Digital and Cryo fibrinogenemia as the Presenting Signs of Unsuspected Lymphoma in a Virus (HBV) Infected Patient: a Case Report

Vinaykumar Bohara, 1 Lalit Raut, 1 Sid dhartha Ray, 1 Utpal Chau dhuri 1

1Institute of and Transfusion Medicine, Kolkata, India.

Coressponding author: Dr. Vinaykumar Bohara. C/O IHTM, 3 rd Flr. MCH Building Medical College Kolkata -73; India Tel.: +919339338322 Fax: +9102580230005 Email : [email protected]

Abstract The most frequently studied association between a hepatitis virus and Non Hodgkin ly mphoma (NHL) has b een with virus (HCV). Association with Hepatitis B virus (HB V) is less studied. In this regard mixed (MC) is more commonly ass ociated with HCV than HBV. Still rarer is in these patients. Lack of symptoms in addition its rarity delays the diagnosis of cryofibrinogenemia and thus the underlying disorders like lymphoma, etc. This case report describes the diagnosis of unsu spected B cell lymphoma in a patient who presented with absolutely no hematological and underscores the importance of integrated multidisciplinary approach in the diagnosis of such rare presentations of common hematological .

Keywords: Non-, Cryofibrinogenemia, Hepatitis B virus

The most frequently studied association between a screening investigations revealed (given in table no hepatitis virus and Non Hodgkin ly mphoma (NHL) 1). has been with (HCV). With the suspicion of small vessel patient Interestingly, the finding which led to the extensive was evaluated for ANA, ANCA which came to be study of this association was near 100 % occurrence negative. Complements were low (C3 : 46 mg%, of HCV positivity in p atients with mixed C4 : 6.7mg%). Anti -cardiolipin , congenital cryoglobulinemia (MC) .(1, 2) There are case screen (Protein C, Protein S and reports of associ ation of cryoglobulinemia with Factor V leiden mutation), anti Ro and anti La were HBV. Rarer than cryoglobulinemia is the negative. Surprisingly patient tested positive for occurrence of cryofibrin ogenemia in HCV and Hepatitis B surface antigen (HbsAg) and negat ive especially HBV assoc iated NHL. for anti -HCV . In this CASE REPORT , we describe a case of unsuspected B cell NHL presenting as dry gangrene of upper limb digits due to cryofibrinogenemia in ass ociation with HBV positivity . A 64 year male and chronic smoker presented with 1 year history of Raynaud’s phenomenon in upper limb. Intermittently, he also had a few episodes of mild epistaxis. His symptoms progressively increased in last 2 months to the e xtent of complete blackening of almost all the fingers. Physical examination revealed mild pallor, just palpable splenomegaly and non-significant cervical lymphad enopathy. The most striking was the presence of dry gang rene with Figure - 1. Shows blackish discolouration of all the fingers line of demarc ation in the fingers (Figure - 1). Initial but the thumbs.

International Journal of Hematology Oncology and Stem Cell Research ( IJHOSCR ), Vol. 6, No. 2; Apr , 201 2  Vinaykumar Bohara

