How to cite this article: Alcocer-Gamba MA, León-González S, Castro-Montes E, Loarca-Piña LM, Lugo-Gavidia LM, García-Hernández. Atypical presentation of diffuse large B-cell non-Hodgkin lymphoma. Rev Med Inst Mex Seguro Soc. 2015 Mar-Apr;53(2):232-8.
Received: March 11th 2014
Accepted: November 4th 2014
Marco Antonio Alcocer-Gamba,a Salvador León-González,b Eliodoro Castro-Montes,c Luis Martín Loarca-Piña,d Leslie Marisol Lugo-Gavidia,e Enrique García-Hernándezf
Instituto del Corazón de Querétaro, Querétaro, Querétaro, México
dHematología, Clinica, Hospital Ángeles Querétaro, Querétaro, México
eServicio Social, Facultad de Medicina, Universidad Autónoma de Querétaro, Querétaro, Querétaro, México
Communication with: Marco Antonio Alcocer-Gamba
Telephone: 01 (442) 216 2745 y 46, fax 01 (442) 216 4922
The non-Hodgkin lymphoma is a neoplastic entity that presents in extranodal form in 20 % of cases, usually occurs as solitary or generalized lymphadenopathy. There may be misdiagnosis if it manifests as primary extranodal disease because the primary infiltration may occur with different organs, despite the difficulty of diagnosis of primary extranodal location of non-Hodgkin lymphoma, histological and immunohistochemical studies are effective in preventing misdiagnosis. The presentation of this case is to describe this condition in its extranodal variety with cardiac infiltration in a 23 year-old woman with progressive dyspnea. Tumor mass was detected in right-atrial, venous catheterization biopsy was performed, this enabled the histopathological diagnosis and establish treatment. We present experiences from the attention of the case and review of the literature with special reference to diagnosis and treatment.
Keywords: Lymphoma; non-Hodgkin; Lymph nodes; Giant cells; B-Lymphocytes
Lymphomas are a heterogeneous group of cancers that affect the cells and organs of the immune system;1,2 malignant transformation can occur in any subpopulation of lymphoid cells of the immune system and in any central or peripheral lymphoid organ.2 Lymphomas represent 4% of thoracic malignancies and, of those, diagnosed non-Hodgkin lymphoma (NHL) corresponds to 3% of adult malignancies. Chronic antigenic stimulation to a deregulated immune system, genomic instability, and loss of control of infection due to potentially oncogenic organisms are important components in the cause and pathogenesis of this disease; biological injuries occurring include activation of proto-oncogenes and dysfunction of suppressor genes. Unlike many types of epithelial cancers, the genome of lymphoma cells is relatively stable.3
NHL consist of neoplastic proliferation of lymphoid cells that spread throughout the body, two-thirds of which are presented as persistent lymphadenopathy, peripheral, painless, usually solitary or widespread; however, NHL present extra-nodal disease (20%) more frequently than Hodgkin's disease (HD),4,5 which can cause misdiagnosis if primary extra-nodal disease is manifested. In those patients not taking into account asymptomatic nodular growth, the problem is greater because it increases the risk of disease progression.5 Extra-nodal lymphomas are a group of diseases that originate in an organ other than the lymph node, which can remain confined, or even arise where there is normally no lymphatic tissue.4,5 The WHO classification recognizes more than 30 different subtypes of NHL of which diffuse B cell is the most common subtype, accounting for 33% of all diagnosed cases and more than 80% of aggressive lymphomas; it is a subtype of high malignancy and rapid growth.1,3,6,7 In young adults diffuse large cell lymphomas are the most frequent extra-nodal presentation, and may manifest with primary infiltration to various organs, in which cardiac involvement occurs in 20 to 28% of cases;8,9 diagnosis is often difficult because the symptoms are nonspecific, dependent on their location and extent, while general symptoms like fever, sweats, and weight loss occur in less than 20%.4,8,10 The most aggressive course of NHL is related to the immunophenotype or elevated expression of Ki-67, a molecule belonging to the tumor necrosis factor family.2,4 Primary cardiac lymphomas are extremely rare, with an incidence of 0.0017 to 0.28%, and are defined as non-Hodgkin’s lymphoma (NHL), which exclusively affects the heart or pericardium or a as a large tumor located in the heart.8-12 Despite the difficulty of diagnosis of Hodgkin's disease with extra-nodal primary location, given its rare presentation, histological and immunohistochemical studies are effective to avoid misdiagnosis.5 As for the NHL, the most sensitive diagnosis method is 18FDG-positron emission tomography,6 still, the diagnostic test of greatest certainty in these cases is undoubtedly histology by biopsy, either of the lymph node or affected tissue.4
Female patient of 23 years who attended consultation due to sudden facial-corporal right hemiparesis and dysarthria. Her condition began two months before admission with significant weight loss (7 kg) and progressive dyspnea, initially of medium strength, that progressed to orthopnea, fully incapacitating her, requiring supplemental oxygen.
