Validity , reliability , and responsiveness of the Kansas City Cardiomyopathy Questionnaire in anemic heart failure patients Background While generic health status measures quantify the impact of all patients ' diseases on their health-related quality of life , disease specific measures focus on only one of the many conditions that a patient may have . If a patient has two diseases with similar clinical manifestations , they may respond differently to a disease-specific instrument if one of their conditions improves while the other worsens or remains stable , thus undermining the instruments in that patient population . We sought empirical evidence of the reliability and validity -LRB- including responsiveness -RRB- of the Kansas City Cardiomyopathy Questionnaire -LRB- KCCQ -RRB- , a disease-specific measure for heart failure -LRB- HF -RRB- , among HF patients with and without anemia , a condition that has similar symptoms to HF . Introduction The quantification of patients ' health status -LRB- their symptoms , function , and health-related quality of life -RRB- is becoming increasingly important as an endpoint in clinical trials -LSB- 1 , 2 -RSB- , as a means of monitoring patients over time -LSB- 3 -RSB- , and even as a marker of health care quality -LSB- 4 -- 6 -RSB- . Measuring patients ' health status is most commonly accomplished by direct solicitation from patients themselves , using either generic or disease-specific health status questionnaires -LSB- 7 -RSB- . Whereas generic health status measures seek to quantify the health-related quality of life limitations of patients ' ` overall health ' , including all combinations of diseases and ailments , disease-specific measures focus upon a specific disease process . Accordingly , an advantage of disease-specific questionnaires is that they can be both more sensitive to clinical change and more interpretable than general health status questionnaires . Because disease-specific instruments tend to be more actionable to clinicians , they can be useful in monitoring patients ' clinical status over time -LSB- 8 -RSB- . An unresolved challenge in the use of disease-specific measures , however , is whether they perform well when patients have other conditions that may also impact their symptoms , function , and quality of life in ways that are similar to the specific disease of interest . While this is not a problem with generic health status measures , if a co-occurring disease manifests similar effects to a primary disease of interest , and if one of the conditions worsens while the other remains stable or improves , then it is unknown whether the disease-specific measure will accurately measure the status of the disease it is designed to quantify . This can undermine the original validity , reliability and responsiveness of the disease-specific measure . One potential setting in which this type of confounding may occur is in the setting of heart failure and anemia . Heart failure -LRB- HF -RRB- affects over 5 million Americans and is responsible for enormous health care costs and resource utilization -LSB- 9 -RSB- . While several disease-specific measures for patients with HF have been created to quantify HF patients ' health status -LSB- 10 -- 13 -RSB- , the psychometric properties of these instruments have all been demonstrated in patients whose predominant medical condition was heart failure . Recently , however , anemia has emerged as an important co-occurring condition that is prognostically important in HF -LSB- 14 -- 21 -RSB- . Importantly , the symptoms of anemia may mimic those of HF . Specifically , chronic anemia manifests itself in patients as `` fatigue , loss of stamina , breathlessness , and tachycardia , particularly with exertion '' -LSB- 22 -RSB- , coupled with the development of `` gradual fatigue and a reduced exercise tolerance '' -LSB- 23 -RSB- . The symptoms of anemia -LSB- 24 -RSB- are therefore remarkably similar to those of HF , for which breathlessness , reduced exercise tolerance , and fatigue are hallmarks of the disease -LSB- 22 , 23 -RSB- . Because of the overlap in symptomatic manifestations of both diseases , it is not clear whether heart failure-specific health status assessments , such as the Kansas City Cardiomyopathy Questionnaire -LRB- KCCQ -RRB- which captures patients ' perspectives of their disease rather than physiologic or anatomic characteristics -LRB- e.g. their hematorit or left ventricular function -RRB- , would perform similarly in patients with and without anemia . For example , if a patient 's heart failure symptoms improve from an increased use of diuretics , would there be an improvement in their KCCQ scores if their anemia did not change ? Consequently , it is unknown whether the psychometric properties of a disease-specific HF instrument would be similar in anemic and nonanemic HF patients , given the potential for both conditions to induce similar symptoms in patients . The purpose of this analysis was to provide empirical evidence supporting the reliability and validity -LRB- including responsiveness -RRB- of the KCCQ in anemic HF patients . We sought to compare the psychometric properties , including reliability -LRB- internal consistency and test -- retest -RRB- and validity -LRB- including responsiveness to clinical change -RRB- , in anemic and nonanemic HF patients . Methods Patient population The STudy of AneMia IN A Heart Failure Population -LRB- STAMINA-HFP -RRB- was a prospective registry of 1,090 HF patients who were initially enrolled in the outpatient clinics of 58 U.S. cardiology centers . The purpose of STAMINA-HFP was to estimate the incidence and prevalence of anemia in patients with HF and to describe the association of anemia with HF progression . As such , the protocol mandated an initial clinical history and physical exam -LRB- including assignment of the New York Heart Association -LSB- NYHA -RSB- classification -RRB- , a measurement of patients ' hemoglobin , and an assessment of their health status , including the KCCQ . Enrolled patients were contacted by telephone within 1 -- 2 days after their initial enrollment and every 3 months for a period of 1 year to assess their health status . In addition , data from outpatient visits during the year of observation were abstracted at each visit . To be eligible for participation , patients had to be > 18 years of age , diagnosed with a history of symptomatic HF and willing to provide informed consent . Patients who had a prior organ transplant , were planning a major surgery , or were participating in another interventional trial were excluded . Data capture was completed in the STAMINA-HFP registry in July 2004 . Patients participating in this study -LRB- n = 811 -RRB- had to have complete baseline health status assessments and a measure of hemoglobin . They were slightly more likely to be white -LRB- 75 % vs. 68 % , P = 0.03 -RRB- and to not smoke -LRB- 90 % vs. 86 % , P = 0.03 -RRB- but had similar distributions of NYHA class , KCCQ scores , and hemoglobin as compared with the entire cohort of 1,090 patients . For the longitudinal assessments of test -- retest reliability and responsiveness , a 3-month health status assessment was also required from these patients -LRB- n = 698 -RRB- . At the time of follow-up interviews , a patient global assessment of change question , asking patients to describe ` how -LSB- they -RSB- think -LSB- their -RSB- condition has changed compared to the start of the study , ' was also asked at each follow-up interview . Responses were on a 7-point categorical response scale ranging from ` markedly improved ' to ` markedly worse . ' The initial 3-month assessment was used