Effect of clinical history on diagnostic accuracy in the cytologic interpretation of bronchial brush specimens
Summary: There has been little study of the effect of clinical history on pathologic diagnostic accuracy. Five pathologists retrospectively examined 97 bronchial brush specimens with and without clinical historic information. Forty-nine patients had a biopsy-proven malignant lesion, and 48 had a benign lesion. Diagnostic accuracy with and without history for each pathologist was determined with likelihood ratios and receiver operating characteristic curves. The overall diagnostic accuracy with and without history was 0.84 and 0.76, respectively. The average negative predictive value of a benign diagnosis decreased from 89.2% (with history) to 74.0% (without history). Overall, the cytopathologists were more reluctant to make a definitive malignant diagnosis without history compared with history. The average positive predictive value of a malignant diagnosis with and without history was almost identical. The absence of history leads to lower diagnostic accuracy in the cytologic interpretation of bronchial brush specimens partly because pathologists underdiagnose malignant lesions.
Comment: Although it has been documented and accepted that any requisition for pathology, laboratory medicine and radiology should have some clinical history information in their requisition form, pathologists are frequently frustrated by the absence of such data. This problem can be seen more or less in any country, but the condition is apparently worse in developing countries like Iran. At some institutions, unfortunately, we are dealing with phrases such as "specimen for biopsy" without any data about patient’s history or the clinical impression. Sometimes even the name, sex and age of the patient is missing in their requisition forms. There have been numerous studies about the outcome of such errors that affect the accuracy of diagnostic pathology and there are over 100 titles in PubMed from January 1998 which indicate the importance and prevalence of this problem, both in cytology and histopathology.
In the study summarized above, Dr. Raab and his colleagues who were from different hospitals of the USA, discuss the differences between knowing and not knowing clinical history information on a simple specimen such as bronchial brushing. It seems simple because there is least confusion regarding the identity of the specimen as well as the patient’s condition. The outcome of such cytopathologic reports on specimens with known or unknown history is significantly variable. Interpretation of soft tissues, bone lesions, breasts FNA or BAL as in case of lung diseases are more difficult. Many cytopathologists are unanimous that clinical history improves diagnostic accuracy of cytological or FNA interpretations in such lesions. This goes also for histologic interpretations, which need more clinical information about the patient’s history. Pathologic interpretation of endometrial curetting products or bone, skin, liver, kidney and pulmonary parenchyma biopsies could lead to potential misinterpretations for the clinician if the necessary clinical information are missing. In another observation, Dr. Layfield et al. calculated the proportion of correct precise diagnosis with the knowledge of clinical history and the expertise of pathologists. They have found that clinical history increased the proportion of correct diagnosis and the accuracy of the classification for all observers. Experienced observers more accurately classified lesions and knowing the clinical history, particularly improved the diagnostic accuracy in less experienced observers (Layfield et al. Am J Clin Pathol. May 1999).
There are some arguments regarding this matter. Some practitioners argue that pathologic diagnosis is a laboratory test and it should be used in a Bayesian manner to calculate the post-test probability of disease from the pre-test probability of disease. They believe that clinical history should not be provided because it produces a bias favoring the pre-test probability of disease. And their argument is that pathologists should just "read the slide", express the diagnostic probabilities and leave the interpretation to the clinician. Some other practitioners do not use the pathologic diagnosis in a Bayesian manner and suffice to the differentiation between benign versus malignant diagnosis. But it is strongly believed that withholding clinical information can cause more damages and may lead to a less definitive diagnoses which in turn disfavors patient’s care. Knowledge of the patient’s clinical history is mandatory for accurate interpretation of pathologic changes in the specimens, and more clinical information yield more accurate diagnosis and better management of the patient.
Moslem Bahadori MD, FCCP, Professor of Pathology, Consultant Pathologist NRITLD
Source: Raab SS, Oweity T, Hughes JH, Salomao DR, Kelley CM, Flynn CM, D’Antonto JA, Cohen MB. Am J Clin Pathol. 2000; 114: 78-83.
