Lymphadenopathy and Splenomegaly (Case 29)

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Lymphadenopathy and Splenomegaly (Case 29)

Bridgette Collins-Burow PhD, MD

Case: A 21-year-old healthy woman presents to her gynecologist in March for her yearly Pap smear. Upon further questioning she reports fatigue, persistent upper respiratory symptoms with a nonproductive cough, as well as persistent low-grade fever for several months. She also reports a weight loss of about 10 pounds over the past several months and attributes this to the fact that she was attempting to lose weight. She denies any travel, sick contacts, or high-risk sexual behaviors. Her physical examination is remarkable for two firm, palpable, rubbery, left anterior cervical nodes that measure 2 cm in diameter. She is reassured by her physician and prescribed a 10-day course of oral penicillin.

Four weeks later, these lymph nodes are still present, and she feels that her left neck is “slightly fuller and tender.” Clearly upset about the swelling in her neck, she returns to her primary-care physician. In addition to her previous pertinent positive findings, on review of systems, she reports early satiety and night sweats. She has looked on the Internet for alternative explanations for her symptoms, and she is nervous now about the possibility that she may have lymphoma. She has lost an additional 7 pounds and is noted to have a palpable spleen on physical examination, in addition to both cervical and axillary lymphadenopathy. Her CBC and peripheral blood smear are normal.

Differential Diagnosis

Hodgkin lymphoma	Non-Hodgkin lymphoma (NHL)	Mononucleosis/EBV infection
Sarcoidosis	Primary HIV infection	Mononucleosis/EBV infection

Speaking Intelligently

When I encounter a patient with lymphadenopathy, I always take a detailed medical history and perform a complete physical examination. Of greatest concern is the possibility of malignancy. While the prevalence of malignancy in the general population presenting with unexplained lymphadenopathy is low, there are both historical and physical clues that can be suggestive of a diagnosis, including the age of the patient, the duration of lymphadenopathy, whether the lymphadenopathy is localized or generalized, the location of the lymphadenopathy, and associated clinical symptoms. Rubbery lymph nodes often suggest the diagnosis of lymphoma, whereas carcinomatous nodes are usually hard. Splenomegaly, in association with lymphadenopathy, focuses the differential on infectious mononucleosis, primary HIV infection, lymphomas, and sarcoidosis. When malignancy is of concern, excisional biopsy of a node is necessary to establish the diagnosis.

PATIENT CARE

Tests for Consideration

• Heterophile antibody test: This test is sensitive for the diagnosis of EBV infection; however, the test will be negative early after infection and will be negative if the mononucleosis is caused by other infections, such as CMV. If the test is negative, serologic assays for specific agents should be considered.	$9
• HIV RNA testing: Could be considered in the setting of a high-risk patient with symptoms of acute HIV infection with a negative enzyme-linked immunosorbent assay (ELISA) and Western blot, which may represent the “window period” before seroconversion.	$120
• Serum angiotensin-converting enzyme (ACE) concentration: Although some studies report an elevated ACE concentration in approximately 75% of patients with sarcoidosis, it is both an insensitive and a nonspecific test.	$30
• Excisional lymph node biopsy: The preservation of the nodal architecture is critical in the evaluation of lymphoma. In patients with Hodgkin lymphoma, the pathologic interpretation based on histology and the putative malignant cell, the Reed-Sternberg cell, is necessary for diagnosis. In patients with non-Hodgkin lymphoma, histologic, cytologic, and immunologic features as well as cytogenetic abnormalities are all instrumental in the classification. Fine-needle aspirates are never adequate to diagnose lymphoma.	$570
• Bone marrow biopsy and aspirate: Important in evaluating disease involvement outside of the lymphatic system in patients with lymphoma.	$500

