Mædica - a Journal of Clinical Medicine C ASE
MAEDICA – a Journal of Clinical Medicine 2014; 9(2): 204-209
REPORTS
Composite Diffuse Large B-Cell Lymphoma and Follicular B-Cell Lymphoma – Case Report and Review of Literature Andrei TURBATUa; Marilena STOIANb; Iulian BREZEANc; Victor Constantin Ion STOICAb; Andrei COLITAa; Camelia DOBREAd; Nicoleta STATEb; Cosmin IONESCUb; Ana-Maria IVANESCUa; Madalina OPREAa; Cecilia GHIMICIa; Anca Roxana LUPUa a
Department of Hematology, Coltea Clinical Hospital, Bucharest, Romania Department of Internal Medicine, “Dr. I.Cantacuzino” Clinical Hospital, Bucharest, Romania c Department of General Surgery, “Dr.I.Cantacuzino” Clinical Hospital, Bucharest, Romania d Department of Hematology, Fundeni Clinical Institute, Bucharest, Romania b
ABSTRACT Composite lymphoma refers to the co-occurrence of two or more morphologically and immunophenotypically separate lymphomas in the same topographic site at the time of clinical presentation. It is an infrequent type of lymphoid neoplasm, present in lymphoid tissue and may be due to the existence of two genetically related neoplasms such as transformation of a single lymphoma into another more aggressive lymphoma or be due to the presence of two clonally unrelated lymphomas. This paper is presenting a case of diffuse non-Hodgkin large B-cell lymphoma with areas of low grade and high grade follicular non-Hodgkin B-cell lymphoma in a retroperitoneal lymph node and spleen of an 62 year old woman. Histopathological examination and immunohistochemistry features proved the diagnosis of composite lymphoma. Keywords: composite lymphoma, diffuse large B-cell lymphoma, low grade follicular lymphoma, ascites
INTRODUCTION
C
omposite lymphomas are rare, with a relative frequency ranging from 1 to 4.7% of lymphoma cases. Currently they are defined as the presence of two or more dif-
ferent architectural and cytological subtypes of lymphoma involving the same anatomic site or tissue (1-3). The term “composite lymphoma” have inconsistently been used over the past years due to the different expert opinions about the characteristics of these neoplasms regarding clona-
Address for correspondence: Andrei Turbatu, Coltea Clinical Hospital, Clinic of Hematology, 1 I.C. Bratianu Boulevard, Bucharest, Romania. E-mail: [email protected] Article received on the 10th of April 2014. Article accepted on the 18th of June 2014.
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COMPOSITE DIFFUSE LARGE B-CELL LYMPHOMA AND FOLLICULAR B-CELL LYMPHOMA – CASE REPORT AND REVIEW OF LITERATURE lity of tumoral cells and location within the same or at different anatomic sites. Various combinations of lymphomas have been reported in the literature under the name of composite lymphoma, but the majority of diagnosed composite lymphoma represents two forms of non-Hodgkin’s lymphoma, e.g., mixed small and large cell lymphoma, composite lymphoma consisting of more than two different lymphomas, such as the type presented in our case, being even rare. CASE REPORT
W
e report the case of a 62-year-old white woman, retired, from the urban environment, firstly admitted at “Dr.I.Cantacuzino” Medical Clinic in January 2014 for digestive intolerance, abdomen enlargement for nearly 3 weeks and inferior limbs edema for about 1 year. The patient was known with hypertension and a right partial recovered hemiparesis after a stroke in 1988, she had allergy to dust and detergents, didn’t have any history of smoking and there was no family history of cancer or chronic disease. The clinical examination showed average overall condition, mild asthenia and fatigue, pale skin, massive inferior limbs edema and abdominal wall edema, without any palpable peripheral lymphadenopathy, pulmonary - abolished breath sounds in the left hemithorax basis, without stasis rales, BP 155/95 mmHg, AV 100 bpm, abdomen enlargement with important ascites, slow bowel transit, difficult abdominal palpation due to ascites.
Variable Hematocrit (%) Hemoglobin (g/dl) Mean corpuscular volume (fl) Mean corpuscular hemoglobin concentration (g/dl) White-cell count (*1000/mm3) Absolute neutrophils (*1000/mm3) Platelet count (*1000/mm3) International normalized ratio Prothrombin Time (sec) Prothrombin Time (%) Sideremia (μg/dl) Serum uric acid (mg/dl) Serum urea (mg/dl) Serum creatinine (mg/dl) Serum albumin (g/dl) Serum total protein (g/dl) Gamma globulin Glucose (mg/dl) Serum amylase (U/l) Serum total bilirubin (mg/dl) Serum alkaline phosphates (U/l) Aspartate aminotransferase (U/l) Alanine aminotransferase (U/l) Serum cholesterol (mg/dl) Serum sodium (mmol/l) Serum potassium (mmol/l) C-reactive protein (mg/l) Alpha-2-macroglobulin (%) TABLE 1. Laboratory Data.
