|Year : 2016 | Volume
| Issue : 3 | Page : 90-94
Combined Chronic Lymphocytic Leukemia and Pancreatic Neuroendocrine Carcinoma: A Collision Tumor Variation
Kaijun Huang1, Panagiotis J Vlachostergios1, Wanhua Yang2, Rajeev L Balmiki3
1 Department of Medicine, NYU Lutheran Medical Center, Brooklyn, NY, USA
2 Department of Pathology, Weill Medical College of Cornell University, New York-Presbyterian Hospital, New York, NY, USA
3 Division of Hematology-Oncology, NYU Lutheran Medical Center, Brooklyn, NY, USA
|Date of Submission||18-Apr-2016|
|Date of Acceptance||03-Jun-2016|
|Date of Web Publication||21-Jun-2016|
Dr. Panagiotis J Vlachostergios
Department of Medicine, NYU Lutheran Medical Center, 150 55th Street, Brooklyn, NY 11220
Source of Support: None, Conflict of Interest: None
Chronic lymphocytic leukemia (CLL)-induced immunodeficiency has been implicated in the occurrence of several secondary or concurrent malignancies. We hereby present the first case of combined CLL and pancreatic neuroendocrine tumor as collision neoplasms within metastatic periportal lymphadenopathy in a 62-year-old patient who presented with obstructive jaundice. An ovoid nodular mass was seen posterior to the head of the pancreas on magnetic resonance cholangiopancreatography and the patient subsequently underwent endoscopic retrograde cholangiopancreatography, with successful placement of two stents within the identified hilar stricture. Tn-111 pentetreotide scintigraphy with single-photon emission computed tomography (CT)/CT disclosed two foci of somatostatin receptor positive tissue in the upper abdomen correlating to the previously seen porta hepatis and portacaval lymphadenopathy and the patient was treated with octreotide. Simultaneous onset of CLL and secondary malignancies that each has a different disease status is a rare phenomenon but is important to diagnose for establishing an appropriate treatment strategy, which in certain cases may involve the use of agents active in both types of malignancy to minimize toxicity.
Keywords: Chronic lymphocytic leukemia, collision tumor, pancreatic neuroendocrine carcinoma
|How to cite this article:|
Huang K, Vlachostergios PJ, Yang W, Balmiki RL. Combined Chronic Lymphocytic Leukemia and Pancreatic Neuroendocrine Carcinoma: A Collision Tumor Variation. Cancer Transl Med 2016;2:90-4
|How to cite this URL:|
Huang K, Vlachostergios PJ, Yang W, Balmiki RL. Combined Chronic Lymphocytic Leukemia and Pancreatic Neuroendocrine Carcinoma: A Collision Tumor Variation. Cancer Transl Med [serial online] 2016 [cited 2019 Mar 20];2:90-4. Available from: http://www.cancertm.com/text.asp?2016/2/3/90/184321
| Introduction|| |
Numerous studies have confirmed an increased incidence of a second neoplasia in patients with chronic lymphocytic leukemia (CLL) including lung, breast, bladder, stomach, skin, colon, and ovaries. , The underlying mechanisms are unclear, but immunodeficiency associated with disease has been proposed.  An example of such an association has been described for Merkel cell carcinoma, a cutaneous neuroendocrine tumor, which was consistently reported to arise either in the course of CLL or concurrently. ,
Furthermore, hematologic malignancies rarely present with primary manifestations outside the blood or lymphatic tissue. Hepatobiliary disease is rarely the presenting feature although it can occur as later complication either from hemolysis or extrahepatic/extrabiliary obstruction. 
