Category 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

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!

Does Screening Reduce Prostate Cancer Mortality?

The risk of prostate cancer increases with age. Men aged 50 or less have a risk of less than one in 30000. This rises to one in 625 for men above the age of 75 years. The corresponding figures for the USA are one in 476 and one in 9 and Japan are one in 31250 and one in 444. The US rates are about 70 times more than Mumbai or Japan.

Race and environmental factors appear to play an important role in prostate cancer. The table below shows the prostate cancer incidence in the US in 2010. The prostate cancer incidence (per 100,000 population) in the US increased from 94.02 in 1975 to 237.21 in 1992 before settling down to 163.06 in 2006. In the same period the annual death rates increased from 30.97 to 39.22 before finally settling down to 23.56. The five year survival which was 68.9 in 1975-1977 increased to 99.9 in 1999-2005. What were the reasons for this apparent epidemic of prostate cancer?

Early diagnosis of cancer means better cure. Screening tests, tests that are performed on individuals with no symptoms to detect occult cancer, are used with the hope of improve the survival of cancer patients. The Pap smear for carcinoma cervix, mammography for breast carcinoma and stool occult blood testing for early detection of colorectal carcinoma are few such tests. Prostatic specific antigen (PSA) is a protein exclusively produced by the prostate gland. PSA estimations with digital rectal examination are used to screen for prostate cancer.

Before the introduction of prostate cancer screening, a large number of patients with prostate cancer presented with locally advanced or metastatic disease. Only palliative treatment could be offered to these patients. Use of PSA has increased the detection rate of prostate cancer and has been responsible for the increase in the incidence of prostate cancer seen during and after the 1990s. Patients whose prostate cancer is detected by PSA screening have smaller and lower grade disease. The disease is more often restricted to the prostate allowing curative treatment. There is also a belief that some cancer so detected would never have caused a problem.

Is there evidence from clinical trials to support the contention that early diagnosis of prostate cancer means better treatment? Why do you need evidence to support something that is so obvious and common sense? It is necessary to understand the cost of a positive screening test.

Sensitivity is the number of patients with a disease who have a positive test. A sensitivity of 100% means no individual with disease has a negative result. The primary aim of a screening test is not to miss out any individual with disease. An individual who is declared to be free of disease by a screening test would become complacent, take symptoms lightly and is likely to present with advanced cancer. A screening test needs to be very sensitive to ensure that no individual with disease is declared disease-free.

Sensitive tests overdiagnose. Specificity of a test determines how many individuals the test diagnoses incorrectly as having disease. A specificity of 100% means there is no incorrect diagnosis. In practice there are tradeoffs between sensitivity and specificity. Sensitive tests tend to be less specific. A disease like cancer needs to be diagnosed with certainty before treatment is initiated. A confirmatory test needs to be performed in patients with a positive screening test to make a definitive diagnosis of cancer. The confirmatory tests come with costs, discomfort and risks.

A positive PSA is followed by a rectal ultrasound and multiple transrectal biopsy of the prostate. Even if the results of confirmatory tests are negative, patients worry about being diagnosed prostate cancer (J Gen Intern Med. 2006 Jul;21(7):715-21). Prostatic biopsy is associated with fever, pain, hematospermia, hematuria, positive urine cultures, and rarely sepsis (Urology. 2002 Nov;60(5):826-30). Finally, radical proctectomy, the treatment for localized prostate cancer, is associated with incontinence and sexual dysfunction. The critical question given the risks, complication and cost of confirmatory tests and therapeutic intervention is, does prostate cancer screening reduce mortality?

Many trials evaluating the ability of PSA and digital rectal examination to reduce prostate cancer mortality have been conducted, with conflicting results. One of the recently published studies, the ERSPC study, one of the studies with a positive result, concluded that 1410 men would have to be screened, and an additional 48 men would have to be treated (N Engl J Med 2009; 360:1320-1328) to prevent one prostate cancer related death. In societies with a lower incidence prostate cancer the number to be screened would be higher. This trial showed a 20% reduction in prostate cancer related mortality by screening. All experts agree on two issues. The benefits of prostate cancer screening, if any, are seen after a prolonged period (10 years or more) and the harms are apparent immediately.

Some prostate cancers, the low grade and small ones, will never cause problem and may not need treatment. Prostate cancer is a disease of the elderly, a group that suffers from other chronic illnesses like diabetes, hypertension, heart disease and stroke. Many patients with low grade prostate cancer would die with the prostate cancer rather than of prostate cancer. The focus in these patients needs should be the co-morbidity. As oncologists understand indolent prostate tumours better and are able to target treatment to those who are likely to succumb to prostate cancer, the impact of prostate cancer screening will become more evident. We are moving towards that goal but are not there.

What do we tell our patients? The American Cancer Society recommends a digital rectal examination and PSA beginning from the age of 50 years. Having a brother or a father with prostate cancer doubles the risk of prostate cancer and having two or more first degree relatives increases the risk seven to eight fold. These patients need to be screened from an earlier age (40 or 45 years). The patients must be informed that screening will result in further tests that can cause morbidity. The benefits if any would not be seen for at least 10 years after starting screening. The morbidity of the tests will on the other hand be immediate. Patients with less than 10 years to live should not be screened.

Finally, with so much controversy about prostate cancer screening, one wonders if what physicians practice and preach are different. Yes, physicians practice what they preach. About 95% of male urologists and 78% of primary care physicians who are 50 years of age or older report that they have had a PSA test themselves (J Gen Intern Med. 2006 Mar;21(3):257-9).