for this study because it was the closest assessment to the time of their anemia evaluation and because it had the shortest recall period with which to assess patients ' perspectives of clinical change of any of the other assessments . The KCCQ is a 23-item , disease-specific measure that quantifies four clinically relevant domains of patients ' health status including physical limitations , symptoms -LRB- frequency , severity , and change over time -RRB- , a heart failure-specific assessment of their quality of life and their perceived social limitations due to heart failure , and a self-efficacy domain -LRB- a measure of patients ' knowledge of how to best manage their disease -RRB- . The four health status scales can be combined into a single , overall summary score -LSB- 10 -RSB- . Scores range from 0 -- 100 , where higher scores indicate better functioning , fewer symptoms , and better disease-specific quality of life . The KCCQs validity and reproducibility have been previously supported and recent studies have demonstrated that both cross-sectional variations -LSB- 25 , 26 -RSB- and changes -LSB- 27 -RSB- in KCCQ scores are prognostic of subsequent mortality and HF hospitalizations . A mean difference between groups of patients and an intra-individual change over time of ≥ 5 points is considered clinically significant . This was established in two studies : a prospective study of 476 outpatients in which a mean change of five points in the KCCQ overall summary scale was observed in those patients who experienced a small , but clinically significant change in their heart failure -LSB- 28 -RSB- and in a prospective study of 1,358 HF patients in which a 5-point change was associated with an 11 % change in the multivariable-adjusted hazard ratio of hospitalization and cardiovascular death -LSB- 27 -RSB- . Classification of anemia Patients were classified as being anemic or not based upon their hemoglobin at the time of study enrollment . Thus , the patients ' hemoglobin value at baseline determined their anemia status throughout the remainder of the study . The World Health Organization -LRB- WHO -RRB- definition of anemia was used -LRB- hemoglobin < 13 g/dl for men , < 12 g/dl for women -RRB- . Statistical analysis The patient population was divided into those with and without anemia , and baseline demographic and clinical characteristics were compared with chi-square tests for categorical variables and t tests for continuous variables . To evaluate the construct validity of the KCCQ in anemic and nonanemic patients , comparisons across NYHA classifications from the baseline interviews were conducted . A two-way ANOVA with KCCQ overall summary score as the dependent variable and baseline anemia classification , NYHA , and an anemia-by-NYHA interaction term as independent variables was constructed to establish whether the association of NYHA and KCCQ was different in patients with and without anemia . Both internal consistency and test -- retest reliability estimates were compared among anemic and nonanemic patients . Internal consistency reliability was estimated using Cronbach 's alpha . This value was calculated independently for patients with and without anemia . Test -- retest reliability was performed using a t test , by comparing the 3-month change in KCCQ scores for patients who responded on the global change in health question that their condition was stable over the previous 3 months . Three months was selected as the interval of analysis to maximize the number of patients included in the analyses , to leverage the existing data in which a 3-month interval was selected , and to replicate the time frame of the original validation studies evaluating the KCCQ -LSB- 10 -RSB- . To compare the responsiveness of the KCCQ in patients with and without anemia , the association of patients ' means change in KCCQ scores with their responses to the global health question were assessed using linear regression . In these linear regression analyses , the mean change in KCCQ scores was used as the dependent variable and baseline anemia status , global assessment of change , and an anemia-by-global assessment of change interaction term were independent variables . As a secondary analysis , patients ' perspectives of their 3-month change in status was categorized into improved -LRB- mildly -- markedly -RRB- , stable -LRB- no change -RRB- , and worsened -LRB- mildly -- markedly -RRB- , and mean change in KCCQ scores were compared for those with and without anemia by these patient-perceived categories of change in health status . All analyses were conducted in SAS version 9.1 -LRB- SAS Institute Inc. , Cary , NC , USA -RRB- . All statistical tests were two-sided and a P value < 0.05 was used as the threshold to declare statistical significance . Results Patient characteristics Overall , 811 patients completed the baseline clinical assessments , including the KCCQ interview , and were used to assess baseline construct validity and internal consistency reliability . Only 4 % of the population had KCCQ scores of 100 , suggesting a minimal ceiling effect of the instrument in this population . Among the patients who completed the baseline assessments , 268 -LRB- 33 % -RRB- met the WHO criteria for anemia . Baseline characteristics of the anemic and nonanemic patients are provided in Table 1 . Compared to nonanemic patients , anemic patients were significantly more likely to be older than -LRB- mean ± SD = 67 ± 13 vs. 63 ± 14 years , P < 0.001 -RRB- , non-Caucasian -LRB- 30 % vs. 23 % , P = 0.03 -RRB- , and to have an ischemic HF etiology -LRB- 46 % vs. 38 % , P = 0.04 -RRB- , diabetes -LRB- 47 % vs. 34 % , P < 0.001 -RRB- , lower glomerular filtration rate -LRB- GFR -RRB- -LRB- 50.8 ± 24.6 vs. 63.9 ± 23.1 ml/min/m2 , P < 0.001 -RRB- , chronic renal insufficiency -LRB- 33 % vs. 15 % , P < 0.001 -RRB- , higher serum creatinine -LRB- 1.7 ± 1.5 vs. 1.3 ± 1.2 mg/dl , P < 0.001 -RRB- , worse NYHA class -LRB- 44 % vs. 32 % class III or IV , P < 0.001 -RRB- , lower KCCQ scores -LRB- 61 ± 23 vs. 65 ± 23 , P = 0.009 -RRB- , and to be treated with diuretics -LRB- 90 % vs. 84 % , P = 0.04 -RRB- . Table 1Baseline clinical characteristics of the populationCharacteristicAnemic -LRB- n = 268 -RRB- Nonanemic -LRB- n = 543 -RRB- P valueAge -LRB- mean + / − SD -RRB- 67.0 + / − 13.162.9 + / − 13.5 < 0.001 Male -LRB- n , % -RRB- 105 -LRB- 39.2 % -RRB- 239 -LRB- 44.0 % -RRB- 0.190Non-Caucasian -LRB- n , % -RRB- 80 -LRB- 29.9 % -RRB- 123 -LRB- 22.7 % -RRB- 0.026 No insurance -LRB- n , % -RRB- 6 -LRB- 2.2 % -RRB- 19 -LRB- 3.5 % -RRB- 0.329 Etiology of HF -LRB- n , % -RRB- 0.038 Hypertensive 49 -LRB- 18.3 % -RRB- 92 -LRB- 17.0 % -RRB- Ischemic124 -LRB- 46.3 % -RRB- 208 -LRB- 38.4 % -RRB- Other95 -LRB- 35.4 % -RRB- 242 -LRB- 44.6 % -RRB- Mean left ventricular ejection fraction -LRB- mean + / − SD -RRB- 36.4 + / − 15.935.9 + / − 16.20.742 Diabetes -LRB- n , % -RRB- 125 -LRB- 46.8 % -RRB- 185 -LRB- 34.1 % -RRB- < 0.001 COPD -LRB- n , % -RRB- 51 -LRB- 19.1 % -RRB- 87 -LRB- 16.0 % -RRB- 0.273 Chronic renal insufficiency -LRB- n , % -RRB- 89 -LRB- 33.3 % -RRB- 82 -LRB- 15.1 % -RRB- < 0.001 Current smoker -LRB- n , % -RRB- 17 -LRB- 6.3 % -RRB- 61 -LRB- 11.2 % -RRB- 0.026 Body mass index -LRB- mean + / − SD -RRB- 30.3 + / − 7.331.1 + / − 7.40.181 NYHA -LRB- n , % -RRB- 0.001 I35 -LRB- 13.1 % -RRB- 99 -LRB- 18.2 % -RRB- II116 -LRB- 43.3 % -RRB- 268 -LRB- 49.4 % -RRB- III105 -LRB- 39.2 % -RRB- 169 -LRB- 31.1 % -RRB- IV12 -LRB- 4.5 % -RRB- 7 -LRB- 1.3 % -RRB- Mean KCCQ overall summary score -LRB- mean + / − SD -RRB- 60.8 + / − 22.865.3 + / − 23.20.009 Current medications -LRB- n , % -RRB- ACE inhibitor/ARB232 -LRB- 86.6 % -RRB- 486 -LRB- 89.5 % -RRB- 0.217 ß-blocker222 -LRB- 82.8 % -RRB- 446 -LRB- 82.1 % -RRB- 0.806 Diuretic240 -LRB- 89.6 % -RRB- 458 -LRB- 84.3 % -RRB- 0.044 Spironolactone76 -LRB- 28.4 % -RRB- 132 -LRB- 24.3 % -RRB- 0.214 Digoxin126 -LRB- 47.0 % -RRB- 245 -LRB- 45.1 % -RRB- 0.610 Mean hemoglobin -LRB- mean + / − SD -RRB- 11.4 + / − 1.114.1 + / − 1.3 < 0.001 Mean creatinine -LRB- mean + / − SD -RRB- 1.7 + / − 1.51.3 + / − 1.2 < 0.001 Glomerular filtration rate -LRB- ml/min/m2 , mean + / − SD -RRB- * 50.8 + / − 24.663.9 + / − 23.1 < 0.001 * Modification of diet in renal disease -LRB- MDRD -RRB- abbreviated formula For the longitudinal analyses of test -- retest reliability and responsiveness , 698 -LRB- 86.1 % -RRB- patients provided both baseline and 3-month assessments . No statistically significant differences in any of the patient characteristics listed in Table 1 were observed between those who did and did not participate in the 3-month interviews . Notably , no difference in anemia classification -LRB- 33.0 % among participants vs. 33.6 % in those without follow-up , P = 0.89 -RRB- or mean hemoglobin -LRB- 13.2 ± 1.8 vs. 13.2 ± 2.1 , P = 0.94 -RRB- was observed between those with and without follow-up . Construct validity Figure 1 illustrates the relationship between the overall KCCQ score by NYHA class in anemic and nonanemic patients . Mean KCCQ scores tracked strongly with NYHA class -LRB- mean summary score ± SE for the entire population = 80.3 ± 1.6 , 68.0 ± 1.0 , 50.9 ± 1.2 , and 45.6 ± 5.4 for NYHA classes I -- IV respectively , P < 0.0001 -RRB- . While the mean KCCQ scores for the patients with NYHA class IV differed substantially , this was likely due to the small numbers of patients in these subgroups , resulting in a large standard deviation of scores -LRB- KCCQ scores in anemic -LSB- n = 12 -RSB- and nonanemic -LSB- n = 7 -RSB- patients = 39.5 ± 20 vs. 56.2 ± 28 -RRB- . Furthermore , the relationship between KCCQ and NYHA did not differ significantly between anemic and nonanemic patients -LRB- P = 0.38 for interaction -RRB- . Fig. 1KCCQ overall summary score by NYHA class in anemic and nonanemic patients Reliability The internal consistency reliability -LRB- Cronbach 's alpha -RRB- of the KCCQ overall summary score for the entire population was 0.93 . In patients who were anemic and nonanemic , the Cronbach alphas were 0.92 and 0.93 , respectively . The mean -LRB- ± SE -RRB- KCCQ overall summary score change in patients who reported no change over 3 months in their clinical condition -LRB- n = 257 -RRB- was − 1.2 ± 0.7 . Among anemic patients -LRB- n = 73 -RRB- the mean change was − 2.8 ± 1.4 , and for nonanemic patients -LRB- n = 184 -RRB- the mean change was − 0.5 ± 0.8 . These mean 3-month changes were similar between anemic and nonanemic patients -LRB- P = 0.14 -RRB- . Importantly , the change between and within both groups was less than five points over time and , thus , not considered clinically significant . The intraclass correlation coefficient for the KCCQ overall summary score was 0.885 in the overall cohort and did not differ among those with and without anemia -LRB- 0.865 for anemic patients and 0.892 for nonanemic patients -LSB- P = 0.11 -RSB- -RRB- . Responsiveness To compare the sensitivity of the KCCQ to patients ' perceptions of change , the mean change in KCCQ scores across each category of change were compared in anemic and nonanemic patients . Figure 2 describes the means and 95 % confidence intervals of change in KCCQ scores across crude categories of improved -LRB- mild to marked -RRB- , no change , and worsening -LRB- mild to marked -RRB- of their overall clinical status during the first 3 months of the study . No significant differences by anemia status were detected within any of the three categories of reported health change . In regression analysis , mean 3-month KCCQ change was found to be linearly related to reported health change , with a slope of − 2.7 points -LRB- 95 % CI = -LSB- − 3.6 , − 1.9 -RSB- -RRB- per 1 step down on the Likert-scale response . Nonlinearity was tested using cubic splines and was found to be nonsignificant -LRB- P = 0.68 -RRB- . The association was consistent in both anemic and nonanemic patients -LRB- slope estimates = − 3.4 -LSB- 95 % CI = -LRB- − 5.0 , − 1.8 -RRB- -RSB- vs. − 2.5 -LSB- 95 % CI = -LRB- − 3.4 , − 1.6 -RRB- -RSB- , P-value = 0.33 -RRB- . Fig. 2Three-month KCCQ change by reported health change and anemia status Discussion We report empirical evidence to support the reliability and validity -LRB- including responsiveness -RRB- of the KCCQ in HF patients with anemia . We found similar associations between the KCCQ overall summary score and NYHA classification , similar internal consistency and test -- retest reliability in stable patients , and similar responsiveness of the KCCQ to patients ' perceptions of 3-month clinical change . In light of the potential overlap in symptoms between anemia and HF , we tested and rejected the hypothesis that the psychometric properties of the KCCQ might differ between HF patients with and without anemia . Thus , the KCCQ could be a valid , reliable , and responsive outcome for clinical trials of anemia treatment in HF . To date , there has been a paucity of literature examining attribution of symptoms to one of a spectrum of potentially co-occurring diseases in patient-reported health status assessments . A common recommendation for the design of clinical trials is to include both disease-specific and generic measures of health status . These recommendations are predicated upon the desire to capture the impact of treatments on a specific disease of interest , as well as the overall impact of treatment on patients ' health outside the condition of interest . The latter intended to capture side effects or other unanticipated complications of therapy . However , since patients are often only aware of the symptoms that they experience , and not the underlying pathophysiology that is responsible for those symptoms , it is unclear whether a distinct pathophysiology -LRB- e.g. anemia -RRB- could confound the psychometric properties of a disease-specific health status measure quantifying a disease with similar clinical manifestations -LRB- e.g. HF -RRB- . While a review of the literature and an independent investigation of Rijken et al. demonstrated that co-occurring diseases are associated , as expected , with worse scores on general health status measures , they did not examine the influence of co-occurring diseases on disease-specific instruments -LSB- 29 -RSB- . To examine the relative performance of generic and disease-specific instruments , Ren and colleagues demonstrated , in both cross-sectional -LSB- 30 -RSB- and longitudinal -LSB- 31 -RSB- analyses , that disease-specific measures outperformed generic measures in terms of their content and discriminative validity among veterans with multiple comorbidities . However , these latter studies did not focus upon the ability of a disease-specific measure to be a psychometrically valid representation of the disease of interest when another co-occurring illness may manifest similar symptoms . One research situation in which one disease has similar symptoms to another is depression and heart failure . Numerous studies have documented that depressed patients have worse health status than nondepressed patients -LSB- 32 -- 35 -RSB- , yet both depression and heart failure can manifest symptoms of fatigue . Interestingly , Rumsfeld et al. were able to demonstrate that depression was associated with worse KCCQ scores over time , regardless of baseline scores , and that among nondepressed patients , poorer health status