Reference Range 36.00 – 48.00 11.70 – 15.00 80.00 – 100.00
On Admission 32.7 9.5 71.42
32.00 – 36.00
29.12
4.00 – 11.00 2.00 – 8.00 150.00 – 450.00 0.84 – 1.12 11.00 – 15.40 76.00 – 120.00 37.00 – 145.00 2.40 – 5.70 10.00 – 50.00 0.50 – 1.10 3.40 – 4.80 6.60 – 8.70 11.1 – 18.8 65.00 – 115.00 28.00 – 100.00 0.10 – 1.00 35.00 – 104.00 10.00 – 31.00 10.00 – 31.00 120.00 – 200.00 135.00 – 148.00 3.60 – 5.20 00.00 – 5.00 7.1 – 11.8
10.15 8.221 297.00 1.06 13.80 82.50 22.81 7.63 25.57 0.66 3.97 4.02 4.9 95.12 31.61 0.35 96.62 22.71 10.94 231.76 139.53 3.52 44.61 19.3
Laboratory tests and other procedures The first laboratory investigations have shown a moderate hypochromic microcytic anemia with low blood iron, hypercholesterolemia, hypoproteinemia with hypogammaglobulinemia, a mild hypokalemia and inflammatory syndrome (Table 1). The chest X-ray revealed left pleural effusion (Figure 1). We also performed an abdominal ultrasound which showed a great accumulation of liquid in the peritoneal cavity, a mild enlarged liver without any signs of portal hypertension and a large spleen (20 cm). The viral hepatitis markers were also negative, so what we actually thought being a liver disease, diminished as fast as our investigations
FIGURE 1. Chest X-ray on admission.
continued. The ECG showed nothing but a sinus tachycardia and we could also discard any cardiac cause. In order to establish the nature of the ascitic fluid, we had to perform an evacuatory diag-
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COMPOSITE DIFFUSE LARGE B-CELL LYMPHOMA AND FOLLICULAR B-CELL LYMPHOMA – CASE REPORT AND REVIEW OF LITERATURE nostic paracentesis. Unfortunately, just a small amount of liquid had been extracted due to its fibrinous sero-hemorrhagic content, the ascitic fluid analysis revealing the presence of numerous atypical mesothelial cells. After a thorough history case repeat, we found out that the patient had some episodes of postmenopausal menometrorrhagia 5 years ago. Considering the facts we had so far, we thought about another condition, called Meigs’ syndrome (defined as the triad of benign ovarian tumor with ascites and pleural effusion). So, the next step was to focus our attention into exploring the genital area. The tumor marker, CA-125, is elevated in Meigs’ syndrome but not up to a level found in malignancy. Although there is a strong correlation between ovarian malignancy and elevated serum CA-125 levels, several benign conditions have been found to cause a rise in CA-125 levels. In our case, the tumor markers showed a normal amount of serum alpha-fetoprotein, but a very elevated serum CA-125 level (1151.5 U/ml). The genital examination suspected the presence of a tumor on the left ovary, therefore performing of an abdominopelvic CT was highly recommended. Yet this hypothesis was not sustained by the CT. However a bulky abdomi-
FIGURE 2. Spleen biopsy - immunohistochemistry. a) BCL6(+) (ob 10x); b) CD10(-) (ob 10x); c) Ki67 in FL1-2 (ob 10x); d) Ki67 in FL3 (ob 10x).
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nal adenopathy which could compromise the vascular structures (celiac trunk, portal vein, inferior vena cava), splenomegaly and peritoneal ascites were discovered, raising the suspicion of a non-Hodgkin lymphoma. The hematological examination revealed nothing but the same anemia without any suggestive changes on the other series and not even the bone marrow biopsy could establish a diagnostic – the immunohistochemistry revealed just the reactive nature of the marrow lymphoid infiltrate composed of small B-lymphocytes CD20+ and small T-lymphocytes CD3+ with normal layout and CD20/CD3 ratio. This was the reason for which the patient was transferred to “Dr. I. Cantacuzino” Surgery Clinic for further investigations of the retroperitoneal tumor. A surgical intervention was performed with splenectomy, drainage of the peritoneal cavity, lymph node and spleen biopsy. The postoperative evolution was favorable. Histopathological outcomes revealed a diffuse infiltration of malignant neoplastic lymphoid cells of medium/ high size with ReedSternberg-like and multinucleated cells, with a mitotic activity. Therefore, the suspicion was of non-Hodgkin’s follicular B-cell lymphoma with areas of diffuse large B-cell lymphoma, without being able to exclude the association with Hodgkin’s lymphoma. Meanwhile, the patient was referred to Coltea Hematology Clinic for other specialized investigations and appropriate therapy. The immunohistochemical examination (Table 2, Figure 2) determined the final diagnosis: diffuse large B-cell lymphoma (~20%) with areas of high grade non-Hodgkin’s follicular Bcell lymphoma (~40%) and low grade (~40%). We also performed a chest CT in order to visualize any potential mediastinal lymphadenopathy and therefore staging the disease. The CT result emphasized nothing but the same left pleural effusion and a few lymphadenopathies smaller than 1.5 cm without any pathological significance. So, we initiated chemotherapy – CHOP (Cyclophosphamide, Hydroxydaunorubicin also called Doxorubicin or Adriamycin, Oncovin or Vincristine and Prednisone) treatment, which was well tolerated by the patient.
