text was available were selected for review. Selected cases are summarized in Table 1. From the table, we see that the reported leukocyte count at presentation has ranged from 11,000 to 110,000/mL. The peak leukocyte count has been reported at between 48,300 and 215,000/mL. Survival of patients with PLR ranged from 10 days up to 2 years. As shown in Figure 3, there was a trend toward negative correlation between the WBC count at presentation and the peak WBC count with survival in patients with PLR. A review of the literature suggests that PLR is a “side effect” of a paracrine mechanism used by tumor cells to stimulate their own growth. Tumor cells produce cytokines (colony-stimulating factors and ILs), which then bind to receptors on the same cells and stimulate proliferation. Some of these cytokines are also hematopoietic growth factors and stimulate myeloid proliferation. Watanabe and colleagues, for instance, described a case of PLR associated with non–small cell cancer of the lung, wherein the serum GM-CSF levels were markedly elevated (77 times higher than normal). Tumor cells expressed both GM-CSF and its cognate receptor, suggesting that PLR was a “side effect” of paracrine growth.20 Serum GM-CSF levels were also elevated together with increased expression of GM-CSF and GM-CSF receptor by non–small cell cancer cells and by eosinophils in another reported case of PLR.1 In a case of PLR associated with prostate cancer metastatic to the bone, serum IL-6 and TNF-a levels were elevated, whereas that of other cytokines was normal.6 Elevated IL-6 levels (with normal G-CSF and GMCSF) has been reported in PLR associated with pancreatic cancer12 and hepatocellular carcinoma.4 In one report, urothelial carcinoma cells in a patient with PLR were observed to express vascular endothelial growth factor (VEGF), HIF-1a (hypoxia inducible factor), and G-CSF.23 The VEGF-HIF-1 axis is an important pathway used by cancer cells to evade apoptosis and might explain the poor prognosis associated with PLR in a portion of the cases. Large-scale studies of PLR are few in the literature. In one single-center study (N = 3770) investigating the incidence and mortality associated with PLR, Granger and colleagues reported that the incidence of PLR (defined as WBC count > 40,000/mL) in solid tumors (n = 758) was 10%. The most common causes of such high leucocytosis in solid tumor patients were exogenous growth factors (69%) and infections (15%). Pneumonia (49%), blood stream infections (27%), and urinary tract infections (16%) were the most commonly reported infections associated with PLR. The majority (68%) of the patients in this study had either a bulky primary tumor or a metastatic cancer. About 50% of the patients had some evidence of lung involvement. The WBC count ranged from 53,000 to 115,000/mL, with nearly all (96%) patients having a 2013 Wolters Kluwer Health, Inc. All rights reserved. www.amjclinicaloncology.com | Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. 327 Chakraborty et al American Journal of Clinical Oncology  Volume 38, Number 3, June 2015 FIGURE 2. A, A low-power peripheral smear showing numerous neutrophils including immature band forms but no blasts in the background of erythrocytes. B, A high-power peripheral smear showing immature neutrophils. C, Hematoxylin and eosin staining of the cell block from ascites fluid showing large atypical cells with hyperchromatic nuclei and irregular borders in a background of neutrophils and fibrin. D, low and E,F, High-power view of hematoxylin and eosin staining of the Omental mass showing pleomorphic malignant cells with a hyperchromatic nucleus and irregular borders with an increased nucleus to cytoplasmic ratio. G, Immunohistochemistry of malignant cells from the omentum showing positivity for pancytokeratin, suggesting a carcinoma. H, Malignant cells staining positive for cytokeratin 7. neutrophilic predominance. Interestingly, the majority of the patients were stable at the time of initial presentation, with 99% being afebrile, 93% normotensive, and 88% with a normal respiratory rate. The short-term and long-term prognosis of patients with PLR, however, was poor. Nearly 76% patients died within 3 months of presentation and only 10% were alive at 1 year. All those who were still alive had received some form of therapy.26 Cvitkovic et al27 in another study reported that the incidence of PLR was about 16% in a cohort of 255 patients with undifferentiated nasopharyngeal carcinoma. 328 | www.amjclinicaloncology.com The distinction between leukemoid reaction and leukemia is usually achieved by the leukocyte alkaline phosphatase (LAP) score. A LAP score that is higher than normal generally favors a benign etiology, whereas a low score should prompt evaluation for possible chronic myeloid leukemia (CML) or paroxysmal nocturnal hemoglobinuria. The low lap score in CML is believed to represent inadequate maturation of granulocytes and is related to low G-CSF levels.6 In our case, we performed a flow cytometric analysis of the peripheral blood, which showed normal myeloid precursors, although there was Copyright r 2013 Wolters Kluwer Health, Inc. All rights reserved. Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. American Journal of Clinical Oncology  Volume 38, Number 3, June 2015 Leukemoid Reaction in Solid Tumors TABLE 1. Selected Case Reports on Leukemoid Reaction in Solid Tumors WBC Count at Presentation (/lL) Peak WBC Count (/lL) Poorly differentiated carcinoma Poorly differentiated large cell carcinoma of lung Poorly differentiated squamous cell carcinoma Non–small cell lung cancer 139,000 180,000 Neutrophilia Died 3 d after presentation 15,000 155,000 Neutrophilia Died 7 mo after diagnosis 7 28,000 151,000 Neutrophilia Died 4 mo after diagnosis 7 71,600 71,600 Neutrophilia 8 Non–small cell lung cancer 52,000 ND Neutrophilia Giant cell carcinoma of the lung Lung adenocarcinoma Large cell lung cancer Pancreatic adenocarcinoma Pancreatic adenocarcinoma Metastatic prostate cancer Thyroid cancer 11,000 90,000 Neutrophilia Died before chemotherapy could be started Died 4 wk after diagnosis despite chemoradiation Died 3.5 mo after presentation 10 21,200 77,400 30,300 99,000 66,800 146,000 120,000 100,000 ND 74,800 103,000 Died 5 mo after diagnosis Died 2 mo after diagnosis Died (time not mentioned) Alive at last follow-up Alive at 4 mo ND 11 1 12 13 6 14 52,000 35,000 52,000 ND Neutrophilia Eosinophilia Neutrophilia Eosinophilia Neutrophilia Neutrophil and eosinophil Neutrophilia Neutrophilia ND Died 2 y after diagnosis 15 16 90,000 92,900 ND 18,100 215,000 120,000 143,000 48,300 ND Neutrophilia ND Neutrophilia Died 30 d after axillary dissection Died 6 wk after presentation Died 5 wk after presentation Death 8 wk after admission 17 18 19 20 68,800 147,800 Neutrophilia Died after 10 d of admission 21 110,000 42,000 ND 121,000 Neutrophilia Neutrophilia Died 10 d after admission Died 4 mo after starting neoadjuvant chemotherapy Died 10 wk after surgery 4 22 Cancer Gastric cancer Adenosquamous carcinoma of the stomach Malignant melanoma Cervical carcinoma Ovarian cancer Metastatic large cell carcinoma Sarcomatoid hepatocellular carcinoma Hepatocellular carcinoma Urothelial carcinoma Differential Count Urothelial carcinoma of renal pelvis Transitional cell carcinoma 39,800 ND Neutrophilia 32,800 60,000 Neutrophilia Transitional cell carcinoma 24,700 100,000 Neutrophilia Renal cell carcinoma Transitional cell carcinoma 50,000 67,000 ND 95,000 Neutrophilia Neutrophilia Outcome Alive at 9 mo postresection of tumor and radiation therapy Died about 11 mo after initial diagnosis Died 6 wk after diagnosis Died 5 wk postsurgery References This study 9 23 24 25 9 2 WBC indicates white blood cell. a left shift indicating rapid myeloproliferation. In patients with suspected PLR, a LAP score or flow cytometric analysis can be a good initial test to rule out CML. A peripheral smear is also recommended as is a rigorous search for an infectious source. Imaging studies should be undertaken to look for a neoplastic source based on the clinical scenario. The management of leukemoid reaction is the treatment of the underlying tumor. In cases where eosinophils are the predominant cell type, hydroxyurea has been shown to be beneficial (in one report, a decreased cell count from 120,000 to < 30,000/mL).1 Complications from leukemoid reaction chiefly result from increased blood viscosity. Gangrene of the foot has been described in one report.1 In our patient, the sudden onset of hypoxia, hypotension, and shortness of breath led us to believe that he may have died from a massive pulmonary embolism. Internists and family physicians are often the first contact of patients who present with PLR. Hence, it is important to be aware of this entity and order appropriate tests to identify the underlying cause. The assistance of a hematologist should be sought early on. Our knowledge of mechanisms underlying Copyright r PLR is still lacking. In many cases, as in ours, it is due to the lack of adequate tissue to conduct more thorough testing. Further, it is evident that in most cases,22 imaging underestimates the tumor burden. Hence, one should always request an autopsy in patients who die of PLR. This is helpful to better understand the mechanism underlying PLR including the evaluation of cytokine levels and cytokine receptor expression in tumor cells. Whether targeting these cytokines or their cognate receptors will have an impact on PLR and the overall outcome remains an open question at this time. Learning Points From This Case:  Leukocyte counts in excess of 20,000 should always prompt workup aimed at distinguishing leukemia from a leukemoid reaction.  Initial tests should include a peripheral smear, a leukocyte alkaline phosphatase score, or a peripheral blood flow cytometry looking for blasts, an infectious workup, and imaging appropriate to the clinical scenario to evaluate for an underlying malignancy. 2013 Wolters Kluwer Health, Inc. All rights reserved. www.amjclinicaloncology.com | Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. 329 American Journal of Clinical Oncology Chakraborty et al 9. 10. 11. 12. 13. 14. 15. 16. 17. FIGURE 3. The correlation of WBC count at presentation (A) and the peak WBC count (B) with the reported survival in cases of paraneoplastic leukemoid reaction (PLR). Source of data is shown in Table 1. WBC indicates white blood cells.  PLR is recognized as a late manifestation of cancer and patients often have an extremely poor prognosis.  The treatment of PLR is the treatment of the underlying condition. 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