tall cell variant papillary thyroid carcinoma ( tcv ) was first described in 1976 by hawk and hazard as an aggressive histological variant of papillary thyroid cancer . tcv is defined as tall papillary epithelial cells with a height at least twice the width and basement membrane oriented nuclei comprising at least 30% of the cells within the tumor [ 13 ] . usual variant papillary thyroid cancer describes conventional papillary thyroid carcinoma composed of papillary epithelial cells arranged in papillae with fibrovascular cores without excessive height compared to cell width . the published incidence of tcv is between 3.8% and 10.4% [ 1 , 410 ] . unlike the usually good prognosis of usual variant papillary thyroid cancer ( uv ) , tcv histology is generally reported as an independently poor prognostic factor [ 1 , 3 , 5 , 6 , 8 , 9 ] . more recently reported case series do not show that tcv histology adversely affects prognosis [ 7 , 10 , 11 ] . one such large retrospective study concluded the poor prognosis of tcv tumors was not particularly related to histology but to factors such as stage and grade . another case series found the higher rate of recurrence in tcv was strictly associated with age over 50 . although these more recent studies improved on previously reported studies by increasing the sample sizes , the number of tcv cases still remain small in comparison to the uv group . a reason for the low tcv numbers could be misclassification bias where the diagnosis of tcv is missed by routine pathologic examination . as first described in a case series of 162 papillary thyroid cancers , initial routine pathological examination failed to detect 8 out of 11 cases of tcv . the additional eight cases were discovered only by an experienced pathologist with a special interest in thyroid pathology and familiar with tcv histology . this may lead to erroneous comparisons of recurrence and mortality data between tcv and uv . the purpose of this meta - analysis is to evaluate the prognostic impact of tcv histology in papillary thyroid cancer in currently published studies by comparing tcv and uv disease - related mortality and recurrence data . we hypothesize that the cumulative published evidence supports tcv as a negative prognostic factor as measured by a greater disease - related mortality and recurrence rate than uv . a systematic literature review was conducted on may 23 , 2007 utilizing the ovid search engine to access the medline database . the term  tall cell variant papillary thyroid cancer  was used as a keyword search and yielded 108 articles . the titles and abstracts were carefully reviewed and those evaluating the prognostic implication of tcv histology in papillary thyroid cancer were included for review . the papers were evaluated based on predetermined inclusion and exclusion criteria and their references were reviewed for additionally relevant papers . the primary inclusion criterion was studies that compared prognostic factors in tcv to uv papillary thyroid cancer . exclusion criteria included those with total sample size less than or equal to 15 , non - english reports , and the absence of recurrence and disease - related mortality data for both tcv and uv groups . the medline and bibliography search after application of the inclusion and exclusion criteria yielded six reports that were included in our study ( table 1 ) . both odds ratios and 95% confidence intervals for both recurrence and disease - related mortality were calculated for each of the studies . in the case of a 0 count in a study , 0.5 was added to all the counts for that study to allow calculation of an odds ratio and 95% confidence interval . the next step determined the combined odds ratio of all six studies for recurrence and disease - related mortality . both the fixed effects cochran - mantel - haenszel and a random effects method for binary data were used to calculate combined odds ratios . a fixed effects method gives each study a weighting in accordance to the precision of its estimate whereas a random effects method accounts for variation between studies by giving a relatively larger weight to the less precise studies .   for both the odds of recurrence and mortality , a test for heterogeneity that accompanies the fixed effects , cochran - mantel - haenszel model was significant ( p =  .023 and p =  .033 , resp . ) suggesting that between - study variability was too great for a fixed effects model . as a result , the random effects method to determine the odds ratio was preferred to account for the extra variation between studies . after application of our inclusion and exclusion criteria , six articles were available for review ( table 1 ) . this allows for our study to have the largest number of tcv cases available for evaluation in the literature to the best of our knowledge . reviewing the data from [ 3 , 810 ] , the tcv patients had a higher rate of extrathyroidal extension ( cumulative average of 60.33% patients ) and higher rate of distant metastases at diagnosis ( cumulative average of 15% ) . in addition , the cumulative average of lymph node metastases in tcv cases is 58.12% versus 34.5% in uv cases . the percentage of recurrence and disease - related mortality is also noted to be higher in tcv group versus uv group . the cumulative average disease - related mortality in tcv group is 23.6% versus 1.5% for uv group . the odds ratios calculated by this study for recurrence and disease - related mortality are provided in table 2 . all of the individual study 's odds ratios demonstrate a greater odds of recurrence in the tcv subjects compared to the uv subjects . the odds ratios are statistically significant in all the studies except the prendiville et al . study . all the calculated odds ratios for individual study disease - related mortality similarly demonstrated an increased rate of disease - related mortality in tcv subjects compared to uv subjects ; however , only three of the six studies [ 6 , 9 , 10 ] had statistically significant odds ratios where the confidence interval did not include one .   