COMPOSITE DIFFUSE LARGE B-CELL LYMPHOMA AND FOLLICULAR B-CELL LYMPHOMA – CASE REPORT AND REVIEW OF LITERATURE DISCUSSION 1) Concerning the differential diagnosis with Meigs’ syndrome Meigs’ syndrome is defined as the triad of benign ovarian tumor with ascites and pleural effusion that resolves after resection of the tumor. Meigs’ syndrome accounts for approximately 1% of all ovarian tumors. It usually occurs after the age of 40 years, with the frequency increasing with each added year. In most cases of Meigs’ syndrome, the type of ovarian tumor is a fibroma and the cause does not appear to be clear although there seems to be an inflammatory reaction that causes the ascites and pleural fluid accumulation. A study carried out on ovarian tumors with ascites revealed that only large tumors (>10 cm in diameter) with a myxoid component caused ascites, as it favored secretion of fluid from the tumor (4). The tumor marker, CA-125, is elevated in Meigs’ syndrome but not up to a level found in malignancy. The significance of Meigs’ syndrome lies in the fact that neither ascites nor pleural effusion is necessarily an ominous sign in women with a pelvic tumor. Although there is a strong correlation between ovarian malignancy and elevated serum CA-125 levels, several benign conditions have been found to cause a rise in CA-125 levels. It is important to remember that a pelvic neoplasm in a woman presenting with pleural effusion, ascites and elevated CA-125 levels might be benign and that this condition can rapidly be resolved with surgical removal (5-7). 2) Concerning the final diagnosis of composite lymphoma The term “composite lymphoma” refers to the presence of two or more morphologically and immunophenotypically distinct lymphomas in a single anatomic site (8). It is a rare finding in the literature. The actual incidence of composite lymphoma maybe underestimated due to the lack of advanced techniques in many parts of the world that are needed to diagnose them (9). Composite lymphoma consisting of three distinct lymphomas is even rarer. In our case, histological examination of the retroperitoneal lymph node biopsy revealed the presence of three different types of lymphomas. There were separate areas of low grade follicular lymphoma (~40%) and diffuse
Results Antibodies
Specificity
CD20 B-cell BCL-6 Lymphocytes CD10 T-cell CD5 T-cell Ki-67 proliferation index TABLE 2. Immunohistochemistry Panel.
FL
DLBCL
+ + 35-40%
+ + 60-65%
FL = non-Hodgkin’s follicular B-cell lymphoma DLBCL = diffuse large B-cell lymphoma
large B-cell lymphoma (~20%) within the same lymph node. Also, an area of high grade follicular lymphoma was identified (~40%). The diffuse large B-cell lymphoma areas revealed a high proliferation index demonstrated by a high KI-67 expression of tumoral cells (60-65%) compared with the low grade follicular lymphoma (10%) and high grade follicular lymphoma (25-30%). B-cell markers were positive in both components including CD20 and BCL-6. Other immunohistochemical markers that were negative included CD10 and CD5. Literature review revealed scattered reports of composite lymphoma, majority of them being distinct types of non-Hodgkin’s lymphoma. Tsang et al presented a case of composite lymphoma with follicular center cells (FCCL) and mantle cell lymphoma (MCL). They reported a 70-year-old woman who had long standing low grade FCCL and subsequently developed in the same lymph node foci persistent FCCL in addition to MCL. These components were proven by immunohistochemistry and molecular genetic analysis (10). Fend et al also reported 3 cases of composite lymphoma low grade B-cell lymphoma combined with FCCL and MCL. They confirmed the diagnosis by molecular genetic analysis and used the laser capture microdissection technique to isolate the two different lymphoma areas. All three lymphomas had two separate clones, which included immunoglobulin heavy chain gene (IgH) and BCL-2 gene rearrangement in the FCCL (11). Steinhoff et al reported a case of composite lymphoma formed of three lymphomas in one patient, but in different anatomic sites. The lymphomas were primary cutaneous marginal zone B-cell lymphoma, nodal Epstein-Barr virus associated classic Hodgkin’s lymphoma of B-cell type and peripheral T-cell lymphoma coexisting in the skin and cervical lymph node (12). In their case, molecular studies proved