Clinical Entities

Medical Knowledge

Hodgkin Lymphoma
Pφ	Hodgkin lymphoma is characterized by the presence of the Reed-Sternberg cell. The exact mechanism by which these cells derive and their role in the malignant process remain unclear. The majority of these cells are monoclonal B cells believed to be derived from preapoptotic germinal-center cells that have lost the capacity to express a high-affinity B-cell receptor. Reed-Sternberg cells are therefore able to subvert the apoptotic process.
TP	The typical presentation of Hodgkin lymphoma is a young, otherwise healthy individual who presents with painless or slightly tender, rubbery lymphadenopathy in a single group of lymph nodes. Hodgkin lymphoma has a biphasic incidence with a peak in young adulthood and in the fifth decade. The most common nodal areas of involvement in a young patient include cervical, axillary, and mediastinal nodes. Hodgkin lymphoma can occur in the presence or absence of B symptoms (i.e., fever, weight loss, night sweats).
Dx	Diagnosis of Hodgkin lymphoma requires an excisional biopsy of a lymph node with review by a hematopathologist. To make the diagnosis with certainty, the Reed-Sternberg cell, or a variant, must be identified. Histologic classification of Hodgkin lymphoma includes the following: (1) nodular/lymphocyte predominant, (2) lymphocyte-rich classical, (3) nodular sclerosis, (4) mixed cellularity, and (5) lymphocyte depleted.
Tx	Accurate diagnosis and staging are critical in the treatment of Hodgkin lymphoma. All stages of Hodgkin lymphoma are treated with intent to cure. Hodgkin lymphoma is sensitive to radiation and several chemotherapeutic regimens. ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) is a commonly used chemotherapeutic regimen. See Cecil Essentials 51.

Non-Hodgkin Lymphoma
Pφ	NHL is a heterogeneous spectrum of diseases characterized by a malignant clonal expansion of B or T cells that occurs through genetic alterations involving a wide spectrum of proto-oncogenes and/or tumor suppressors.
TP	There is a tremendous variation in clinical presentation of this spectrum of diseases. Follicular lymphomas, which constitute approximately one-third of all cases of NHL, are considered a low-grade lymphoma and typically present in mid- to late adulthood, are slow growing, and may evolve over years. The majority of these patients have disseminated disease at diagnosis. On the other hand, diffuse large B-cell lymphoma is an intermediate-grade lymphoma that constitutes approximately 40% of all cases of NHL. These patients typically present with one or more rapidly growing nodal sites, and approximately half have evidence of disseminated disease at presentation.
Dx	Diagnosis of NHL requires an excisional lymph node biopsy demonstrating lymphocyte destruction of the normal architecture of the tissue. Histologic, cytologic, and immunologic features, along with cytogenetics, are utilized for further classification.
Tx	Treatment of NHL is based on the aggressiveness of each histologic type. The take-home message is that low-grade lymphomas, such as follicular lymphoma, have an indolent course and are characterized by repeated relapses. Generally speaking, it is considered an incurable disease; therefore, the standard of care with regard to treatment in advanced-stage disease in an asymptomatic individual has often entailed an observational approach. The initiation of treatment is dictated by the development of symptomatic disease or development of cytopenias requiring supportive therapy. Many treatment options have been established in the literature, including the use of chemotherapy, monoclonal antibodies, and more recently chemoimmunotherapy with maintenance immunotherapy. In contrast, intermediate- or high-grade lymphomas, such as diffuse large B-cell lymphoma, are considered potentially curable with aggressive therapy. In this setting, chemoimmunotherapy with CHOP-R (cyclophosphamide, doxorubicin, vincristine, prednisone, rituximab) is the standard of care. There are also prognostic indices that can be utilized to define therapy, such as the International Prognostic Index (IPI) and the Follicular Lymphoma International Prognostic Index (FLIPI) scores; these scores are based on pretreatment characteristics found to be independent predictors of death. See Cecil Essentials 51.