Treatment of hepatitis C infection
Summaries: 1) Chronic hepatitis C virus (HCV) infection in patients with cirrhosis is difficult to treat. In patients with chronic hepatitis C but without cirrhosis, once-weekly administration of interferon modified by the attachment of a 40-kd branched-chain polyethylene glycol moiety (peginterferon alfa-2a) is more efficacious than a regimen of unmodified interferon. We examined the efficacy and safety of peginterferon alfa-2a in patients with HCV-related cirrhosis or bridging fibrosis. We randomly assigned 271 patients with cirrhosis or bridging fibrosis to receive subcutaneous treatment with 3 million units of interferon alfa-2a three times weekly (88 patients), 90 microg of peginterferon alfa-2a once weekly (96), or 180 microg of peginterferon alfa-2a once weekly (87). Treatment lasted 48 weeks and was followed by a 24-week follow-up period. We assessed efficacy by measuring HCV RNA and alanine aminotransferase and by evaluating liver-biopsy specimens. A histologic response was defined as a decrease of at least 2 points on the 22-point Histological Activity Index. In an intention-to-treat analysis, HCV RNA was undetectable at week 72 in 8 percent, 15 percent, and 30 percent of the patients treated with interferon alfa-2a and with 90 microg and 180 microg of peginterferon alfa-2a, respectively (P=0.001 for the comparison between 180 microg of peginterferon alfa-2a and interferon alfa-2a). At week 72, alanine aminotransferase concentrations had normalized in 15 percent, 20 percent, and 34 percent of patients, respectively (P=0.004 for the comparison between 180 microg of peginterferon alfa-2a and interferon alfa-2a). In the subgroup of 184 patients with paired liver-biopsy specimens, the rates of histologic response at week 72 were 31 percent, 44 percent, and 54 percent, respectively (P=0.02 for the comparison between 180 microg of peginterferon alfa-2a and interferon alfa-2a). All three treatments were similarly tolerated. In patients with chronic hepatitis C and cirrhosis or bridging fibrosis, 180 microg of peginterferon alfa-2a administered once weekly is significantly more effective than 3 million units of standard interferon alfa-2a administered three times weekly.1
2) Covalent attachment of a 40-kd branched-chain polyethylene glycol moiety to interferon alfa-2a results in a compound (peginterferon alfa-2a) that has sustained absorption, a slower rate of clearance, and a longer half-life than unmodified interferon alfa-2a. We compared the clinical effects of a regimen of peginterferon alfa-2a with those of a regimen of interferon alfa-2a in the initial treatment of patients with chronic hepatitis C. We randomly assigned 531 patients with chronic hepatitis C to receive either 180 microg of peginterferon alfa-2a subcutaneously once per week for 48 weeks (267 patients) or 6 million units of interferon alfa-2a subcutaneously three times per week for 12 weeks, followed by 3 million units three times per week for 36 weeks (264 patients). All the patients were assessed at week 72 for a sustained virologic response, defined as an undetectable level of hepatitis C virus RNA (<100 copies per milliliter). In the peginterferon group, 223 of the 267 patients completed treatment and 206 completed follow-up. In the interferon group, 161 of the 264 patients completed treatment and 154 completed follow-up. In an intention-to-treat analysis in which patients who missed the examination at the end of treatment or follow-up were considered not to have had a response at that point, peginterferon alfa-2a was associated with a higher rate of virologic response than was interferon alfa-2a at week 48 (69 percent vs. 28 percent, P=0.001) and at week 72 (39 percent vs. 19 percent, P=0.001). Sustained normalization of serum alanine aminotransferase concentrations at week 72 was also more common in the peginterferon group than in the interferon group (45 percent vs. 25 percent, P=0.001). The two groups were similar with respect to the frequency and severity of adverse events, which were typical of those associated with interferon alfa. In patients with chronic hepatitis C, a regimen of peginterferon alfa-2a given once weekly is more effective than a regimen of interferon alfa-2a given three times weekly.2
Comment: Hepatitis C virus infection has emerged as a major global health problem in recent years. Considering the reported prevalence of 1:1000 of anti HCV antibody positivity among healthy Iranian blood donors, an estimated 195,000 of the Iranian population are infected with this virus3, almost half of them may need treatment. Until recently, the only available treatment for these patients was interferon alfa with a sustained virologic response of only 10%. Combination of interferon alfa with ribavirin is now considered as the treatment of choice for chronic hepatitis C infection.4 Recent introduction of peginterferon was another progress in the treatment of hepatitis C. Attaching the large molecule of polyethylene glycol (Peg) to interferon increases its half-life while decreasing its clearance. This, in turn, increases the extent and duration of interferon’s therapeutic activity and allows for the once weekly dosing. These two trials demonstrate that peginterferon is more effective than interferon monotherapy. Comparison of these preliminary data with data on interferon/ribavirin suggests that monotherapy with pegylated interferon will not be as effective as the current choice, which is combination therapy using interferon/ribavirin. However, it is anticipated that pegylated interferon/ribavirin will be more effective than standard interferon/ribavirin. Compared with standard interferon, pegylated interferon appears to be better tolerated, more convenient and therefore may succeed as a therapeutic modality for those who cannot tolerate interferon/ribavirin or maintenance therapy.
K. Bagheri Lankarani MD
Folate deficiency beyond megaloblastic anemia: hyperhomocysteinemia and other manifestations of dysfunctional folate status
Summary: Folate plays a key role in nucleic acid synthesis. As a consequence, the most conspicuous complication of folate deficiency or of derangements of folate metabolism is megaloblastic macrocytic anemia caused by interdiction of normal proliferation of rapidly dividing bone marrow cells. Other rapidly dividing cells, including those in the gastrointestinal tract, may also be affected by the megaloblastic process. This may result in malabsorption. However, there is mounting evidence to indicate that there are other earlier manifestations of folate deficiency or of longstanding suboptimal folate nutrition. Chief among these manifestations of folate deficiency are an increased predisposition to occlusive vascular disease and thrombosis, which have been linked to increased levels of homocysteine found in folate deficiency and abnormal states of folate metabolism. In addition, folate deficiency, previously considered free of neurological consequences, is now known to be associated with disturbances of mood, and even spinal cord syndromes similar to those seen in vitamin B12 deficiency. Finally, there is both experimental and clinical evidence to suggest that folate deficiency may interfere with immunologic status and may be associated with an increased predisposition to neoplasia. Nutritional as well as genetic factors may contribute to these various nonhematological manifestations of folate insufficiency.
Comment: Folates are no longer considered a simple medication for the treatment of megaloblastic anemia secondary to malabsorption, poor diet intake, or increased demand. Regarding this report, similar studies have been performed. Folate supplementation should be provided by nurses and physicians involved in public health. Folate fortification of food was begun in a few countries with little controversy.2, 3 It is our concern that at least the high-risk groups including children, pregnant women, chronically ill patients, patients with cardiovascular disorders and neuropsychiatric patients should receive folate supplementation. We must attempt to develop advanced laboratory tests, to detect these patients in the early stages of folate deficiency.
H. Nourani Khojasteh MD, Shiraz, Iran
Source: Green R, Miller JW. Semin Hematol. 1999; 36: 47-64