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COMPOSITE DIFFUSE LARGE B-CELL LYMPHOMA AND FOLLICULAR B-CELL LYMPHOMA – CASE REPORT AND REVIEW OF LITERATURE that the three lymphomas were clonally unrelated. In our case, three lymphomas were found in a single lymph node. These lymphomas were one low grade lymphoma (FL I-II) and two high grade lymphomas (FL IIIA and DLBCL). From these reports, it seems that the histological progression in B-lineage lymphoma is most evident in patients whose initial biopsies show features of low grade lymphoma. The incidence of progression in pattern or cell type in follicular lymphoma is different in the literature. It accounts up to 80% in autopsy series compared to 40% from biopsy series or relapses that occurred within 5 months of the initial presentation. Some reports presenting data obtained from staging laboratory showed 5% of patients with low grade follicular lymphoma affecting peripheral sites have unsuspected large cell lymphoma in abdominal site and 10% of patients with large cell lymphoma affecting peripheral site have follicular lymphoma in abdominal sites (13). The management of this lymphoma depends on histology of the highgrade component present in the biopsy (14). Takimoto et al (15) reported a case of follicular low grade lymphoma that underwent transformation into high grade lymphoma small non cleaved. They proposed in their report the initial development of the low grade lymphoma is due to rearrangement of BCL-2 gene, and then there is mutation in P53 (tumor suppressor gene) and rearrangement of C-myc gene which are both found in the high grade small non cleaved-cell, non-Burkitt’s lymphoma. These molecular changes in the lymphoma were the initiator of the transformation of low grade to high grade. Unique to our case is the presence of a high grade lymphoma in addition to low grade follicular lymphoma. The DLBCL component char-
acterized a small part of the atypical lymphoid infiltrate seen in the lymph node. Of note, there were several follicular pattern adjacent to the DLBCL. This may indicate a large cell transformation from an underlying follicular lymphoma. High grade FL and transformed DLBCL have been shown to be clonally related (16,17). One suggested mechanism of the transformation of high grade FL to DLBCL could be via increased expression of genes involved in cellular proliferation. Unfortunately, cytogenetic and PCR exams couldn’t be performed in our case in order to establish this fact for sure. Interestingly, neoplastic low grade FL cells are focally present and intersperse in the DLBCL areas. However, there were no obvious transitional zones as seen in the high grade FL/ DLBCL areas. It does not appear to be a Richter transformation in our case. The Richter transformation describes the development of an aggressive non-Hodgkin’s lymphoma or Hodgkin’s lymphoma from an indolent lymphoma (18). The clinical outcome of Richter’s transformation is generally poor. Numerous therapies can induce a response, but patients typically die within a few months after Richter’s transformation (19,20). In conclusion, DLBCL arising from a composite lymphoma including indolent lymphomas is not common and it needs meticulous examination of the lymph node or lymphoid tissue to avoid missing its diagnosis. The therapy of this form of lymphoma is towards the high grade component in its histology. In order to overpass the diagnostic challenges imposed by the morphology of composite lymphoma, immunohistochemistry, cytogenetics and molecular genetics with different techniques could help in making specific diagnostic entities. Conflict of interests: none declared. Financial support: none declared.
REFERENCES 1.
2.
Custer RP – Pitfalls in the diagnosis of lymphoma and leukemia from the pathologist’s point of view. Proceedings of the Second National Cancer Conference. New York: American Cancer Society, 1954. 554-557 Hicks EB, Rappaport H, Winter WJ – Follicular lymphoma; a re-evaluation of its position in the scheme of malignant lymphoma, based on a survey of 253 cases. Cancer 1956; 9:792-821
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3.
4.
5.
6.
Kim H, Hendrickson R, Dorfman RF – Composite lymphoma. Cancer 1977; 40:959-976 Riker D, Goba D – Ovarian mass, pleural effusion, and ascites: revisiting meigs syndrome. J Bronchology Interv Pulmonol. 2013; 20:48-51 Jones OW, Surwit EA – Meigs syndrome and elevated CA 125. Obstet Gynecol. 1989; 73(3 Pt 2):520-1 Lin JY, Angel C, Sickel JZ – Meigs syndrome with elevated serum CA 125.
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7.
8.
