Tag Archives: Cancer Diagnosis

Hodgkin’s Lymphoma – Pitfalls in Diagnosis


Hodgkin’s lymphoma has been known for over 175 years. For about 140 of these the malignant nature of the disease was not certain. The hallmark of Hodgkin’s lymphoma is the Reed-Sternberg cell, which was described independently by Dorothy Reed (1902) and Carl Sternberg (1898). Neither considered Hodgkin’s lymphoma malignant. Diagnosis of Hodgkin’s lymphoma is a challenge even today as the case discussed illustrates.

A 21 year old male presented with a swelling of the right side of the neck and fever. Examination revealed cervical lymphadenopathy. No other nodes were enlarged. An FNAC was reported as chronic lymphadenitis. Anti-tuberculous therapy was started. The lymph nodes increased over the next three months and the fever failed to abate. This was attributed to a paradoxical reaction to treatment and the anti-tuberculous therapy was continued. The patient sought a second opinion after four months of therapy. A lymph node biopsy was performed and a diagnosis of Hodgkin’s lymphoma was made. When staged this patient has stage IIIB Hodgkin’s lymphoma.

The common cause of lymphadenopathy are infections – bacterial, viral, mycobacterial or fungal; malignancy – lymphomas or metastatic; and autoimmune diseases. Lymphadenopathy of acute infection resolves spontaneously or following treatment with antibiotics. These nodes are usually inflamed and tender and are rarely confused with malignancy. Persistent lymphadenopathy is commonly due to tuberculosis, malignancy or autoimmune diseases and needs investigation.

Fine needle aspiration cytology (FNAC) is performed by aspirating material, usually using a 21 or 22 gauge needle, and smearing it onto a slide. It has the advantage of being less invasive than a biopsy. The processing time for FNAC is short and reports are often available on the same day. On the flip side only a small part of the lymph node is sampled and the process of smearing disrupts architecture. FNAC is best for diagnosis of malignancies where a diagnosis can be made by examination of single cells e.g. squamous cell carcinoma or an adenocarcinoma.  FNAC has limitations in the diagnosis of lymphoma. A negative report does not exclude the diagnosis of lymphoma and all lymphomas can not be classified by FNAC.

Though described by Thomas Hodgkin in 1928, it was only in 1967, when the Reed-Sternberg cell was shown be clonal by cytogenetics, that Hodgkin’s lymphoma was proven to be a malignancy. The two terms prevalent for the disease, Hodgkin’s disease and Hodgkin’s lymphoma reflect the uncertainty about the pathogenesis of Hodgkin’s lymphoma. Hodgkin’s Lymphoma is a lymphoma that almost always arising from the B lymphocytes. What makes Hodgkin’s lymphoma different from other common B cell lymphomas like follicular lymphoma or diffuse large B cell lymphoma?

Most of the cells in non-Hodgkin’s lymphomas like diffuse large B cell lymphoma are malignant. Most of the cells in Hodgkin’s lymphoma are reactive cells – lymphocytes, eosinophils, neutrophils, histiocytes and plasma cells (figure 1). The lymphadenopathy of Hodgkin’s lymphoma is because of normal cells whereas the lymphadenopathy of diffuse B lymphocytic lymphoma or a follicular lymphoma is because of malignant cells. The lymphadenopathy of tuberculosis or any other chronic inflammatory process is due to a reactive infiltrate, much like Hodgkin’s lymphoma. FNAC of a lymph node of a diffuse large B cell lymphoma shows malignant cells making diagnosis possible. FNAC of a node involved by Hodgkin’s lymphoma is most like to give a normal inflammatory infiltrate making it impossible to differentiate between Hodgkin’s lymphoma and a cause of chronic lymphadenopathy like tuberculosis. If a Reed-Sternberg cell is seen on FNAC a diagnosis is possible, but given the paucity of the Reed-Sternberg cell in Hodgkin’s lymphoma this rarely happens. FNAC is appropriate for the initial evaluation of a lymphadenopathy, but a biopsy should to be performed when the results of FNAC are not diagnostic.

Figure 1. Histology of Hodgkin’s lymphoma. The malignant cell of Hodgkin’s lymphoma is the Reed-Sternberg (RS) cell. The RS cell is surrounded by a reactive infiltrate consisting of T-lymphocytes along with a varying number of eosinophils, neutrophils, histiocytes and plasma cells. A node involved by Hodgkin’s lymphoma has very few RS cells. The bulk of the node is made up by normal cell. (Modified from http://www.flickr.com/photos/euthman/3884125493/)

Eleven to fifteen percent of the patients with tuberculosis have a paradoxical reaction after starting anti-tuberculous therapy characterized by increasing fever and worsening of clinical and X ray findings (Eur J Clin Microbiol Infect Dis 2003;22:597-602). Paradoxical reaction was first described by Chloremis in 1955 (Am Rev Tuberc 1955;72:527-36) and may be seen 14-270 days after starting anti-tuberculous therapy (Eur J Clin Microbiol Infect Dis 2002;21:803-9). Tuberculoproteins released as a result of rapid killing of bacteria are responsible for paradoxical reaction. Paradoxical reaction in a patient who has been initiated on anti-tuberculous therapy on the basis of diagnosis of tuberculosis made by FNAC, unlike those diagnosed on biopsy, raises the possibility of lymphoma.

Diagnosis of Hodgkin’s lymphoma is not complete without immunophenotyping. This is best done on a biopsy specimen. Given the limitations of FNAC in the diagnosis of lymphoma, it is ideal to perform an excision biopsy of the lymph node if a definitive diagnosis is not possible by FNAC. In case an excision is not possible a large wedge biopsy should be performed. Deep seated lymphomas can be diagnosed by a needle (Tru-Cut) biopsy. The specimen must be sent to a pathologist with experienced and equipment to diagnose lymphoma.

Every oncologist practicing in regions of the world where tuberculosis is prevalent sees patients who have been diagnosed with advanced Hodgkin’s lymphoma after months of anti-tuberculosis therapy. FNAC is an attarctive test in a resource constrained practice but the limitations need to be appreciated. The clinician must understand what the pathologist is trying to say. A report of “chronic lymphadenitis”  must not be treated as tuberculosis. The pathologist must not say more than what the FNAC shows. Every “chronic lymphadenitis” is not tuberculosis!