was associated with a greater likelihood of becoming depressed -LSB- 36 -RSB- . These studies did not address whether the KCCQ was equally valid in both depressed and nondepressed patients , but did show important interrelationships between diseases that can have similar clinical manifestations . Several potential limitations of this article should be considered in interpreting our findings . First , validation is always difficult to establish given the absence of a criterion standard for a patient-centered outcome such as health status . We selected the NYHA classification because it is a commonly used metric with which to quantify HF patients ' health status . Yet the reproducibility and interobserver variability of NYHA assessments is known to be lower than directly soliciting such data from patients themselves . -LSB- 37 -RSB- . A second concern is that our assessments of change in HF came from a global patient-reported estimate of change . At best this is a crude assessment and much more detailed examinations of clinical change in the KCCQ have been conducted -LSB- 28 -RSB- . Although the quantitative assessments of change in KCCQ scores may be different than in previous studies , there is no a priori reason to suspect that these patient-reported assessments of global change would differ by patients ' anemia status . Therefore , finding similar associations between 3-month change in KCCQ scores and patients ' global assessments of change between those with and without anemia supports the fact that the responsiveness of the KCCQ to clinical change is similar in both populations of patients . In addition , concluding that no differences exist in the performance characteristics of the KCCQ in anemic and nonanemic patients could be incorrect due to a type II error . However , the point estimates for all of our analyses were extremely similar and included more than 800 patients , which is greater than six times as large as the original study documenting the reliability and validity -LRB- including responsiveness -RRB- of the KCCQ -LSB- 10 -RSB- . Finally , 12 % of patients were lost to follow-up and we can not exclude the introduction of a potential bias from failing to include these patients . Supporting the generalizability of our study , however , is the similar degree of association between KCCQ scores and NYHA classification , the similar estimates of internal consistency and test -- retest reliability , and similar responsiveness observed in this population as seen in other studies testing the psychometric properties of the KCCQ -LSB- 10 , 28 -RSB- . In summary , we provide empirical evidence to support the ability of a disease-specific measure of heart failure patients ' health status , the KCCQ , regardless of the presence of anemia . As such , we believe that patient-reported health status outcomes are a valid , reliable , and sensitive means to quantify the impact of anemia treatment on HF-specific outcomes . Given that the improvement in patients ' health status is a primary goal of treatment , being able to accurately capture HF patients ' health status in trials of anemia therapy are important . The KCCQ should be a valid and sensitive measure for accomplishing these goals .

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O O O O O O O O O O O O O O O B O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O B I O O O O O O O O O B O O O O O O O O B I O O O O O O O O O O O O O O O B O O O O O O O O O O O O B I O O O O O O O O O O O O O O O B I O O O B O O O O O O O O O O O O O O O O O O


Luteal regression : a redefinition of the terms The corpus luteum is a transient endocrine gland that is specialized for the production of progesterone and that plays a critical role in the establishment and maintenance of pregnancy . The life span of the corpus luteum varies between species and , within a species , can be dramatically altered by events such as mating or pregnancy . Regardless of the duration of its life span , the corpus luteum eventually enters a dynamic regression process during which it loses the capacity to produce progesterone and undergoes structural involution . The overall process of luteal regression has been referred to by a variety of terms over the last several decades . In Table 1 , we show the results of a cursory MEDLINE/PubMed search on luteal regression performed in November of 2002 , which reveals that the most frequently utilized term for this process is `` luteolysis , '' followed by `` luteal regression , '' and then , to a lesser extent , by `` functional luteolysis '' and `` structural luteolysis . '' Other terms , such as `` luteal involution , '' `` functional luteal regression , '' or `` structural luteal regression '' lag far behind in usage . The necessity of using several keywords to search for information on luteal regression is illustrated by the fact that in our sample MEDLINE/PubMed search , only 47 % of the manuscripts retrieved using the keyword `` luteal regression '' were also retrieved when using the keyword `` luteolysis . '' This inconsistency in terminology can result in serious under-retrieval and under-citation of papers using less popular keywords . Table 1 Results of a cursory MEDLINE/PubMed search performed on November 2002 using the terms as listed . Rank Terms Total Number of Articles Retrieved Retrieval Period Number of Articles Retrieved for Period 2001 -- 2002 1 `` luteolysis '' 1251 1967 -- 2002 96 2 `` luteal regression '' 403 1966 -- 2002 35 3 `` functional luteolysis '' 82 1973 -- 2002 5 4 `` structural luteolysis '' 72 1969 -- 2002 14 5 `` luteal involution '' 41 1978 -- 2002 8 6 `` functional luteal regression '' 10 1984 -- 2002 0 7 `` structural luteal regression '' 5 1988 -- 2002 1 To quote Rossdale and Cox in their communication entitled Terminology : a mark of scientific progress -LSB- 1 -RSB- : `` Scientific terminology must be as exact as is possible within the state of knowledge available . '' As our knowledge of the molecular mechanisms participating in the process of luteal regression evolves , some of the commonly used terms cited above have been rendered obsolete , inappropriate , and even incorrect . The foremost of these is `` luteolysis , '' still one of the most common terms used to define the process of luteal regression , most probably because it is listed among Medical Subject Headings -LRB- MeSH -RRB- , and , therefore , used most frequently . MeSH is the U.S. National Library of Medicine 's controlled vocabulary used for indexing articles in PubMed . MeSH terminology provides a consistent way to retrieve information that may use different terminology for the same concepts . In MeSH , `` luteolysis '' is defined as `` degradation of corpus luteum '' and further described as '' ... characterized by the involution and cessation of its endocrine function . '' From a cell biology point of view , `` lysis '' means `` rupture of cell plasma membrane , leading to the release of cytoplasm and the death of the cell '' -LSB- 2 -RSB- . If interpreted with strict accordance to the Latin , lysis refers to `` disintegration , '' as recently discussed by Davis and Rueda -LSB- 3 -RSB- . Over the last decade , it has become clear that the involution of the corpus luteum is associated with a phenomenon of programmed cell death or apoptosis -LSB- 4 -RSB- . Because apoptosis is an organized process that does not involve a major inflammatory response , and because the majority of cells are removed prior to rupture , the term `` lysis '' when applied to luteal regression is largely inaccurate . Therefore , while the term luteolysis remains very popular -- 1251 manuscripts were retrieved using the word `` luteolysis '' and only 403 were retrieved using the terms `` luteal regression '' in the MEDLINE/PubMed search -LRB- see Table 1 -RRB- -- this term no longer accurately reflects the mechanisms involved in luteal regression . In 1999 , McCraken et al. -LSB- 5 -RSB- stated that `` the term luteolysis may be something of a misnomer ; '' but also referred to the deep entrenchment of this term in the literature . However , the exponential increase in the number of scientific manuscripts published in recent years ensures that a prompt move to replace the older term with a more accurate descriptor will rapidly result in an overturn of the current ranking displayed in Table 1 and that only a minority of papers will continue to be retrieved using the older term . Despite the fact that a strict definition of `` luteolysis '' appears to regard only the structural disintegration of the corpus luteum , broader interpretations are rife within the literature . Rothchild -LSB- 6 -RSB- defined luteolysis as `` stopping the secretion of progesterone by the corpus luteum . '' Two other recent reviews take a middle road . Hoyer -LSB- 7 -RSB- refers to the fall in progesterone secretion as functional regression but considers structural regression , or cell death , the `` true '' regression . Niswender et al. -LSB- 8 -RSB- , while referring to luteal regression as the structural demise of the corpus luteum , go on to describe the loss of progesterone synthesis and secretion -- not a structural event -- as part of the regression of the corpus luteum . As the previous paragraph shows , the adjectives `` structural '' and `` functional '' can not be overlooked when addressing terminology in the field of luteal regression . These words have had a consistent presence in literature concerning the regression of the corpus luteum since Malven and Sawyer -LSB- 9 -RSB- described the process of luteal regression in the rat as having two components : `` 1 -RRB- an initial termination of luteal secretory function and 2 -RRB- a subsequent morphological regression of the nonfunctioning corpora lutea . '' A few years later Malven et al. -LSB- 10 -RSB- used the term `` structural luteolysis '' to describe the morphological regression of persistent , nonfunctional corpora lutea in the hypophysectomized rat . The definition of `` nonfunctional '' provided in this manuscript expanded upon the 1966 description of the first component of luteal regression in the rat by explaining that the corpora lutea `` did not secrete enough progesterone to induce deciduoma formation following endometrial traumatization . '' Thus , the corpora lutea were `` nonfunctional '' in terms of progesterone production and the potential for establishment of pregnancy . Since the appearance of these early papers , the terms functional and structural regression of the corpus luteum -LRB- or the more popular phrasing `` functional and structural luteolysis '' -RRB- have gained relative acceptance and usage . The cursory MEDLINE/PubMed search shown in Table 1 turned up 82 references containing the phrase `` functional luteolysis , '' of which 5 were 2001 and 2002 publications , and 72 references containing the phrase `` structural luteolysis , '' of which 14 were 2001 and 2002 publications . The prevalence of the term `` structural luteolysis '' over `` functional luteolysis '' in recently published articles may be due in part to a greater disparity in the perceived meaning of the latter term . This stems largely from studies in rats , in which it was revealed that corpora lutea which no longer secreted significant quantities of progesterone retained many functions , including active steroidogenesis -LSB- 11-13 -RSB- . It is our contention that these two frequently described components of the process of luteal regression -LRB- i.e. cessation of progesterone secretion and disappearance of the structure -RRB- merit equal attention . However , the timing and inter-relationship of these two types of regressive changes appears to vary by species . As new information on the molecular steps triggered during luteal regression is obtained , these mechanisms will need to be defined as they relate to these facets of the overall regressive process . Davis and Rueda -LSB- 3 -RSB- advised that the terms functional and structural used in the context of luteal regression should be adequately defined by the authors in the context of the particular species and reproductive stage being studied , with which we concur . It is not extreme to predict that with the advancement of knowledge in the process of luteal regression researchers will find increasing difficulties in establishing the limits as to what mechanisms belong to the `` functional '' facet of luteal regression , and which ones are part of the `` structural '' facet , as luteal regression is a process of synchronized events . For example , it now appears that progesterone itself is responsible for preventing the onset of apoptosis and structural disintegration -LSB- 14-17 -RSB- . Conclusions These authors strongly recommend that the term luteal regression should be used to refer to the process of regression of the corpus luteum . Luteal regression represents a broad definition of the process of demise of the corpus luteum that is capable of accommodating all new knowledge evolved on the molecular mechanisms activated or inhibited during the process of regression of the corpus luteum regardless of species or reproductive stage . Further , according to the etymology of the word , luteolysis has a very limited meaning that no longer describes properly the complex sequence of synchronized molecular events associated with the demise of the corpus luteum . The modifying terms `` functional '' and `` structural '' can be used in conjunction with the term luteal regression to further identify aspects of the overall process but must be adequately defined within the context of the publication .

B I O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O B O O O O O B I O O O O O O O O O O O O O B O O O O B O O O O O O O O O O O O O O B I O O O O O B I O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O B I O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O B O O O O O O O O O O O O B O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B I O O O O O O O O O O O O O O B O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O B I O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O B I O B I O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O

luteal regression
luteolysis
corpus luteum

structural luteolysis
functional luteolysis