Mononucleosis/EBV
Pφ	It is estimated that approximately 90% of cases of infectious mononucleosis are caused by EBV. B cells become infected upon contact with EBV-infected epithelium of the oropharynx and salivary glands. Enlargement of lymphoid tissue occurs with the expansion of EBV-infected B cells and reactive T cells.
TP	While a childhood infection is often subclinical, it is estimated that approximately 30% of adolescents and young adults will present with the classic triad of fever, pharyngitis, and generalized lymphadenopathy. Other reported symptoms and signs include headache, GI symptoms, splenomegaly, hepatomegaly, and rash.
Dx	The heterophile antibody test is a diagnostic test for evaluation of infectious mononucleosis due to EBV infection; 90% of cases are heterophile positive. The basis of this test is the Paul-Bunnell antigen, which is present on the surface of EBV-infected cells. In heterophile-negative cases, determination of EBV antibodies may be helpful to establish the diagnosis.
Tx	Supportive care. Corticosteroids may be helpful in complicated cases—tonsillar enlargement causing airway compromise, autoimmune hemolytic anemia, severe thrombocytopenia, and aplastic anemia. See Cecil Essentials 51, 95.

Sarcoidosis
Pφ	Sarcoidosis is a multisystem disorder of unknown cause. Affected organs demonstrate an accumulation of T lymphocytes and mononuclear phagocytes, noncaseating epithelioid granulomas, and distortion of normal tissue architecture.
TP	Although sarcoidosis can be discovered as an incidental finding on chest radiograph in an asymptomatic person, many clinical presentations can include constitutional symptoms of fever, fatigue, and weight loss. The typical presentation of sarcoidosis includes cough, dyspnea, chest discomfort, and polyarthritis. Hilar lymphadenopathy has been estimated to occur in 75% to 90% of patients. Splenomegaly has been estimated to occur in 5% to 10% of patients. The eyes and skin may also be involved.
Dx	A diagnosis of sarcoidosis is made by clinical presentation, radiographic studies, and the presence on biopsy of noncaseating granulomas, with exclusion of other causes of the abnormalities such as infection.
Tx	First-line therapy for sarcoidosis is corticosteroids. The most difficult dilemma is often when and if therapy should be initiated. Spontaneous remission of disease has been reported in up to two thirds of patients. See Cecil Essentials 18, 95.

Primary HIV Infection
Pφ	The acute HIV syndrome is estimated to occur in approximately 50% to 70% of individuals within 2 to 6 weeks after primary infection. This acute viral syndrome is proposed to be secondary to wide dissemination of the virus and the retrafficking of lymphocytes.
TP	The typical presentation is characterized by symptoms consistent with many acute viral syndromes, including such symptoms as fever, pharyngitis, lymphadenopathy, headache, fatigue, weight loss, mucocutaneous lesions, and GI symptoms.
Dx	Diagnosis of HIV in the setting of the acute HIV syndrome is particularly difficult because it usually precedes by several weeks the development of HIV-specific antibodies detected by screening measures (ELISA/Western blot analysis). HIV RNA testing could be considered in the setting of a high-risk patient with symptoms of acute HIV infection with a negative ELISA and Western blot, which may represent the “window period” before seroconversion.
Tx	There is a lack of randomized clinical data that demonstrate a value in initiating highly active antiretroviral therapy (HAART) during the acute HIV syndrome. See Cecil Essentials 95, 108.

a. Other infectious causes of lymphadenopathy and splenomegaly: include mycobacterial infections such as tuberculosis and disseminated fungal infections such as histoplasmosis. Appropriate stains of excised lymph nodes may confirm the diagnosis.

b. Autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus: can present with lymphadenopathy and splenomegaly. Specific serologic studies will establish the diagnosis.

c. Other malignant diseases in which lymphadenopathy and splenomegaly can be observed: include chronic and acute myeloid and lymphoid leukemia, Waldenström macroglobulinemia, and amyloidosis.

d. In certain storage diseases, such as Gaucher disease, as well as in certain endocrinopathies such as hyperthyroidism, lymphadenopathy and splenomegaly may be observed.

Practice-Based Learning and Improvement: Evidence-Based Medicine

Title
Chemotherapy plus involved-field radiation in early-stage Hodgkin’s disease

Authors
Ferme C, Eghbali H, Meerwaldt JH, et al.