Obstet Gynecol. 1992; 80(3 Pt 2):563-6 Morán-Mendoza A, Alvarado-Luna G, Calderillo-Ruiz G, et al. – Elevated CA125 level associated with Meigs’ syndrome: case report and review of the literature. Int J Gynecol Cancer. 2006; 16 Suppl 1:315-8 Sanchez S, Holmes H, Katabi N, et al. – Composite lymphocyte-rich Hodgkin’s lymphoma and peripheral T-cell lymphoma associated with Epstein-Barr virus: A case report and review of the
COMPOSITE DIFFUSE LARGE B-CELL LYMPHOMA AND FOLLICULAR B-CELL LYMPHOMA – CASE REPORT AND REVIEW OF LITERATURE literature. Arch Pathol Lab Med 2006; 130:107-112 9. Mokhtar NM – Composite Lymphoma. J Egyptian Nat Cancer Inst 2007; 19:171-175 10. Tsang P, Pan L, Cesarman E, et al. – A distinctive composite lymphoma consisting of clonally related mantle cell lymphoma and follicle center cell lymphoma. Hum Pathol 1999; 30:988-992 11. Fend F, Quintanilla-Martinez L, Kumar S, et al. – Composite low grade B-cell lymphomas with two immunophenotypically distinct cell populations are true biclonal lymphomas. A molecular analysis using laser capture microdissection. Am J Pathol 1999; 154:1857-1866 12. Steinhoff M, Assaf C, Anagnostopoulos I, et al. – Three coexisting lymphomas in one patient: genetically related or only a coincidence? J Clin Pathol 2006; 59:1312-1315
13. Warnke RA, Lawrence M, Weiss MD, et al. – Atlas of Tumor Pathology, Tumors of Lymph Nodes and Spleen. 3rd series. AFIP 1995:329 14. Altaf FJ, Al Maghrabi JA – Composite Lymphoma. Med Sci 2006; 14:3-17 15. Takimoto Y, Takafuta T, Imanaka F, et al. – Histological progression of follicular lymphoma associated with P53 mutation and rearrangement of the C-myc gene. Hiroshima J Med Sci 1996; 45:69-73 16. Matolcsy A, Schattner EJ, Knowles DM, et al. – Clonal evolution of B cells in transformation from low- to high-grade lymphoma. Eur J Immunol 1999; 29:1253-1264 17. Zelenetz AD, Chen TT, Levy R – Histologic transformation of follicular lymphoma to diffuse lymphoma represents tumor preogression by a single malignant B cell. J Exp Med 1991; 173:197-207
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18. Davies AJ, Rosenwald A, Wright G, et al. – Transformation of follicular lymphoma to diffuse large B-cell lymphoma proceeds by distinct oncogenic mechanisms. Br J Haematol 2007; 136:286-293 19. Tsimberidou AM, O’Brien S, Khouri I, et al. – Clinical Outcomes and Prognostic Factors in Patients with Richter’s Syndrome Treated with Chemotherapy or Chemoimmunotherapy with or without Stem-Cell Transplantation. J Clin Oncol 2006; 24:23432350 20. Koshy J, Dadfornia T, Qian YW – Diffuse large B-cell lymphoma arising in a composite lymphoma with biclonality by flow cytometry and one monoclonal band by PCR. Int J Clin Exp Pathol 2014; 7:407-410.
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MAEDICA – a Journal of Clinical Medicine 2014; 9(2): 204-209
REPORTS
Composite Diffuse Large B-Cell Lymphoma and Follicular B-Cell Lymphoma – Case Report and Review of Literature Andrei TURBATUa; Marilena STOIANb; Iulian BREZEANc; Victor Constantin Ion STOICAb; Andrei COLITAa; Camelia DOBREAd; Nicoleta STATEb; Cosmin IONESCUb; Ana-Maria IVANESCUa; Madalina OPREAa; Cecilia GHIMICIa; Anca Roxana LUPUa a
Department of Hematology, Coltea Clinical Hospital, Bucharest, Romania Department of Internal Medicine, “Dr. I.Cantacuzino” Clinical Hospital, Bucharest, Romania c Department of General Surgery, “Dr.I.Cantacuzino” Clinical Hospital, Bucharest, Romania d Department of Hematology, Fundeni Clinical Institute, Bucharest, Romania b
ABSTRACT Composite lymphoma refers to the co-occurrence of two or more morphologically and immunophenotypically separate lymphomas in the same topographic site at the time of clinical presentation. It is an infrequent type of lymphoid neoplasm, present in lymphoid tissue and may be due to the existence of two genetically related neoplasms such as transformation of a single lymphoma into another more aggressive lymphoma or be due to the presence of two clonally unrelated lymphomas. This paper is presenting a case of diffuse non-Hodgkin large B-cell lymphoma with areas of low grade and high grade follicular non-Hodgkin B-cell lymphoma in a retroperitoneal lymph node and spleen of an 62 year old woman. Histopathological examination and immunohistochemistry features proved the diagnosis of composite lymphoma. Keywords: composite lymphoma, diffuse large B-cell lymphoma, low grade follicular lymphoma, ascites
INTRODUCTION
C
omposite lymphomas are rare, with a relative frequency ranging from 1 to 4.7% of lymphoma cases. Currently they are defined as the presence of two or more dif-
ferent architectural and cytological subtypes of lymphoma involving the same anatomic site or tissue (1-3). The term “composite lymphoma” have inconsistently been used over the past years due to the different expert opinions about the characteristics of these neoplasms regarding clona-
Address for correspondence: Andrei Turbatu, Coltea Clinical Hospital, Clinic of Hematology, 1 I.C. Bratianu Boulevard, Bucharest, Romania. E-mail: [email protected] Article received on the 10th of April 2014. Article accepted on the 18th of June 2014.