Primary retroperitoneal mucinous cystadenoma with sarcoma-like mural nodule Primary retroperitoneal cystadenomas are extremely rare . This is the first report in literature to describe a primary retroperitoneal cystadenoma with a sarcoma-like mural nodule . A 45-year-old woman complained of a left-sided abdominal mass . A computed tomography scan revealed a cystic mass with a mural nodule , which seemed to originate from the tail of the pancreas . At laparotomy the cyst was not adhered to the pancreas but localized retroperitoneally . Histologic examination showed a mucinous cystadenoma with only foci of borderline malignancy with a mural `` sarcoma-like '' nodule . In view of the surgical and histopathological findings , the mucinous cystadenoma was regarded as primary retroperitoneal . This case demonstrates that in the era of radiological preoperative refinement , pathological diagnosis remains of utmost importance , especially for rare cases . Introduction Mucinous cystadenomas of the ovary are clinically and histopathologically well-established and common tumors . Primary retroperitoneal mucinous cystadenomas are extremely rare . Such tumors are histologically similar to ovarian mucinous cystadenomas . Their histogenesis is still unclear . We report a case of primary retroperitoneal mucinous cystadenoma with foci of borderline malignancy containing a mural `` sarcoma-like '' nodule . Case report Clinical history A 45-year-old , para 2 , woman presented at the emergency room with a 3-week history of left-sided abdominal pain . She had felt a mass in the left lower quadrant 2 days before . Her clinical history included endometriosis and a car accident . The mass was progressive but not painful . Apart from the palpable mass of 15 cm in the left lower abdomen , physical examination was unremarkable . Ultrasonography demonstrated a 15-cm cystic mass with a 3.8-cm nodule in its wall . The uterus was normal in size , and internal ultrasonography showed small ovaries . Carcinoembryonic antigen , cancer antigen -LRB- CA -RRB- 125 , and CA 19-9 levels were within normal limits . The next day , a contrast-enhanced computed tomography scan of the abdomen revealed a 15-cm left-sided cystic mass , which seemed to originate from the tail of the pancreas -LRB- Fig. 1a -RRB- . The cystic mass showed a 4-cm nodule in its wall -LRB- Fig. 1b -RRB- and was suspected for a cystic papillary adenocarcinoma . At laparotomy , the cyst was not adhered to the pancreas and could be easily separated from its location near the tail without opening the pancreatic capsule . Vascularization appeared to arise from the mesentery of the left colon . It was localized in the retroperitoneal space extending caudally from the spleen to the lower abdomen with medial displacement of the left colon . Total resection of the cyst was performed , and the specimen was sent for histopathological examination . Further inspection showed two normal ovaries . Her postoperative recovery was uneventful . One year after surgery , the patient was without signs of recurrence or metastasis . Fig. 1Contrast enhanced CT scan shows images of a pancreatic cyst -LRB- arrowheads -RRB- originating from the tail of the pancreas -LRB- a -RRB- and a mural nodule within the wall of the cystic mass -LRB- b -RRB- Materials and methods The specimen was fixed in 4 % buffered formalin . Representative samples were routinely processed and embedded in paraffin blocks . Four-micrometer-thick sections were stained with hematoxylin and eosin and with parallel routine immunohistochemical procedures . The antigens tested by immunohistochemistry were : pan-keratin , keratin Cam 5.2 , cytokeratin 7 , cytokeratin 10 , cytokeratin 18 , cytokeratin 20 , epithelial membrane antigen , vimentin , desmin , actin , myosin , CD34 , CD68 , CD99 , CD117 , S-100 protein , and bcl-2 . Pathological findings The specimen consisted of a unilocular cyst measuring 20 × 11 cm with a smooth surface . The content was a watery mucinous material . The wall was thin with a smooth gray-white inner surface and contained a circumscribed bean-shaped solid mural nodule of 3.5 × 3.5 × 2.5 cm , which showed a brown-yellow and focally hemorrhagic cut surface . Microscopically , most of the cyst was lined by single-layered tall columnar cells , abundant clear cytoplasm , and small basally located nuclei -LRB- Fig. 2a -RRB- . Fig. 2Cyst wall with typical tall columnar mucous-secreting epithelium and fibrous wall -LRB- a -RRB- . Low cellular proliferation with some stratification of the cells and slight nuclear atypia -LRB- b -RRB- . Heterogenous proliferation of pleomorphic cells , spindle cells , osteoclast-like giant cells , and some mononuclear cells with some pigment -LRB- c -RRB- . Detail of sarcoma-like nodule -LRB- d -RRB- Occasionally -LRB- over less than 1 % of the surface -RRB- , the epithelium showed slightly atypical proliferation with glandular budding , tufting of the epithelium , decreased cytoplasmic mucin , some stratification of slightly irregular nuclei , and an occasional mitoses -LRB- Fig. 2b -RRB- . There was no infiltrative growth but foci of borderline malignancy . The nodule was well circumscribed without vascular invasion and consisted of a heterogenous population of spindle-shaped cells , pleomorphic cells with bizarre nuclei , mixed mononuclear inflammatory cells , benign osteoclast-like giant cells , and foci of hemorrhage . There were mitotic figures , including some atypical forms -LRB- Fig. 2c and d -RRB- . The sarcoma-like cells proved to be keratin negative -LRB- Table 1 -RRB- . Table 1Immunohistochemical results of the sarcoma-like cellsAntigenResultPan-keratin − Keratin Cam 5.2 − Cytokeratin 7 − Cytokeratin 10 − Cytokeratin 18 − Cytokeratin 20 − Epithelial membrane antigen − Vimentin + Desmin − Actin + / − -LRB- some -RRB- Myosin − CD34 − CD68 + CD99 − CD117 − S-100 protein − bcl-2 + / − -LRB- some -RRB- Discussion Mucinous cystadenomas can be located in the ovaries , pancreas , and in the retroperitoneum . The mucinous cystadenoma presented was localized retroperitoneally near the pancreas but was clearly not adhered to it . Because normal-appearing ovaries were found , the cystadenoma was thought to be primary retroperitoneal . According to the literature , symptoms are nonspecific , and most patients complained of an abdominal distension or mass with or without pain -LSB- 9 -RSB- . Mucinous cystadenomas were relatively large , varying from 10 to greater than 20 cm in diameter , which is large enough to cause symptoms like abdominal fullness -LSB- 9 -RSB- . Preoperative diagnosis is very difficult , not because the tumors are often overlooked in the differential diagnosis but also because no sensitive methods or reliable markers are available -LSB- 2 -RSB- . As retroperitoneal mucinous cystadenomas are histologically similar to mucinous cystadenomas of the ovary , the ultrasonographic image pattern is in general of no help in distinguishing between ovarian and retroperitoneal origin . In our case , the diagnosis of the retroperitoneal mucinous cystadenoma could not be established preoperatively by ultrasonography or computed tomography . Although ultrasonography , computed tomography , or magnetic resonance imaging can detect retroperitoneal cysts , the diagnosis of mucinous cystadenoma is seldomly made preoperatively . The usual preoperative differential diagnosis consists of ovarian cyst , cystic mesothelioma , cystic lymphangioma , nonpancreatic pseudocyst , and renal cyst -LSB- 4 , 9 , 18 -RSB- . Although aspiration is a good method for delineating the nature of the cyst , cytologic analysis of the aspirated fluid frequently fails to reveal the type of epithelial cells lining the cyst . Therefore , exploratory laparotomy with complete excision of the cyst is usually indicated both for diagnosis and treatment -LSB- 2 -RSB- . Retroperitoneal mucinous cystadenomas are histologically similar to mucinous cystadenomas of the ovary . The histogenesis of these tumors is still unclear . Four main hypotheses have been proposed -LSB- 2 , 14 -RSB- . According to the first three hypotheses , the tumor arises either from ectopic ovarian tissue , although ovarian tissue was only rarely found -LSB- 14 -RSB- , from a teratoma in which the mucinous epithelium has overgrown all other components or from urogenital remnants . The most widely accepted theory suggests coelomic metaplasia as the causal agent , whereby tumors arise from invagination of the peritoneal mesothelial layer that undergoes mucinous metaplasia with cyst formation -LSB- 3 , 9 -RSB- . Such origin rather than from ectopic ovarian tissue is supported by the occurrence of such a tumor in a male patients -LSB- 5 , 8 , 10 , 17 -RSB- . Primary mucinous tumors of the