Physical examination revealed significant respiratory distress, tachypnea of 30 breaths per minute, hypoxemia with arterial oxygen saturation of 62% with mask and pallor +/+++, with subcutaneous tumor measuring 2 x 3 cm in left pectoral region, the biopsy of which reported breast fibroadenoma.
Laboratory tests showed HB 10.9 g/dL, lactate dehydrogenase (LDH) 1.7 times the upper limit of normal (ULN), elevated CA125 antigen 2.3 ULN; carcinoembryonic antigen, alpha-fetoprotein, CA 15-3 antigen and chorionic gonadotropin beta fraction were in normal ranges; the viral panel and anti-nuclear, anti-DNA, anti-Smith, anti-Beta 2 glycoprotein 1 and anti-cardiolipin antibodies were all negative. Computerized axial tomography (CT) of the head was performed, which showed subacute cerebral infarction complicated with mild hemorrhage and perilesional edema; the CT of the chest, abdomen, and pelvis showed right intra-atrial tumor, significant widening in the upper anterior mediastinum, and increase in volume of the adrenal gland, left kidney, and both ovaries.
The transthoracic echocardiogram showed an intracavity lesion in the right atrium, measuring 4.27 x 3.37 cm and that almost totally occupied it, causing significant tricuspid stenosis; color 76th mode Doppler transesophageal echocardiogram showed patent foramen ovale (FO) and tumor (T) fixed to the free wall of the right atrium. Paradoxical right-left short circuit by atrial occupation and increased intra-atrial pressure was documented; in this way with color Doppler 4 chambers at 0°, a tumor was identified protruding toward the inflow tract of the right ventricle (RV) and acceleration of inflow by blockage caused by the tumor, as well as an aneurysm of the interatrial septum (Figure 1). Biopsy was performed by right femoral venous catheterization guided by transthoracic echocardiography. Histopathological examination showed proliferation of large lymphoid cells, which had vesicular nuclei with little evident nucleolus and little cytoplasm; sclerosis was observed in some areas between the cells (Figure 2). Immunohistochemical study showed immunoreactivity in the cytoplasmic membrane of the neoplastic cells with anti-CD45, anti-CD20 and anti-CD30; further, intense nuclear staining was observed with anti-bcl-6 and proliferation index up to 80% with anti-Ki67 (Figure 3). With these results, diffuse large cell non-Hodgkin’s lymphoma was diagnosed, anaplastic variant, immunophenotype "B" CD20 positive, with co-expression of CD30 and bcl-6, with involvement of right atrium, both adrenal glands, left kidney, and both ovaries, so that an Ann Arbor clinical stage IV-B was established. Management began urgently with CHOP chemotherapy (cyclophosphamide 1200 mg, 70 mg doxorubicin, vincristine 2 mg and hydrocortisone equivalent to 100 mg per day dose of prednisone).
Figure 1 Transesophageal echocardiogram with modality color 4 Doppler chambers at 0 °. It clearly shows the tumor (T) in the right atrium (RA) and protruding into the inflow tract of the right ventricle (RV) and acceleration of inflow by blockage caused by the tumor is observed. One can also see atrial septal aneurysm (An)
Figure 2 Histological appearance of neoplasia. A) shows detail of nuclei, which are vesicular, with little evident nucleolus and little cytoplasm. Staining with hematoxylin-eosin, 40X. B) Large cells are seen, with vesicular nuclei, small isolated lymphocytes, and accentuated sclerosis between them.
Figure 3 Staining for immunohistochemistry, immunoreactivity of the cytoplasmic membrane with A) anti-CD20 and B) anti-CD30 and nuclei with B) anti-bcl-6 and C) anti-Ki67. 40X
A new color Doppler transesophageal echocardiography, completed after 8 cycles of the chemotherapy described, besides specific immunotherapy with anti-CD20 (intravenous rituximab at 550 mg), showed two nodules in the right atrium, one on the superior wall, near the inferior vena cava measuring 1.5 x 0.9 cm, and the other on the free wall measuring 1.7 x 1.3 cm, showing a significant reduction of the tumor (Figure 4), also multislice positron emission tomography (PET/CT) was performed with iodinated contrast and 18F-FDG at 370MBq, which showed a hypodense image in the right atrium of approximately 1.7 cm without metabolic activity, indicating devitalized tissue without evidence of remote tumor activity. At two years follow-up the patient was neurologically intact, functional NYHA class I, ECG with low atrial rhythm, transthoracic echocardiography with absence of atrial tumor (Figure 4), no short circuits, the new PET showed the same hypodense image 1.3 cm above the right atrium (Figure 5) demonstrating complete remission at two years.
