Tag Archives: Cancer

Tongue Pigmentation Following Chemotherapy


A 56 year old woman presented with a history of a lump in the breast for 2 weeks. A fine needle aspiration confirmed the diagnosis of breast carcinoma for which she underwent modified radical mastectomy. She has a 3.5cm X 2 cm grade three infiltration duct carcinoma that was ER -ve, PR -ve and HER2 -ve. She had 5 positive axillary nodes with perinodal extension. She was initiated in chemotherapy with FEC (Epirubicin 100mg/mg/m2, Cyclophosphamide 500mg/m2 and 5-Fluorouracil 500mg/m2). She developed tongue pigmentation which increased with each cycle turning the entire tongue bleu-black after four cycles when this picture was taken.

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!

Pseudomyxoma Peritonei

A 62 year old male who had been operated for a carcinoma of the rectum presented with pain and distension of the abdomen. The CT scan showed a fluid with a density more than simple fluid and scalloping of the liver. A diagnosis of pseudomyxoma peritonei was made. There was no evidence of a rectal tumour.

The term pseudomyxoma peritonei was used by Werth to describe a patient with ruptured ovarian cystadenoma and gelatinous intraperitoneal material. It is a term used to describe a clinical picture associated with release of intraperitoneal mucin from malignant and benign tumours. The malignant tumours associated with pseudomyxoma peritonei are low grade tumours, usually of the appendicular ovarian origin. The cells produce mucin but have a very low metastatic potential. This results in a predominant intraperitoneal growth resulting in accumulation of mucin and severe abdominal dissention and symptoms.

The CT scan shows scalloping of the liver and spleen. Scalloping is distortion of the liver/spleen margins because of extrinsic pressure of adjacent peritoneal implants without liver parenchymal metastasis. There is ascitic fluid that is slightly denser than simple fluid density. Occasionally amorphous calcifications may be seen. Primary tumour is usually not visible at diagnosis. Scalloping of the liver and ascitic fluid with a greater than fluid density is seen on this scan.

The outcome of pseudomyxoma peritonei depends of the malignant potential and the origin of the tumour responsible for pseudomyxoma. Appendiceal tumours have the best outcome and gastric tumours have the worst outcome. Tumours which show invasive features have a worse outcome.

The disease is treated by surgical debunking. Intraperitoneal chemotherapy may be given. Hyperthermic intraperitoneal chemotherapy (HIPEC) or early post-operative intraperitoneal chemotherapy (EPIC) may be given. HIPEC is associated with better tolerability, lesser adverse effects and better survival.

Mediastinal Adenopathy with Brain lesions

A 26 year old male patient presented with fever of five days duration. The complete haemogram showed a haemoglobin of 13.2g/dL, WBC count of 13500/mm3 with a differential count of 75% polymorphs, 21% lymphocytes, 2% eosinophils and 2% monocytes and a platelet count of 232,000/mm3. The smear did not show plasmodium and the serology for dengue and HIV was negative. The liver and kidney functions and the X-ray Chest was normal.

A CT scan of the chest was performed which showed mediastinal adenopathy which showed patchy enhancement on injection of contrast. The site was deemed as inaccessible for a biopsy

The patient was initiated on four drug anti-tuberculous therapy. The fever subsided in a week.

About two weeks after discharge the patient has a left sided seizure with unconsciousness. He was admitted to the hospital anti-convulsants given and an MRI of the brain preformed.

The MRI showed multiple ring enhancing lesions in the bilateral fronto-parietal temporal lobes with significant peri-lesional oedema and a significant midline structures to the left due to the right frontoparafalcine lesion.

Lymphoma is a highly curable tumour that mimics tuberculous lymphadenitis. Delay in treatment of high grade lymphomas compromises the chance of cure. Lymph node biopsy is an invasive procedure sometimes needing laparotomies and thoracotomies. The issues that arise when a lymph node is relatively inaccessible are:

Is biopsy needed for all patients with lymphadenopathies?

Patients with lymphadenopathy and an infective/inflammatory pathology in the drained areas need not be biopsied. Patients with inflamed nodes need not be biopsied. Patients with deep seated nodes in whom a certain diagnosis can be made by non-invasive tests need not be biopsied. All other patients should be biopsied. FNAC, unless it yields a specific diagnosis, is an inadequate investigation for lymphadenopathy. An excision biopsy is ideal. A large wedge biopsy is acceptable for large nodes and a trucut biopsy is appropriate for deep seated nodes. Many patients have succumbed to an advanced lymphoma because of delayed diagnosis from an inappropriate or inadequate biopsy. From the pathologists point of view the diagnosis of lymphoma may be one of the most challenging. Not everyone is experienced enough to make the diagnosis. Even the experienced pathologists can only report on the material provided. Providing appropriate material is the responsibility of the clinician. When one is treating on a clinical diagnosis the patients needs a close monitoring for signs of treatment failure and an alternative diagnosis.