retroperitoneum are very uncommon . These tumors can be classified into three clinicopathologic types : mucinous cystadenoma , mucinous cystic tumor of borderline malignancy , and mucinous cystadenocarcinoma . Our case was diagnosed as a primary retroperitoneal mucinous cystadenoma with only foci of borderline malignancy and a mural `` sarcoma-like '' nodule . Mural nodules have been described in ovarian and pancreatic mucinous cystic tumors -LSB- 7 , 16 -RSB- . Mural nodules may be malignant representing anaplastic carcinoma , containing a predominant population of cytokeratin-positive cells with high-grade malignant nuclei , or a genuine soft tissue-type sarcoma -LSB- 7 , 15 , 16 -RSB- . Benign pseudosarcomatous mural nodules are composed of a heterogeneous cell population of epulis-type giant cells , atypical spindle cells with bizarre nuclei and mitotic figures , mixed inflammatory cells , and signs of hemorrhage and necrosis . In these cases , immunohistochemical staining shows a weakly or focally cytokeratin positivity in the pseudosarcomatous cells . We performed a literature review using Embase and Medline starting in 1966 and identified approximately 45 cases of retroperitoneal mucinous cystadenoma and 25 cases of mucinous cystadenocarcinoma . Only eight cases of mucinous cystadenoma with borderline malignancy have been reported -LRB- Table 2 -RRB- . Thus , our case is the ninth case of a retroperitoneal mucinous cystadenoma of borderline malignancy . By our knowledge , however , combination with a mural `` sarcoma-like '' nodule has not been described earlier in the literature . The patient should be followed . However , in this case , long-term follow-up seems not warranted regarding the only focal aspect -LRB- < 1 % of the surface -RRB- of borderline malignancy of the cyst and the benign reactive nature of the mural nodule . Table 2Cases of primary retroperitoneal mucinous cystadenomas of borderline malignancyStudy -LRB- year -RRB- Age -LRB- years -RRB- SexSymptomSize , imageTumor markerPreoperative diagnosisHistoryPathologyExtracystic extensionTherapyOutcomeNagata et al. -LSB- 11 -RSB- -LRB- 1987 -RRB- 41FAbdominal swelling , pain12 × 10 × 9 cmUDUDUDMCAborNoTRUDBanerjee and Gough -LSB- 1 -RSB- -LRB- 1988 -RRB- 47FAbdominal mass10 cm -LRB- US -RRB- next to spl.NDLt adrenal tumorApp HystMCAborNoTR , resection spl . + lt adrenalNEDMotoyama et al. -LSB- 10 -RSB- -LRB- 1994 -RRB- 63MAbdominal pain6 cm -LRB- US -RRB- , under rt kidneyHigh CEA in cystic fluidRt renal cystNRMCAborNoNDNEDPearl et al. -LSB- 13 -RSB- -LRB- 1996 -RRB- 33FAbdominal swelling , painLarge , unilocular lt -LRB- CT -RRB- NDNDNRMCAborNoLRNED , 10 monthsPapadogiannakis et al. -LSB- 12 -RSB- -LRB- 1997 -RRB- 33FAbdominal mass13 × 9 cm -LRB- US + CT -RRB- NDMesenteric cystNRMCAborNoTRNED , 12 monthsChen et al. -LSB- 2 -RSB- -LRB- 1998 -RRB- 48FAbdominal fullness15 × 13 × 9 cm -LRB- CT -RRB- NDMesenteric cystNRMCAborNoLRNED ,8 monthsGutsu et al. -LSB- 6 -RSB- -LRB- 2003 -RRB- 41FFlank pain , abdominal distension21 × 16 cm rt -LRB- CT -RRB- NDRetroperitoneal cystNRMCAborNoTRNED , 18 monthsMatsubara et al. -LSB- 9 -RSB- -LRB- 2005 -RRB- 36FAbdominal distension12 × 8 cm rt -LRB- CT -RRB- CA 125:51 CA 19-9 : 55Ovarian cystNRMCAborNoTR , App , MyoNED , 6 monthsPresent case -LRB- 2007 -RRB- 45FAbdominal pain15 cm -LRB- US + CT -RRB- CEA , CA125 , CA19-9 : normalCystic papillary adenocarcinoma or mucinous cystic neoplasmEndomMCAborNoTRNED , 12 monthsF Female ; M male , UD unknown data , NR not remarkable , MCAbor mucinous cystadenoma borderline malignancy , TR tumor resection , LR laparoscopic resection , NED no evidence of disease , US ultrasonography , spl . spleen , App appendectomy , Hyst hysterectomy , Myo myomectomy , Endom endometriosis , rt right , lt left

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retroperitoneum
mucinous cystadenoma
mural nodule


The significance of lobular neoplasia on needle core biopsy of the breast The management of a core biopsy diagnosis of lobular neoplasia is controversial . Detailed radiological -- pathological review of 47 patients with cores showing classical lobular neoplasia was performed -LRB- patients with pleomorphic lobular carcinoma in situ -LRB- LCIS -RRB- or associated risk lesions were considered separately -RRB- . Immediate surgical excision in 25 patients showed invasive carcinoma in 7 , ductal carcinoma in situ -LRB- DCIS -RRB- in 1 and pleomorphic LCIS in 1 ; radiological -- pathological review showed that the core biopsy missed a mass in 5 , missed calcification in 2 and that calcification appeared adequately sampled in 2 . Nineteen patients had follow-up of at least 2 years . Four patients developed malignancy at the site of the core biopsy -LRB- invasive carcinoma in three , DCIS in one -RRB- ; one carcinoma was mammographically occult , one patient had dense original mammograms and two had calcifications apparently adequately sampled by the core . In conclusion , most carcinomas identified at the site of core biopsy showing lobular neoplasia were the result of the core missing the radiological lesion , emphasising the importance of multidisciplinary review and investigation of any discordance . Some carcinomas were found after apparently adequate core biopsy , raising the question of whether excision biopsy should be considered after all core biopsy diagnoses of lobular neoplasia . Introduction Lobular carcinoma in situ -LRB- LCIS -RRB- was described by Foot and Stewart -LSB- 25 -RSB- . The term atypical lobular hyperplasia -LRB- ALH -RRB- was later introduced to describe a similar lesion , but with less marked changes . We prefer the term lobular neoplasia -LSB- 30 -RSB- , which includes both LCIS and ALH , particularly for core biopsies in which there is limited tissue , making distinction between ALH and LCIS difficult . The relationship between lobular neoplasia and invasive carcinoma of the breast is controversial -LSB- 28 -RSB- . Lobular neoplasia is often multifocal and bilateral -LSB- 4 -RSB- . There is evidence that it is a risk factor for invasive carcinoma in both breasts : after a diagnosis of lobular neoplasia , there is an increased risk of subsequent invasive carcinoma in both breasts -LSB- 30 -RSB- , and the majority are ductal in type . Recent evidence suggests that lobular neoplasia may , like ductal carcinoma in situ -LRB- DCIS -RRB- , be a non-obligate precursor for invasive carcinoma at the same site . There is a higher risk of invasive carcinoma in the ipsilateral than in the contralateral breast . The proportion of subsequent carcinomas that are of lobular type is higher than in unselected series of carcinomas -LSB- 45 -RSB- . The morphology of the cells in lobular neoplasia and invasive lobular carcinoma is similar . The same truncating mutation in the E-cadherin gene has been found in invasive lobular carcinoma and adjacent LCIS -LSB- 57 -RSB- . The significance of lobular neoplasia in breast needle core biopsies is uncertain . Invasive carcinomas are sometimes identified after a core biopsy diagnosis of lobular neoplasia . Some studies suggest this occurs because the core biopsy missed the lesion and so does not explain the clinical or radiological abnormality -LSB- 41 -RSB- . Other studies suggest that carcinomas may be identified after the diagnosis of lobular neoplasia on core biopsy even if the core biopsy explains the clinical or radiological abnormality -LSB- 20 -RSB- . An important consideration in radiological -- pathological correlation is whether classical lobular neoplasia is associated with calcification . The traditional view is that lobular neoplasia does not have a radiological correlate -LSB- 4 -RSB- , but