Institution
EORTC-GELA (Groupe d’Etudes des Lymphomes de l’Adulte) H8 trial results as of January 2006

Reference
N Engl J Med 2007;357:1916–1927

Problem
Radiation therapy with or without combination chemotherapy in treating patients with previously untreated stage I or stage II Hodgkin lymphoma

Intervention
Patients with favorable prognostic features were randomized to subtotal nodal radiation therapy or combination therapy consisting of three cycles of MOPP (mechlorethamine, vincristine, procarbazine, prednisone)-ABV (doxorubicin, bleomycin, vinblastine) plus involved-field radiation therapy. Patients with unfavorable prognostic features were randomized to one of three regimens: six or four cycles of MOPP-ABV plus involved-field radiation therapy or four cycles of MOPP-ABV plus subtotal nodal radiation therapy.

Quality of evidence
Level I

Outcome/effect
In the patients with the favorable prognostic features, the difference in the estimated 5-year event-free survival rate was 24 percentage points (95% confidence interval [CI], 18 to 29; P < 0.001), favoring the combination-therapy group consisting of three cycles of MOPP-ABV plus involved-field radiation therapy. There were 19 deaths in the group receiving subtotal nodal radiation therapy and 4 in the combination-therapy group. The 10-year overall survival estimate was significantly higher in the combination-therapy group (97%) than in the group receiving subtotal nodal radiation therapy (92%, P = 0.001). In the patients with the unfavorable prognostic features, there were no significant differences in the 5-year event-free survival estimates or estimated overall survival among the three groups.

Historical significance/comments
This study demonstrated that patients with favorable prognostic features can no longer be treated with subtotal nodal radiation therapy alone. The new standard of care should be a combination of chemotherapy and radiation therapy based on an increased event-free survival rate and overall survival. The standard treatment is three courses of doxorubicin-containing regimen followed by involved-field radiation therapy. This study supports the use of four cycles of a doxorubicin-containing regimen and involved-field radiation therapy in patients with unfavorable prognostic features as the standard of care.

Interpersonal and Communication Skills

Avoid Technical Terms and Medical Jargon

When communicating with patients, be mindful to avoid technical terms and medical jargon that you would use with colleagues. This matter is particularly important when discussing oncologic issues. Offer explanations using clear and simple language. Here are a few suggestions to keep in mind when talking to patients.

Instead of saying	Say
Inoperable	Can’t be cured by an operation
Malignant	Cancerous
Metastasized	Cancer has spread
Monitor	Keep an eye-on; check
Noninvasive	Without surgery or cutting skin
Oncologist	Cancer doctor
Palliative care	Will provide symptom management
Radiology	X-ray department
Referral	Send to another doctor
Toxic	Poisonous
Ventilator	Breathing machine

From Mann BD. Surgery: a competency-based companion. Philadelphia: Elsevier; 2009, p. 205.

Professionalism

Show Commitment to Professional Excellence and Lifelong Learning

The importance of commitment to lifelong learning in the profession of medicine is clearly illustrated in the fields of hematology and medical oncology. What we know today to be the standard of care will not necessarily remain the standard of care tomorrow. The treatment of Hodgkin lymphoma is a success story in this field. Over the past four decades advances in the field of radiation oncology and the introduction of combination chemotherapy have improved the cure rates of this disease to as high as 80% to 90%. This advancement has been driven by the scientific research that works to gain an understanding of the biology of the disease and in doing so serves as the basis for the establishment of clinical trials.

Systems-Based Practice

Respond to Critical Laboratory Results

In patients with lymphoma who are treated with chemotherapy, certain laboratory parameters may need to be periodically monitored, and critical test results must be addressed in a timely manner (i.e., called to the physician within 60 minutes of the result becoming available) to avoid the possibility of adverse outcome. The following process should be utilized in the hospital setting by the staff informed of the critical value:

images Always use two patient identifiers to ensure the correct patient.