Figure 4 A) Transesophageal echocardiogram 4 chambers at 0° after 8 treatment cycles. Reduction is seen in the tumor (T) dimensions fixed to the upper wall of right atrium (RA), tricuspid valve (TV) is observed without obstructing compromise, and absence of patent foramen ovale and interatrial aneurysm. B) Image of 4 chambers where one no longer can identify tumor at right atrial level, without the presence of pericardial effusion and without echocardiographic evidence of parietal infiltrative process, left ventricular function preserved after chemotherapy
Figure 5 PET/CT study contrasted with 18F-FDG A) Follow-up at eight months of axial section finds hypermetabolism in left ventricle of non-pathological physiological nature, with no evidence of tumor activity in the right atrium. B) Follow-up at 2 years of coronal section, left ventricle hypermetabolism without concentration of contrast medium in the right atrium indicative of tumor inactivity
Diffuse large B-cell NHL is a heterogeneous entity that displays multiple clinical presentations conditioned by histologic subtype, stage, and primary location.1,6 Its morphology consists of large cells (core twice the size of a normal lymphocyte, usually larger than the nucleus of a macrophage) with vesicles, basophilic cytoplasm, and moderately elevated proliferation fraction.14
Cardiac tumors are rare entities in medical practice, the literature reports an incidence of 0.05% and a prevalence of 0.002 to 0.3% as determined by autopsy;15 approximately 75% are benign and 25% malignant, of which lymphoma is recognized as an uncommon entity, representing about 0.25%.11,12 These are unusual entities that are characterized usually by settling in the right heart chambers, often in the right atrium (RA), where they invade other structures.9,12,16 The clinical manifestations are nonspecific, there are no specific cardiac signs or symptoms to suspect a CT,8,20 as these are determined by the location of the implementation and extension of the tumor; embolization is an important and relatively common complication that occurs in 25% of cases.16 In the case that this happens, the initial clinical presentation corresponded to severe dyspnea with posterior subacute stroke, corresponding to this group of complications.
The use of MRI and/or CT are options for evaluating NHL as they provide information on tissue infiltration and extra-nodal extension, as well as help detect metastasic lesions.16 CT imaging has clinical utility for diagnosing this disease, and to assess the response to treatment and to define remission.5 This is a tomographic technique using a beam of X-rays to produce anatomical images.17 It is currently used in combination with metabolic imaging techniques combining molecular anatomical information, which increases the sensitivity and specificity of the study, making it possible to detect lesions smaller than 1 cm and significantly reducing false positives.17 Gallium-17 gammagraphy is useful in locating the disease, although it may submit false positives and negatives, so it is currently being replaced by the PET/CT,1 a noninvasive tomographic imaging technique from nuclear medicine, which provides information about the metabolic activity of different tissues generated by detection of annihilation photons after introducing to the body a radiopharmaceutical that decays and emits positrons. F-FDG,18 a glucose analogue labeled with a positron emitting isotope, is the most widely used radiopharmaceutical, and it shows varying physiological uptake in viable tissue, especially in brain, kidneys, and myocardium; its usefulness stems from its high activity in multiple cancer processes, so it is a method with greater sensitivity and specificity in detecting, monitoring, and status determination of neoplastic processes.17,18 However, accurate diagnosis, typing, and staging are pathological and can only safely be confirmed by tumor mass biopsy.1,2,16 To determine prognosis in this disease, it is important to determine the immunophenotype, so complementary immunohistochemistry tests are required and in these cases flow cytometry and cytogenetic study can define the lymphocyte lineage, detect the monoclonal population, and define treatment.4,10 The safest diagnostic test is biopsy of the affected tissue and in the case of cardiac lymphomas, this is accomplished intravenously with a sensitivity of 100%.8,10 Endomyocardial biopsy can be performed via the femoral or internal jugular vein, both performed with echocardiographic and fluoroscopic control, the probability of making a successful endomyocardial biopsy via femoral vein being 99.3%. The literature reports a higher probability of both failure and complication (> 12%) when the jugular vein is used compared to the femoral.8 The low frequency of complications makes it a safe procedure guided by adequate technology, making it a diagnostic method used to definitively classify the disease.13
Due to the challenge of treating patients with NHL since it may be manifested in different ways, prognostic markers have been developed whose main objectives are: to provide adequate prediction of survival to guide the choice of treatment and identify unique subsets of patients that allow the rational identification of therapeutic targets; for this purpose the international prognostic index was created, which is a tool to predict the future of a patient with aggressive NHL based on the number of negative prognostic features found at diagnosis.
