Lymphadenopathy

Today we discussed the unfortunate case of a 25 year old young man presenting with a multitude of complaints, including 4-weeks of right shoulder pain, 8-months of lower back pain, head ache, RUQ pain, dyspnea, non-productive cough, night sweats, and an "intentional" weight loss of ~30 pounds over 2 months. He had recently returned from South America, where he had spent the past few months.

We generated a broad differential diagnosis for this diffuse constellation of complaints. The 3 main categories we reviewed were:

1) Neoplasm - hematologic vs. solid organ (ie: testicular, given his gender and age)

2) Infectious - TB, liver abscess, amoebic infection, liver fluke, malaria, infectious endocarditis

3) Inflammatory - inflammatory bowel disease, SLE, sarcoidosis

A CT scan revealed multiple lesions within the liver as well as porta hepatis and para-aortic lymphadenopathy. Large volume lymphadenopathy was also seen in the chest, along with some lytic bone lesions. The clinical picture, along with these imaging findings, raise the most likely diagnosis to lymphoma.

Lymphomas are a heterogeneous group of cancers arising from the reticuloendothelial and lymphatic systems, which often present as solid tumors of lymphoid cells. Historically lymphomas have been categorized as Hodgkins Lymphoma (HL) or Non-Hodgkin Lymphoma (NHL), but as we learn more and more about these cancers the classifications are constantly being upgraded. Currently lymphomas are still broadly categorized as HL and NHL, with the latter group being further subclassified based on the type of cell from which they originate: B-cell, T-cell, or Natural Killer cell.

HL results from clonal transformation of cells of B-cell origin, giving rise to the pathognomic Reed-Sternberg cells. The cause is unknown, but genetic susceptibility and environmental associations are thought to play a role. HL is slightly more common in patients with immunosuppression secondary to post-transplant drugs, congenital immunodeficiency, HIV, and autoimmune diseases (SLE, RA, Sjogren's, etc.). Patients often present with painless lymphadenopathy, that can become painful after consumption of alcohol... for no clear reason! Usually the lymphadenopathy arises in one area and spreads in a contiguous manner. The classic "B symptoms" are often described: fever, night sweats, and unintentional weight loss. Diagnosis requires a lymph node core biopsy +/- a fine needle biopsy. Depending on the specific type of HL identify on pathology, and the stage at diagnosis, treatment usually involves chemotherapy +/- radiation therapy, surgery, or stem cell transplant.

NHL is also a disease of clonal transformation, most often of B-cells, but different subtypes of NHL can develop as a result of clonal transformation of T-cells or Natural Killer cells; classification depends on immunophenotyping, genotyping, and cytogenetics. NHL is much more common than HL. Immunosuppressed patients are also at risk for NHL. The exact etiology of NHL is yet to be discovered, but it is hypothesized that a viral cause may be at play. Patients often present again with painless lymphadenopathy; however, in NHL they can often have multiple areas of involvement. Occasionally patients can present with SVC syndrome secondary to compression of the SVC from nodal enlargement, or acute renal failure secondary to obstruction of the ureters from retroperitoneal or pelvic lymph nodes.

Diagnosis requires a lymph node core biopsy for nodal architecture as well as immunophenotyping and cytogenetics for subclassification of the lymphoma. Full imaging with CT of the chest/abdo/pelvis and a BM biopsy is required for staging +/- a PET scan (this image shows lymphoma with increased uptake of 18-FDG in the brain, chest, and spleen). Although not fully validated in clinical settings, PET scans can be used in the proper setting, as determined by the oncologist and the radiologist.

Staging of NHL follows the Cotswold Modified Ann Arbour Staging. Prognosis is generally better for those with B-cell NHL compared to T-cell NHL. The International Prognostic Index (IPI) is used to help guide clinicians and patients with aggressive lymphomas. There are 5 risk factors with the IPI, and outcomes deteriorate as the number of risk factors increases.

1) Age over 60

2) Poor performance status measured by the ECOG (Eastern Cooperative Oncology Group)

3) Elevated LDH

4) More than 1 extranodal site

5) Stage III or IV disease

Patients in the highest IPI risk group (4-5 risk factors) have a 50% survival rate at 5-years, whereas those in the lowest IPI risk group (no risk factors) have a very high cure rate. Modifications to the IPI have been made to account for diffferent NHL, including the FLIPI (follicular lymphoma) and the R-IPI (diffuse large B-cell lymphoma).

Treatment for NHL is again specific to the subtype of lymphoma and the stage at diagnosis; however, it generally incorporates chemotherapy "R-CHOP" (rituximab (anti-CD20 monoclonal antibodies), cyclophosphamide, doxorubicin, vincristine, prednisone), radiation therapy, or both +/- stem cell transplantation.

Here is a great review article on the approach to a patient with lymphadenopathy.