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COMPOSITE DIFFUSE LARGE B-CELL LYMPHOMA AND FOLLICULAR B-CELL LYMPHOMA – CASE REPORT AND REVIEW OF LITERATURE lity of tumoral cells and location within the same or at different anatomic sites. Various combinations of lymphomas have been reported in the literature under the name of composite lymphoma, but the majority of diagnosed composite lymphoma represents two forms of non-Hodgkin’s lymphoma, e.g., mixed small and large cell lymphoma, composite lymphoma consisting of more than two different lymphomas, such as the type presented in our case, being even rare. CASE REPORT
W
e report the case of a 62-year-old white woman, retired, from the urban environment, firstly admitted at “Dr.I.Cantacuzino” Medical Clinic in January 2014 for digestive intolerance, abdomen enlargement for nearly 3 weeks and inferior limbs edema for about 1 year. The patient was known with hypertension and a right partial recovered hemiparesis after a stroke in 1988, she had allergy to dust and detergents, didn’t have any history of smoking and there was no family history of cancer or chronic disease. The clinical examination showed average overall condition, mild asthenia and fatigue, pale skin, massive inferior limbs edema and abdominal wall edema, without any palpable peripheral lymphadenopathy, pulmonary - abolished breath sounds in the left hemithorax basis, without stasis rales, BP 155/95 mmHg, AV 100 bpm, abdomen enlargement with important ascites, slow bowel transit, difficult abdominal palpation due to ascites.
Variable Hematocrit (%) Hemoglobin (g/dl) Mean corpuscular volume (fl) Mean corpuscular hemoglobin concentration (g/dl) White-cell count (*1000/mm3) Absolute neutrophils (*1000/mm3) Platelet count (*1000/mm3) International normalized ratio Prothrombin Time (sec) Prothrombin Time (%) Sideremia (μg/dl) Serum uric acid (mg/dl) Serum urea (mg/dl) Serum creatinine (mg/dl) Serum albumin (g/dl) Serum total protein (g/dl) Gamma globulin Glucose (mg/dl) Serum amylase (U/l) Serum total bilirubin (mg/dl) Serum alkaline phosphates (U/l) Aspartate aminotransferase (U/l) Alanine aminotransferase (U/l) Serum cholesterol (mg/dl) Serum sodium (mmol/l) Serum potassium (mmol/l) C-reactive protein (mg/l) Alpha-2-macroglobulin (%) TABLE 1. Laboratory Data.
Reference Range 36.00 – 48.00 11.70 – 15.00 80.00 – 100.00
On Admission 32.7 9.5 71.42
32.00 – 36.00
29.12
4.00 – 11.00 2.00 – 8.00 150.00 – 450.00 0.84 – 1.12 11.00 – 15.40 76.00 – 120.00 37.00 – 145.00 2.40 – 5.70 10.00 – 50.00 0.50 – 1.10 3.40 – 4.80 6.60 – 8.70 11.1 – 18.8 65.00 – 115.00 28.00 – 100.00 0.10 – 1.00 35.00 – 104.00 10.00 – 31.00 10.00 – 31.00 120.00 – 200.00 135.00 – 148.00 3.60 – 5.20 00.00 – 5.00 7.1 – 11.8
10.15 8.221 297.00 1.06 13.80 82.50 22.81 7.63 25.57 0.66 3.97 4.02 4.9 95.12 31.61 0.35 96.62 22.71 10.94 231.76 139.53 3.52 44.61 19.3
Laboratory tests and other procedures The first laboratory investigations have shown a moderate hypochromic microcytic anemia with low blood iron, hypercholesterolemia, hypoproteinemia with hypogammaglobulinemia, a mild hypokalemia and inflammatory syndrome (Table 1). The chest X-ray revealed left pleural effusion (Figure 1). We also performed an abdominal ultrasound which showed a great accumulation of liquid in the peritoneal cavity, a mild enlarged liver without any signs of portal hypertension and a large spleen (20 cm). The viral hepatitis markers were also negative, so what we actually thought being a liver disease, diminished as fast as our investigations
FIGURE 1. Chest X-ray on admission.
continued. The ECG showed nothing but a sinus tachycardia and we could also discard any cardiac cause. In order to establish the nature of the ascitic fluid, we had to perform an evacuatory diag-
Maedica
A Journal of Clinical Medicine, Volume 9 No.2 2014
205
COMPOSITE DIFFUSE LARGE B-CELL LYMPHOMA AND FOLLICULAR B-CELL LYMPHOMA – CASE REPORT AND REVIEW OF LITERATURE nostic paracentesis. Unfortunately, just a small amount of liquid had been extracted due to its fibrinous sero-hemorrhagic content, the ascitic fluid analysis revealing the presence of numerous atypical mesothelial cells. After a thorough history case repeat, we found out that the patient had some episodes of postmenopausal menometrorrhagia 5 years ago. Considering the facts we had so far, we thought about another condition, called Meigs’ syndrome (defined as the triad of benign ovarian tumor with ascites and pleural effusion). So, the next step was to focus our attention into exploring the genital area. The tumor marker, CA-125, is elevated in Meigs’ syndrome but not up to a level found in malignancy. Although there is a strong correlation between ovarian malignancy and elevated serum CA-125 levels, several benign conditions have been found to cause a rise in CA-125 levels. In our case, the tumor markers showed a normal amount of serum alpha-fetoprotein, but a very elevated serum CA-125 level (1151.5 U/ml). The genital examination suspected the presence of a tumor on the left ovary, therefore performing of an abdominopelvic CT was highly recommended. Yet this hypothesis was not sustained by the CT. However a bulky abdomi-
FIGURE 2. Spleen biopsy - immunohistochemistry. a) BCL6(+) (ob 10x); b) CD10(-) (ob 10x); c) Ki67 in FL1-2 (ob 10x); d) Ki67 in FL3 (ob 10x).