Factors that generally have been associated with poor prognosis include > 60 years, stage III/IV or disseminated, increased DHL, B symptoms, abdominal mass greater than 10 cm in diameter, three or more extra-nodal sites, bone marrow involvement, and low-grade histology transformation,3,6 while the ECOG group identified a 5-year survival of 26-73% in disease with involvement of 2 or more extra-nodal sites.16 The staging currently used is the Ann Arbor staging (Table I), stages I and II cover 35-40% of NHL and have good prognosis (95% survival); stages III and IV have unfavorable prognosis (stage III survival is 75% and stage IV somewhat lower).1,2 Therapeutic regimens used should account for histologic type of NHL, age, extent of the disease, and risk factors. Historically radiotherapy had been used as a treatment of choice but it was inadequate, 15% of patients relapsed;3 currently the standard therapy for NHL management for decades has been the CHOP regime (cyclophosphamide, doxorubicin, vincristine, and prednisone). Systemic treatment is critical given the rapid growth and early metastatic spread; the role of surgery has been limited to very specific situations.1,2 Extra-nodal lymphomas should be treated as nodal disease, aggressive lymphomas treated with combination chemotherapy, resulting in 80% 5-year survival, showing 10-30% improvement over radiotherapy alone.3 Treatment currently has incorporated the use of monoclonal antibodies for the treatment of NHL. Rituximab is a therapeutic IgG1 chimeric monoclonal antibody that binds specifically with CD20, on the surface of normal and malignant B lymphocytes. Upon binding, the body's immune response is activated to lyse the marked B cells. In patients treated with refractory NHL, rituximab was found to have an effectiveness in 50%.4,6,10 The Gela (Groupe d'etude de lymphome d'adultes) study showed the benefit of adding rituximab in patients > 65 years newly diagnosed with cell NHL, indicating improvement in the cure rate of this population. At the same time, this study found that increased β2- microglobulin > 3 mg/L combined with more than one site of extra-nodal disease is a negative prognostic factor in survival,19 while the MabThera International Trial (MINT) study investigated it in young patients < 60 years,20 showing satisfactory results with the new scheme, so that the use of CHOP with rituximab is proposed as first-line therapy for diffuse B cell NHL.6,7
|Table I Ann Arbor staging|
|Stage I||Involvement of a single lymph node region (I) or a single extra-nodal site or organ (I-E)|
|Stage II||Involvement of two or more lymph node regions on the same side of the diaphragm (II) or localized involvement of extra-nodal site or organ (II-E) and one or more region of the lymph nodes on the same side of the diaphragm|
|Stage III||Involvement of lymph node regions on both sides of the diaphragm (III), which may be accompanied by localized involvement of an extra-nodal site or organ (III-E) or spleen (IIIS) or both (III-ES)|
|Stage IV||Diffuse or disseminated involvement of one or more extra-nodal distant organs, with or without associated involvement of lymph nodes|
Within the treatment one must consider the side effects that it can cause, especially tumor lysis syndrome, a metabolic emergency defined by the presence of electrolyte disturbances accompanied, or not, by kidney failure. Tumor destruction implies the release of products that exceed the capacity of renal excretion, and is defined as at least two of the following changes: increase in serum creatinine twice the normal value; serum uric acid > 7 mg/dL; serum phosphorus > 3 mmol/L; serum potassium > 6 mmol/L; serum calcium < 2 mmol/L, or calcium-phosphorus product > 5.
Current management includes hyper-hydration, correction of metabolic disturbances, and increased removal of uric acid.1,2,7
Up to 40% of patients with lymphoma tend to present residual masses after completion of the initial treatment, but less than 20% relapse; studies show that patients with advanced disease have relapses in different sites of the initial disease.3 As mentioned above, several studies have shown increased uptake of FDG in most lymphomas, so that 18FDG PET/CT is a technique with greater sensitivity and specificity (over 80 and 90% respectively). Thus one of the main objectives of PET-FDG will be to provide the clinic with the tumor’s metabolic response to treatment, identifying whether residual masses correspond to viable tumor tissue or fibrotic or inactive lesions. As for the NHL, fundamentally diffuse large cell lymphoma, this technique has shown a positive predictive value of 90-100% and a negative predictive value of 80-84% in the evaluation of residual lesions at the end of treatment.9 Based on the above, the patient showed the presence of hypodense mass without metabolic activity, confirming the response to treatment.
Our case corresponded to an unusual clinical presentation, despite the challenge that extra-nodal NHL represents due to its diverse clinical presentations; diagnostic approach is essential to establish a correct staging and treatment. The prognostic markers should also be considered that give a guideline on the future of the disease, in this case the patient was in an advanced stage and with poor prognosis, despite this, correct and timely diagnosis made it possible to establish treatment with excellent results.
Conflict of interest statement: The authors have completed and submitted the form translated into Spanish for the declaration of potential conflicts of interest of the International Committee of Medical Journal Editors, and none were reported in relation to this article.