Table - 1. Shows the results of initial investigations. Discussion Laboratory parameters Values and special comments (If The association of NHL with HBV has been studied any) Hemogram Hb: 9.2 gm/dl much less intensively than with HCV. This is TLC: 4500 /µL with normal somehow surprising because the first report of a differential positive a ssociation between HBV and NHL was Platelet: 1.2 lakh/ µL published in the same year as the first reports on the ESR: 75mm at the end of 1 hr HCV -NHL associ ation.(4) Renal function tests Within normal limits Liver function tests Total protein: 7.5 gm/dl. A recently published meta -analysis ,(5) gave the : 2.8 gm/dl odds ratio of 2.56 (95% CI, 2.24-2.92) for the Globulin: 4.7 gm/dl. association of HBV with the development of NHL. Lactate dehydrohenase 882 IU/L (nor mal, 313 -618 IU/L) On the other hand cryo fibrinogenemia is a rarely (LDH) symptomatic disorder that is under recognized due CT Abdomen Mild splenomegaly and para - aortic lymphadenopathy (5 -6 to the i nfrequency with which it causes symptoms. lymph nodes largest of which There are case reports describing the occurrence of measured 2×2 cm) secondary cryofibrin ogenemia in a ssociation with NHL or HBV and HCV .(6, 7) However to our Serology for with EBV, CMV, and knowledge, this case report of simultaneous Mycoplasma was negative. On confirmation, HBV occurrence of LPL, secondary cryofibrinogenemia DNA copies were >1 00,000 IU/ml an d HCV copies and HBV i nfection is the first of its own kind. The were undetectable on PCR analysis. In spite having underlying disorders may not be evident at the time strong suspicion for cryoglobulinemia, work up of diagnosis of cryofibrinogenemia, but may came neg ative for the same. become clinically apparent later which has o ccurred Assays of plasma for the presence of cryofibrinogen in our patient too. were found to be qualit atively positive (i.e. plasma Cryofibrinogens were first named and described by at 4°C for 72 hours) .(3) Korst and Kratochvil in 1955.(8) These proteins are Meanwhile unlike initial blood smears, the recent composed of a complex of , , and smear was reported to have plenty of .(9) ly mphoplasmacytoid cells for which patient When plasma is re frigerated at 4ºC for up to 72 underwent bone marrow trephine biopsy. This hours, proteins may precipitate (cryoprecip itate). If showed focal and interstitial infiltrates of refrigerated serum and plasma both form a lymphopla smacytoid and plasma cells. These were precip itate, then the precipitated proteins are later proven on immunohisto chemistry to be the referred to as cryoglobulins. If, however, infiltrates from lymphoplasmacytoid ly mphoma precipitation develops after refrigera tion of plasma (LPL). only, the plasma precipitate is r eferred to as One of the few para -aortic lymph nodes which were cryofibrinogen. initially thought to be of doubtful significance was Cryofibrinogens are not present in normal plasma biopsied under CT guidance. This lymph node on but can be found in the plasma of patients with histopathology and immunohistochemistry was neoplastic or thrombotic conditions. confirmed to have lymhoplasmacytoid Cryofibrinogen emia has been reported to occu r in ly mphoma.(Lymphoid cells were CD20 positive, association with conditions such as multiple VS38 stained plasma cells and plasmac ytoid cells. myeloma, carcinoma, leukemia, pregnancy, oral - MIB1 proloiferation index was 20%). contraceptive use, inflammatory processes, collagen Serum protein electrophore sis did not show ‘M’ vascular disease, and diabetes mell itus.(10, 11) band and 24 hour urine protein was 200 mg/24 Cryofibrinogenemia has been classified into an hours with negative . essential (pri mary) and a secondary form. E ssential Patient was thus diagnosed to have B cell cryo fibrinogenemia develops spontaneously in lymphoma (LPL) with secondary prev iously healthy persons. Too few cases have cryofibrinogen emia in association with HBV been reported, however, to determine the clinical infection. presentation by patient chara cteristics. Secondary Patient is undergoing treat ment with the cryo fibrinogenemia occurs w ith a female to male comb ination for B cell lymphoma ratio of 1.4 to 1, but with no age or racial along with anti -virals for HBV infection. Nothing predilection.(10, 11) The diagnosis of much could be offered for digital gangrene as line cryofibrinogenemia is based on clinical findings, of demarcation had already set in. histopathology, and the presence of cryofibrinogens