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nal adenopathy which could compromise the vascular structures (celiac trunk, portal vein, inferior vena cava), splenomegaly and peritoneal ascites were discovered, raising the suspicion of a non-Hodgkin lymphoma. The hematological examination revealed nothing but the same anemia without any suggestive changes on the other series and not even the bone marrow biopsy could establish a diagnostic – the immunohistochemistry revealed just the reactive nature of the marrow lymphoid infiltrate composed of small B-lymphocytes CD20+ and small T-lymphocytes CD3+ with normal layout and CD20/CD3 ratio. This was the reason for which the patient was transferred to “Dr. I. Cantacuzino” Surgery Clinic for further investigations of the retroperitoneal tumor. A surgical intervention was performed with splenectomy, drainage of the peritoneal cavity, lymph node and spleen biopsy. The postoperative evolution was favorable. Histopathological outcomes revealed a diffuse infiltration of malignant neoplastic lymphoid cells of medium/ high size with ReedSternberg-like and multinucleated cells, with a mitotic activity. Therefore, the suspicion was of non-Hodgkin’s follicular B-cell lymphoma with areas of diffuse large B-cell lymphoma, without being able to exclude the association with Hodgkin’s lymphoma. Meanwhile, the patient was referred to Coltea Hematology Clinic for other specialized investigations and appropriate therapy. The immunohistochemical examination (Table 2, Figure 2) determined the final diagnosis: diffuse large B-cell lymphoma (~20%) with areas of high grade non-Hodgkin’s follicular Bcell lymphoma (~40%) and low grade (~40%). We also performed a chest CT in order to visualize any potential mediastinal lymphadenopathy and therefore staging the disease. The CT result emphasized nothing but the same left pleural effusion and a few lymphadenopathies smaller than 1.5 cm without any pathological significance. So, we initiated chemotherapy – CHOP (Cyclophosphamide, Hydroxydaunorubicin also called Doxorubicin or Adriamycin, Oncovin or Vincristine and Prednisone) treatment, which was well tolerated by the patient.
COMPOSITE DIFFUSE LARGE B-CELL LYMPHOMA AND FOLLICULAR B-CELL LYMPHOMA – CASE REPORT AND REVIEW OF LITERATURE DISCUSSION 1) Concerning the differential diagnosis with Meigs’ syndrome Meigs’ syndrome is defined as the triad of benign ovarian tumor with ascites and pleural effusion that resolves after resection of the tumor. Meigs’ syndrome accounts for approximately 1% of all ovarian tumors. It usually occurs after the age of 40 years, with the frequency increasing with each added year. In most cases of Meigs’ syndrome, the type of ovarian tumor is a fibroma and the cause does not appear to be clear although there seems to be an inflammatory reaction that causes the ascites and pleural fluid accumulation. A study carried out on ovarian tumors with ascites revealed that only large tumors (>10 cm in diameter) with a myxoid component caused ascites, as it favored secretion of fluid from the tumor (4). The tumor marker, CA-125, is elevated in Meigs’ syndrome but not up to a level found in malignancy. The significance of Meigs’ syndrome lies in the fact that neither ascites nor pleural effusion is necessarily an ominous sign in women with a pelvic tumor. Although there is a strong correlation between ovarian malignancy and elevated serum CA-125 levels, several benign conditions have been found to cause a rise in CA-125 levels. It is important to remember that a pelvic neoplasm in a woman presenting with pleural effusion, ascites and elevated CA-125 levels might be benign and that this condition can rapidly be resolved with surgical removal (5-7). 2) Concerning the final diagnosis of composite lymphoma The term “composite lymphoma” refers to the presence of two or more morphologically and immunophenotypically distinct lymphomas in a single anatomic site (8). It is a rare finding in the literature. The actual incidence of composite lymphoma maybe underestimated due to the lack of advanced techniques in many parts of the world that are needed to diagnose them (9). Composite lymphoma consisting of three distinct lymphomas is even rarer. In our case, histological examination of the retroperitoneal lymph node biopsy revealed the presence of three different types of lymphomas. There were separate areas of low grade follicular lymphoma (~40%) and diffuse
Results Antibodies
Specificity
CD20 B-cell BCL-6 Lymphocytes CD10 T-cell CD5 T-cell Ki-67 proliferation index TABLE 2. Immunohistochemistry Panel.