Here, we report a case of a 62-year-old male patient presenting with obstructive jaundice which was caused by enlarged periportal lymph nodes infiltrated with a combination of pancreatic neuroendocrine tumor (PNET) and chronic lymphocytic leukemic cells.
| Case Report|| |
A 62-year-old male with a past medical history of diabetes mellitus, rheumatoid arthritis, hyperlipidemia, chronic insomnia, and asthma, presented with painless jaundice, dark-colored urine, and light-colored stool for 2 days. On examination, the patient had icteric sclerae and skin, but no stigmata of cirrhosis. Laboratory tests were significant for leukocytosis of 17,600/μL with an absolute lymphocyte count of 8300/μL, as well as a hemoglobin of 8.2 g/dL. Liver chemistry was significantly abnormal, with total and direct hyperbilirubinemia (total bilirubin: 12 mg/dL, direct bilirubin: 9.8 mg/dL), aspartate aminotransferase: 165 IU/L, alanine aminotransferase: 377 IU/L, gamma-glutamyl transferase: 1514 IU/L, and lactate dehydrogenase: 322 IU/L. Computed tomography (CT) and magnetic resonance imaging (MRI) of the abdomen showed multiple nodules and masses representing lymphadenopathy in the porta hepatis and foramen of Winslow, with the most pronounced appearing as an ovoid nodular mass posterior to the head of the pancreas. The patient subsequently underwent endoscopic retrograde cholangiopancreatography (ERCP), with successful placement of two stents within the identified hilar stricture [Figure 1]. Cytology from a fine-needle aspiration of an enlarged lymph node from the portal cava region revealed high-grade neuroendocrine carcinoma, with positive immunoreactivity to synaptophysin and focally to chromogranin and with Ki-67 immunostaining consistent with a 50-60% proliferative index [Figure 2]. Serum chromogranin A level was found elevated at 46 ng/mL (normal < 15 ng/mL). Gastrin and 5-hydroxyindoleacetic acid were within normal limits, whereas serotonin (9238 ng/mL) and histamine (9 nmol/L) serum levels were mildly elevated.
|Figure 1. (a) Computed tomography of the abdomen showing intrahepatic biliary duct dilatation (arrow), (b) magnetic resonance cholangiopancreatography demonstrating an ovoid nodular mass posterior to the head of the pancreas representing an abnormally enlarged node causing intrahepatic bile duct dilatation, and (c) endoscopic retrograde cholangiopancreatography showing hilar stricture|
Click here to view
|Figure 2. Cytology fine-needle aspiration of lymph node. (a) Diff-Quik stain, (b) H and E stain, (c) chromogranin immunostaining, and (d) Ki-67 immunostaining|
Click here to view
Due to unresolving lymphocytosis, a flow cytometric analysis of both the lymph node [Figure 3] and peripheral blood [Figure 4] was pursued, showing monotypic, CD5+, CD23+ (32%) kappa restricted B-cells consistent with CLL. Bone marrow aspiration biopsy was also diagnostic of CLL, disclosing a monoclonal kappa B-cell population co-expressing CD5 and CD23, with dim kappa and dim CD20 expression and positive ZAP-70 immunostaining.
|Figure 3. Flow cytometry from lymph node fine-needle aspiration. Monotypic, CD5 (+), CD23 (+), kappa-restricted B-cells consistent with chronic lymphocytic leukemia|
Click here to view
|Figure 4. Peripheral blood flow cytometry showing dim-monotypic, CD20-weak, CD5+, CD23 + B cells consistent with chronic lymphocytic leukemia|
Click here to view
Further diagnostic workup to identify the origin of the neuroendocrine neoplasm with upper endoscopy and colonoscopy, as well as with further CT imaging failed to reveal disease outside the abdomen. An octreotide scan was subsequently performed, identifying two foci of somatostatin receptor positive tissue in the upper abdomen correlating to the previously seen porta hepatis and portacaval lymphadenopathy [Figure 5].