Is there a blood test for the diagnosis of lymphomas?

Lymphomas are of two types Hodgkin’s and non-Hodgkin. Non-Hodgkin’s lymphoma is a collection of about 30 distinct malignancies of the lymphoid cells. Non-Hodgkin’s lymphomas have a leukaemic phase i.e. the phase when the malignant cells spill into the blood. Leukaemic phase occurs early in the course of the disease in patients with low grade lymphomas e.g. small lymphocytic lymphoma, follicular lymphomas and splenic marginal zone lymphomas and very high grade lymphomas e.g. Burkitt’s lymphoma and lymphoblastic lymphoma. The leukaemic phase of small lymphocytic lymphoma is chronic lymphocytic leukaemia and that of very high grade lymphomas is acute lymphoblastic leukaemia. Blood tests can only diagnose lymphomas which are in the leukaemic phase. There are no other blood tests for the diagnosis of lymphomas

Does an MRI scan differentiate a lymphoma from tuberculosis?

A tuberculous granuloma caseates resulting in ring enhancement and oedema around the lesion. The other ring enhancing lesions include primary brain tumour (glioblastoma), metastasis (especially post chemotherapy), abscess, Toxoplasma and Cryptococcus in HIV, resolving hematoma (10-21 days), radiation necrosis, and aneurysm. The MRI features of a primary CNS lymphoma in an immune competent host are quite distinct. The tumour is isointense on T1 and show pronounced uniform enhancement and very little peri-lesional oedema. Ring enhancement is seen rarely. In immunocompromised patients ring enhancement, multiple lesions, spontaneous haemorrhage and non-enhancing lesions are common making it difficult to distinguish CNS lymphoma from infections in these patients. A patient with high index of suspicion of lymphoma must undergo a biopsy.

Could these CNS lesions be from a lymphoma?

The MRI picture is inconsistent with a lymphoma in an immune competent patient. Synchronous CNS and systemic lymphomas are very rare and have been reported only in immunocompromised patients. One report of AIDS related lymphomas described synchronous CNS involvement in 5/19 patients (Annals of Oncology 18 (Supplement 9): ix178–ix182, 2007, abstract 71). Synchronous CNS involvement has also been described in a child with immunodeficiency J Pediatr Hematol Oncol. 2008 Apr;30(4):317-9. Isolated CNS relapse from a lymphoma is seen in less than 1% of the patients. This patient was treated as 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).

Osteoporosis Therapy Reduces the Risk of Breast Cancer

The drug therapy of postmenopausal osteoporosis includes hormone replacement therapy, selective oestrogen receptor modifiers (SERMS) and bisphosphonates. Unlike hormone replacement therapy and SERMS bisphosphonates do not carry the risk of breast cancer. In fact, in vitro studies have shown that bisphosphonates may have an anti-cancer effect and this effect may not be limited to bone metastasis. There are two classes of bisphosphonates nitrogen containing (alendronate, risedronate, zoledronate and ibandronate) and those without nitrogen (clodronate, etidronate). Nitrogen containing bisphosphonates have anti-cancer properties. Are women receiving bisphosphonates for osteoporosis protected from cancer?

Two recently published studies suggest that bisphosphonates taken for osteoporosis reduce the risk of cancer. The Women’s Health Initiative Observational Study, that included 154,768 women receiving bisphosphonates for osteoporosis suggest that bisphosphonates reduce the risk of breast cancer by 32%. The Breast Cancer in Northern Israel Study showed a 28% risk reduction in breast cancer in receiving bisphosphonates for osteoporosis. An earlier study has shown a 33% reduction in breast cancer with the use of bisphosphonates.

Breast cancer is one of the most common cancers in women. Breast cancer accounts for about one million cancers per year. Bisphosphonates could prevent 300,000 of these. Should bisphosphonates be used for chemoprophylaxis of breast cancer?

Bisphosphonates are associated with rare serious adverse effects including gastric and oesophageal ulcers, jaw necrosis and possible atrial fibrillation and increased risk of oesophageal carcinoma. Use of bisphosphonates for chemoprophylaxis of breast cancer would expose normal individuals to this risk. Unless the benefits of bisphosphonates in breast cancer prevention are documented in a controlled trial, bisphosphonates can not be recommended for use in prophylaxis of breast cancer. However the reduction in the risk of breast cancer may be a reason of choosing bisphosphonates over other drug therapy for osteoporosis.