FL
DLBCL
+ + 35-40%
+ + 60-65%
FL = non-Hodgkin’s follicular B-cell lymphoma DLBCL = diffuse large B-cell lymphoma
large B-cell lymphoma (~20%) within the same lymph node. Also, an area of high grade follicular lymphoma was identified (~40%). The diffuse large B-cell lymphoma areas revealed a high proliferation index demonstrated by a high KI-67 expression of tumoral cells (60-65%) compared with the low grade follicular lymphoma (10%) and high grade follicular lymphoma (25-30%). B-cell markers were positive in both components including CD20 and BCL-6. Other immunohistochemical markers that were negative included CD10 and CD5. Literature review revealed scattered reports of composite lymphoma, majority of them being distinct types of non-Hodgkin’s lymphoma. Tsang et al presented a case of composite lymphoma with follicular center cells (FCCL) and mantle cell lymphoma (MCL). They reported a 70-year-old woman who had long standing low grade FCCL and subsequently developed in the same lymph node foci persistent FCCL in addition to MCL. These components were proven by immunohistochemistry and molecular genetic analysis (10). Fend et al also reported 3 cases of composite lymphoma low grade B-cell lymphoma combined with FCCL and MCL. They confirmed the diagnosis by molecular genetic analysis and used the laser capture microdissection technique to isolate the two different lymphoma areas. All three lymphomas had two separate clones, which included immunoglobulin heavy chain gene (IgH) and BCL-2 gene rearrangement in the FCCL (11). Steinhoff et al reported a case of composite lymphoma formed of three lymphomas in one patient, but in different anatomic sites. The lymphomas were primary cutaneous marginal zone B-cell lymphoma, nodal Epstein-Barr virus associated classic Hodgkin’s lymphoma of B-cell type and peripheral T-cell lymphoma coexisting in the skin and cervical lymph node (12). In their case, molecular studies proved
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COMPOSITE DIFFUSE LARGE B-CELL LYMPHOMA AND FOLLICULAR B-CELL LYMPHOMA – CASE REPORT AND REVIEW OF LITERATURE that the three lymphomas were clonally unrelated. In our case, three lymphomas were found in a single lymph node. These lymphomas were one low grade lymphoma (FL I-II) and two high grade lymphomas (FL IIIA and DLBCL). From these reports, it seems that the histological progression in B-lineage lymphoma is most evident in patients whose initial biopsies show features of low grade lymphoma. The incidence of progression in pattern or cell type in follicular lymphoma is different in the literature. It accounts up to 80% in autopsy series compared to 40% from biopsy series or relapses that occurred within 5 months of the initial presentation. Some reports presenting data obtained from staging laboratory showed 5% of patients with low grade follicular lymphoma affecting peripheral sites have unsuspected large cell lymphoma in abdominal site and 10% of patients with large cell lymphoma affecting peripheral site have follicular lymphoma in abdominal sites (13). The management of this lymphoma depends on histology of the highgrade component present in the biopsy (14). Takimoto et al (15) reported a case of follicular low grade lymphoma that underwent transformation into high grade lymphoma small non cleaved. They proposed in their report the initial development of the low grade lymphoma is due to rearrangement of BCL-2 gene, and then there is mutation in P53 (tumor suppressor gene) and rearrangement of C-myc gene which are both found in the high grade small non cleaved-cell, non-Burkitt’s lymphoma. These molecular changes in the lymphoma were the initiator of the transformation of low grade to high grade. Unique to our case is the presence of a high grade lymphoma in addition to low grade follicular lymphoma. The DLBCL component char-
acterized a small part of the atypical lymphoid infiltrate seen in the lymph node. Of note, there were several follicular pattern adjacent to the DLBCL. This may indicate a large cell transformation from an underlying follicular lymphoma. High grade FL and transformed DLBCL have been shown to be clonally related (16,17). One suggested mechanism of the transformation of high grade FL to DLBCL could be via increased expression of genes involved in cellular proliferation. Unfortunately, cytogenetic and PCR exams couldn’t be performed in our case in order to establish this fact for sure. Interestingly, neoplastic low grade FL cells are focally present and intersperse in the DLBCL areas. However, there were no obvious transitional zones as seen in the high grade FL/ DLBCL areas. It does not appear to be a Richter transformation in our case. The Richter transformation describes the development of an aggressive non-Hodgkin’s lymphoma or Hodgkin’s lymphoma from an indolent lymphoma (18). The clinical outcome of Richter’s transformation is generally poor. Numerous therapies can induce a response, but patients typically die within a few months after Richter’s transformation (19,20). In conclusion, DLBCL arising from a composite lymphoma including indolent lymphomas is not common and it needs meticulous examination of the lymph node or lymphoid tissue to avoid missing its diagnosis. The therapy of this form of lymphoma is towards the high grade component in its histology. In order to overpass the diagnostic challenges imposed by the morphology of composite lymphoma, immunohistochemistry, cytogenetics and molecular genetics with different techniques could help in making specific diagnostic entities. Conflict of interests: none declared. Financial support: none declared.
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