|Figure 5. In-111 pentetreotide scintigraphy with single-photon emission computed tomography/computed tomography showing somatostatin receptor positive tissue in the upper abdomen correlating to porta hepatis and portacaval lymphadenopathy|
Click here to view
Patient's deteriorating performance status and elevated liver function tests were limiting factors for initiation of cytotoxic chemotherapy or everolimus. Repeat MRI showed more extensive changes including massive lymphadenopathy in the region of porta hepatis as well as increased size with mass effect upon the portal vein and inferior vena cava with invasion into adjacent liver parenchyma representing the progression of malignancy, with intra- and extra-hepatic biliary duct dilatation [Figure 6]. Patient was started on octreotide treatment after undergoing repeat ERCP with additional stent placement, and his aggressive disease demonstrated a minor response, with improvement of his abnormal liver tests.
|Figure 6. Magnetic resonance imaging of the abdomen showing (a) increased and new infiltrative mass in lesser sac, porta hepatis, portacaval area, and (b) invasion into gallbladder fossa and adjacent liver parenchyma|
Click here to view
| Discussion|| |
CLL is a low-grade lymphoproliferative disorder of B-cells and the most common adult leukemia in the United States. , While the disease typically has an indolent course, patients with CLL have a 3-fold increased risk of developing a second malignant tumor. ,, There is a clear evidence of a remarkable suppression of T lymphocyte function and reduced IgA concentration in active disease, which has been supported as an explanation of the frequent occurrence of secondary malignancies. , The most frequent event is CLL transformation to large B-cell non-Hodgkin's lymphoma, also known as Richter's syndrome.  However, the spectrum of secondary malignancies complicating CLL includes also prolymphocytic leukemia, Hodgkin's disease, acute lymphoblastic leukemia, and multiple myeloma. In addition, the secondary development of myeloproliferative disorders or myelodysplastic syndrome as well as solid tumors, including lung, breast, bladder, stomach, skin, colon, and ovaries, have also been documented in CLL patients. ,
The incidence of neuroendocrine cancers in the context of CLL was a very rare event and was previously reported twice. The first case was described as nodal metastasis of neuroendocrine carcinoma, of unknown primary site, in a patient affected by chronic B-CLL.  The patient was resistant to various conventional treatments and following locoregional progression, hypoxic pelvic perfusion of cisplatin plus mitomycin for three cycles resulted in a dramatic reduction of > 75% in the evaluable lesions was observed, and a cumulative complete response from CLL.  In the second case, metastatic neuroendocrine carcinoma with diffuse metastases was discovered by fluorine-18 fluorodeoxyglucose positron emission tomography/CT in a CLL patient during evaluation for detection of Richter's transformation.  The existence of a collision tumor, with CLL as component, is an even more rare event, and it has been reported twice, in combination with Merkel cell neuroendocrine carcinoma. ,
To the best of our knowledge, this is the first reported case of collision CLL and PNET neoplasms. The past medical history of this patient did not include a diagnosis of CLL. Thus, there is a probability that CLL occurred simultaneously or after the onset of PNET. Given the rarity of the combination of CLL with neuroendocrine tumors, there is no single optimal systemic therapy in advanced cases. However, there is Phase 2 data supporting the use of somatostatin analogs in lymphoproliferative disorders including CLL.  In addition, octreotide combination with cyclophosphamide, bromocriptine, retinoids, melatonin, and adrenocorticotropic hormone has led to partial responses in a case series.  Everolimus, a mammalian target of rapamycin inhibitor approved for the treatment of PNETs, consists another potential viable option since it has shown activity in CLL, either alone or in combination with alemtuzumab, resulting in mobilization of CLL cells into the circulation and partial responses. ,
Cancer translational medicine focuses on new knowledge about the molecular and cellular basis of cancer and applies high-throughput laboratory technologies for studying and targeting those pathways for treatment purposes in patients, particularly in the context of large prospective cohorts with associated biobanks. Here, we present the first case of collision CLL and PNET neoplasms. Further experience is required to identify the best therapeutic options for such patients; however, our case report, in addition to being the first describing a collision tumor of CLL and PNET neoplasms, it brings up the central role of molecular techniques and their exploitation for identification of the best therapeutic strategies relevant to common targets of both CLL and PNET in a personalized way, with the aim of increasing efficacy and reducing toxicities.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Robak T. Second malignancies and Richter′s syndrome in patients with chronic lymphocytic leukemia. Hematology
2004; 9 (5-6): 387-400.