the combined odds ratios for recurrence and disease - related mortality using both the fixed and random effects methods are provided in table 3 . the test for heterogeneity ( p =  .023 ) that accompanies the random effects method in determining the odds of recurrence indicates the random effect method would be preferable to account for the extra between - study variation by giving a relatively larger weight to the less precise studies . although both combined odds ratios of recurrence demonstrate a greater rate of recurrence in the tcv subjects compared to uv subjects , the preferred random effects model odds ratio suggests that recurrence occurs with 4.50 times greater odds in tcv tumors versus uv tumors and that this is statistically significant ( 95% ci 2.906.99 ) . similarly , the combined odds of disease - related mortality is greater for tcv subjects compared to uv subjects regardless of whether a fixed versus random effects method is used . using the preferred random effects model , the odds of disease - related mortality in tcv patients are 14.28 times greater than uv patients . tcv is a negative prognostic indicator in papillary thyroid cancer . by performing a meta - analysis on published research , we hoped to overcome the limitations of small sample sizes of individual articles to examine the impact of such a rare histological subtype on prognosis . additionally , we found tcv has a 14.28 times greater disease - related odds of mortality compared to uv . we also noted higher trends in lymph node metastasis , distant metastasis , and extrathyroidal extension in tcv patients versus uv patients . the adverse effects of tcv on prognosis , as represented by our study , necessitate a careful and perhaps more aggressive approach than typically followed with uv . whereas partial thyroidectomy ( defined as thyroid lobectomy with or without isthmusectomy ) is an acceptable conservative approach to patients with low - risk uv for recurrence and mortality ( by ames criteria ) , our research suggests a more aggressive approach for tcv ( e.g. , total thyroidectomy with central neck dissection ) may be indicated . the problem at hand is that tcv is detected at pathological evaluation , which occurs after the initial thyroid surgery has been performed . hence , we propose that if a newly diagnosed patient with tcv has undergone partial thyroidectomy , then the patient should return to the operating room for at least a completion thyroidectomy and central neck dissection followed by radioactive iodine ablation of residual tissue . if a total thyroidectomy was performed at initial surgery , then careful consideration should be given for return to the operating room for a central neck dissection ( depending on surgeon experience ) followed by radioactive iodine ablation versus radioactive iodine ablation alone . if the tumor is not radioactive iodine avid , then early intervention with external beam radiation should be considered . additional issues , such as longer follow - ups and extensive screening for distant metastasis , may also be warranted . a recent review of papillary thyroid cancer variants recommended an aggressive approach to tcv   with at least a total thyroidectomy . in a recent matched - pair analysis comparing tcv patients to the matched uv cohort , 5-year disease specific survival was poorer in the tcv cohort ( 81.9% versus 91.3% , p =  .049 ) . the number of deaths in the tcv cohort was higher than in the matched papillary thyroid cancer cohort ( p =  .043 ) . this study further affirms the results of our study showing higher rate of recurrence and mortality in tcv patients . our results stress the necessity of accurate pathological diagnosis . since the discovery of tcv in 1976 , the ability to study and evaluate the prognostic implications of histology in papillary thyroid cancer resides solely on accurate pathological identification . hence , there is no substitute for an experienced pathologist in the management of this disease . firstly , we have large confidence intervals which reflect the variation between studies and the relatively small number of studies included in the meta - analysis . this is also reflected in the test of heterogeneity that we performed that directed us to use the random effects model rather than the fixed effects model . in addition , the articles by segal et al .   and terry et al .   did not have data on patient age , tumor size , lymph node metastasis , extrathyroidal extension , or distant metastases . these articles were included due to the presence of recurrence and disease - related mortality data . in conclusion , the data supports tcv as a poor prognostic factor as determined by disease - related mortality and recurrence rates . as a result , this data supports early aggressive surgical and adjuvant radioactive iodine management and the necessity for accurate pathologic diagnosis . it unequivocally supports the absolute need for further study of tvc as an independent prognostic factor in future studies on papillary thyroid cancer .