International Journal of Hematology Oncology and Stem Cell Research ( IJHOSCR ), Vol. 6, No. 2; Apr , 201 2  in the p atient’s plasma. It is important to work up 5. Nath A, Agarwal R, Malhotra P, Varma S. extensively to rule out secondary causes before Prevalence of hepatitis B virus infection in non- making a diagnosis of primary cryofibrinogenemia Hodgkin’s lymphoma. A systematic review and as during the follow up some cases of meta -analysis. Intern Med J. 2010;40(9):633-641. cryofibrin ogenemia that were initially considered as 6. Junsuke Shimbo, Atsuo Miwa and Kenju A oki essential actually had underlying se condary Brief report Cryofibrinogenemia associated with causes .(12) Clinical Rheumatology 2006; In fact t he conditions to be included in the 25(4 ): 562-563. differential diagnosis of gangrenous skin lesions are 7. A Shimoni, M Körbling, R Champlin and J cryoglobulinemia, cryofibrinogenemia, Molldrem. Cryofibrinogenemia and skin n ecrosis in antiphospholipid antibody syndrome (APLA), a patient with diffuse large cell lymphoma after thrombotic thrombocytopenic (TTP), high -dose chemotherapy and autologous stem cell , coumarin , and transplantation. Bone marrow tran splantation. 2000; ch olesterol crystal emboliz ation.(13) 26(12):1343-1345. When cryofibrinogenemia is associated with other 8. Korst D, Kratochvil C. “Cryofibrinogen” disease processes, treatment of the underlying formation in a case of lung neoplasm associat ed disease is often effective in producing a remission. with thrombophlebitis migrans. Blood 1955; 10: For esse ntial cryofibrinogenemia, treatments 945-953. include dipyridamole, , wa rfarin, 9. Williamson AE, Cone LA, Huard GS 2nd. , streptodornase, stanozolol, oral Spontaneous necrosis of the skin associated with , immunosuppressive therapy, and cryofibrinogenemia, cryoglobulinemia, and ,(14) heparin but r elapses often homocystinuria. Ann Vasc Surg 1996; 10:365-369. occur upon decreasing dosage or discontinuing therapy .(13, 14) Our patient was treated with both 10. Smith SB, Ark in C. Cryofibrinogenemia: oral corticosteroids (as a part of combination incidence, clinical correlations, and a review of the chemotherapy for NHL) and anti -virals for HBV literature. Am J Clin Pathol 1972; 58: 524-530. infection with therapeutic success. Presently 11. Mckee PA, Kalbfleisch JM, Bird RM. Incidence patients plasma does not show cryofibrinogens and and significance of cryo globulinemia. J Lab Clin NHL shows complete response .(15) Med 1963; 61: 203-210 Finally , d espite the uncommon occ urrence of 12. C. B elizna L. Loufrani J.F. Subra. A 5 -year cryofibrinogenemia as a presenting sign of prospective follow-up study in essential haematological , it is important to cr yofibrinogenemia patients. Autoimmunity co nsider this condition in the differential when Revie ws 2011;10(9): 559–562 lymphoma is a possibility. Of considerable 13. Zouboulis CC, Gollnick H, Weber S, et al. importance is the attention that must be given to the Intravascular necr osis of the skin ordering of the proper diagnostic tests required for associated with cryofibrinogenemia, diabetes the diagnosis of this condition, as morbidity - mellitus, and card iolipin autoantibodies. J Am Acad reducing ther apies are available. Dermatol 1991; 25:882- 888 14. Rachmilewit z EA, Sacks MI, Zlotnick A. References Essential cryofibrinogenemia. 1. Pascual M, Perrin L, Giostra E, Schifferli JA. Clinical, pathological and immunological studies. Hepatitis C virus in patients with cryoglobulinemia Isr J Med Sci 1970; type II. J Infect Dis. 1990;162(2):569-570. 6:32-43. 2. Agnello V, Chung RT, Kaplan LM. A role for 15. Bruce D. Cheson, Beate P fistner, Malik E. hepatitis C virus infection in type II Juweid, Randy D. Gascoyne, Lena Specht, Sandra cryoglobulinemia. N Engl J Med. J. Horning Revised Response Criteria for Malignant 1992;327(21):1490-1495. Ly mphoma. JCO;25:579-586. 3. Tshering D. Amdo, MD, James A. Welker, DO. An Approach to the Diagnosis and Trea tment of Cryofibrinogenemia Am J Med. 2004;116:332–337 4. Galun E, Ilan Y, Livni N, et al. Hepatitis B virus infection associated with h ematopoietic tumors. Am J Pathol. 1994;145(5):1001-1007.

International Journal of Hematology Oncology and Stem Cell Research ( IJHOSCR ), Vol. 6, No.2; Apr. , 201 2