Molica S. Second neoplasms in chronic lymphocytic leukemia: incidence and pathogenesis with emphasis on the role of different therapies. Leuk Lymphoma
2005; 46 (1): 49-54.
Quaglino D, Di Leonardo G, Lalli G, Pasqualoni E, Di Simone S, Vecchio L, Ventura T. Association between chronic lymphocytic leukaemia and secondary tumours: unusual occurrence of a neuroendocrine (Merkel cell) carcinoma. Eur Rev Med Pharmacol Sci
1997; 1 (1-3): 11-6.
Zhang H, Gupta G, Yang XY, Rosenbluth R, Bhattacharyya PK. A unique case of merkel cell carcinoma and chronic lymphocytic leukaemia presenting in a single cutaneous lesion (collision tumour). BMJ Case Rep
2009; 2009. pii: bcr09.2008.1016.
Pandey J, Bhowmik KT. Chronic lymphocytic leukemia presenting as jaundice. Indian J Gastroenterol
1998; 17 (1): 28.
Travis LB, Curtis RE, Hankey BF, Fraumeni JF Jr. Second cancers in patients with chronic lymphocytic leukemia. J Natl Cancer Inst
1992; 84 (18): 1422-7.
Everaus H, Luik E, Lehtmaa J. Active and indolent chronic lymphocytic leukaemia-immune and hormonal peculiarities. Cancer Immunol Immunother
1997; 45 (2): 109-14.
Everaus H, Lehtmaa J, Luik E, Kŏdar H. Immune and hormonal changes in early-stage chronic lymphocytic leukemia patients. Ann Hematol
1992; 65 (5): 219-23.
Russo F, Guadagni S, Corazzelli G, Frigeri F, Monda VM, Abate G. Chronic lymphocytic leukaemia and neuroendocrine cancer. Br J Haematol
1999; 105 (4): 989-92.
Bruzzi JF, Macapinlac H, Tsimberidou AM, Truong MT, Keating MJ, Marom EM, Munden RF. Detection of Richter′s transformation of chronic lymphocytic leukemia by PET/CT. J Nucl Med
2006; 47 (8): 1267-73.
Li Z, Yang JJ, Wu M. Collision tumor of primary merkel cell carcinoma and chronic lymphocytic leukemia/small lymphocytic lymphoma, diagnosed on ultrasound-guided fine-needle aspiration biopsy: a unique case report and review of literature. Diagn Cytopathol
2015; 43 (1): 66-71.
Witzig TE, Letendre L, Gerstner J, Schroeder G, Mailliard JA, Colon-Otero G, Marschke RF, Windschitl HE. Evaluation of a somatostatin analog in the treatment of lymphoproliferative disorders: results of a phase II North Central Cancer Treatment Group trial. J Clin Oncol
1995; 13 (8): 2012-5.
Todisco M. Chronic lymphocytic leukemia: long-lasting remission with combination of cyclophosphamide, somatostatin, bromocriptine, retinoids, melatonin, and ACTH. Cancer Biother Radiopharm
2009; 24 (3): 353-5.
Zent CS, Bowen DA, Conte MJ, LaPlant BR, Call TG. Treatment of relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma with everolimus (RAD001) and alemtuzumab: a Phase I/II study. Leuk Lymphoma
2016; 57 (7): 1585-91.
Zent CS, LaPlant BR, Johnston PB, Call TG, Habermann TM, Micallef IN, Witzig TE. The treatment of recurrent/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) with everolimus results in clinical responses and mobilization of CLL cells into the circulation. Cancer
2010; 116 (9): 2201-7.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]