recent reports have described an association between classical lobular neoplasia and calcification . We also wished to investigate our impression that , in core biopsies containing classical lobular neoplasia , calcification is often associated with columnar cell change . Pleomorphic LCIS is a recently described variant of lobular neoplasia . The growth pattern and absence of E-cadherin expression resemble classical LCIS . However , the marked nuclear pleomorphism , frequent presence of central necrosis and calcification and expression of c-erbB-2 are similar to high-grade DCIS -LSB- 50 -RSB- . In the past , pleomorphic LCIS would usually have been diagnosed as high-grade DCIS . The main aim of this study was to assess the risk of invasive carcinoma and DCIS at the site of classical lobular neoplasia diagnosed on breast needle core biopsies . In view of the clear morphological differences , pleomorphic LCIS was considered separately . A second aim was to investigate the localisation of calcification in core biopsies containing lobular neoplasia . Materials and methods This project was discussed with the chair of the Nottingham University Hospitals Research Ethics Committee who considered that it was a service evaluation and , therefore , did not require formal ethical approval . A multidisciplinary review of the pathology and radiology of patients with a core biopsy diagnosis of lobular neoplasia from July 1998 to June 2006 was performed . The biopsies from July 1998 to June 2000 were included in a previous study -LSB- 35 -RSB- . The diagnosis of lobular neoplasia was made on haematoxylin and eosin sections . Immunohistochemistry for E-cadherin was performed for lesions with a differential diagnosis including DCIS or pleomorphic LCIS . Lobular neoplasia was subdivided into ALH and LCIS using the criteria described by Page et al. -LSB- 44 -RSB- . Pleomorphic LCIS was defined as a high-grade dyscohesive intra-acinar proliferation that was E-cadherin negative . Patients were excluded if they had synchronous or previous invasive carcinoma or DCIS in the same breast . Two patients with contralateral invasive carcinoma were included . Core biopsies containing invasive carcinoma , DCIS or an area suspicious of either diagnosis were excluded . Cores containing pleomorphic LCIS , an atypical intraductal epithelial proliferation -LRB- including atypical ductal hyperplasia -RRB- , radial scar or a papillary lesion were considered separately . Thus , the main group of core biopsies studied contained classical lobular neoplasia with no other risk lesions : we termed this group `` simple '' classical lobular neoplasia . The core biopsies were reviewed for the following features : location of any calcification and presence of columnar cell change . Six cores were not available , so could not be reviewed . The frequency of columnar cell change was compared with 87 consecutive core biopsies reported by one observer -LRB- AHSL -RRB- as normal or benign . Results Simple classical lobular neoplasia on core biopsy Forty-nine core biopsies with lobular neoplasia from 47 women satisfied the entry criteria -LRB- 0.3 % of the 14,597 diagnostic core biopsies performed during this period -RRB- . Two patients had two core biopsies from the same area of the breast containing lobular neoplasia : both are only counted once in the following results . The median age was 52 years -LRB- range 33 to 81 -RRB- . Twenty-six patients presented with mammographic screening abnormalities : 20 with calcification , 3 with a mass , 2 with calcification and distortion and 1 with a mass and calcification . Nineteen patients presented symptomatically : ten with a mass , seven with a thickening and two with a thickening and calcification . Two women had calcification identified by mammography performed in one patient as part of the investigation of a contralateral carcinoma and , in the other , as follow-up of a contralateral carcinoma . Eight core biopsies were freehand , 14 were ultrasound guided and 25 were performed under stereotactic guidance . There was an association between lobular neoplasia and columnar cell change -LRB- see Table 1 -RRB- . Calcification was seen in 25 of 41 cores with slides available for review . It was seen in lobular neoplasia in six biopsies -LRB- 15 % -RRB- ; in one the calcification was only seen in the lobular neoplasia , but in the other five , it was also present in other changes -LRB- columnar cell change in three , sclerosing adenosis in one , fibroadenoma in one -RRB- . Of the other 19 biopsies with calcification , columnar cell change was the most commonly associated pathology -LRB- 10 biopsies -RRB- . Table 1Extent of columnar cell change in cores with lobular neoplasia and controlsColumnar cell changeCore biopsy with lobular neoplasiaControls -LRB- normal or benign core biopsy -RRB- None12 -LRB- 29 % -RRB- 58 -LRB- 67 % -RRB- One lobule or duct9 -LRB- 22 % -RRB- 14 -LRB- 16 % -RRB- At least two lobules or ducts20 -LRB- 49 % -RRB- 15 -LRB- 17 % -RRB- χ2 = 18 , P = 0.0001 Surgical excision within 2 months of core biopsy was performed in 25 patients . Excision showed malignancy in nine patients -LRB- see Table 2 -RRB- . In seven patients , pathology -- radiology correlation showed that the core biopsy did not explain the radiological abnormality -LRB- a mass in five and calcification in two -RRB- . Five of these seven patients were seen in the first 2 years of this study . Excision showed benign changes in 16 , although one woman had invasive carcinoma of mixed ductal and lobular type diagnosed 33 months after the core biopsy in a separate quadrant of the same breast . Table 2Details of patients with invasive carcinoma , DCIS or pleomorphic LCIS at the site of the core biopsy showing simple lobular neoplasiaAgePresentationCore pathologyTime to excision/monthsFinal diagnosis -LRB- surgical procedure -RRB- Pathology -- radiology correlation60Screen-detected massALH , CCCh , calcs113 mm IDC , G3 , LN 0/4 -LRB- Mx -RRB- Core missed mass75Symptomatic massLCIS , UEH , CCCh26 mm IDC , G2 , LN not examined -LRB- Mx -RRB- Core missed mass63Screen-detected distortion and calcification . Mass on USALH114 mm ILC , G2 , LN 0/5 -LRB- WLE -RRB- Core missed mass54Screen-detected calcificationALH14 mm tubulobular carcinoma G1 + 50 mm DCIS , LN 0/6 -LRB- Mx -RRB- Core missed calcs43Symptomatic massLCIS19 mm IDLC , G2 , LN 0/7 -LRB- Mx -RRB- Core missed mass68Screen-detected massALH112 mm ILC , G2 , LN 0/6 -LRB- Mx -RRB- Core missed mass64Symptomatic mass , no mass on US . Mammographic calcificationALH , cyst , calcs17 mm DCIS -LRB- WLE -RRB- Calcs sampled by core54Screen-detected calcificationALH112 mm tubular carcinoma + 35 mm DCIS , LN 0/4 -LRB- WLE -RRB- Core missed calcs45Symptomatic cysts . Mammographic calcificationLCIS , calcs15 mm pleomorphic LCIS -LRB- WLE -RRB- Calcs sampled by core52Screen-detected calcificationALH , UEH , CCCh , calcs319 mm ILC , G2 , LN 1/6 -LRB- Mx -RRB- Mammographically occult mass70Screen-detected calcificationALH , calcs2936 mm IDC , G3 , LN 6/16 -LRB- Mx -RRB- Dense original mammogram51Screen-detected calcificationALH , CCCh , calcs2630 mm DCIS + extensive LCIS -LRB- Mx -RRB- Calcs sampled by core55Screen-detected calcificationALH , CCCh , calcs29IDC 8 mm , G3 , 45 mm DCIS , LN 1/4 -LRB- Mx -RRB- Calcs sampled by coreUS ultrasound , ALH atypical lobular hyperplasia , LCIS lobular carcinoma in situ , UEH epithelial hyperplasia of usual type , CCCh columnar cell change , calcs calcification , IDC invasive ductal carcinoma , ILC invasive lobular carcinoma , IDLC invasive ductal and lobular carcinoma , DCIS ductal carcinoma in situ , G histological grade , LN axillary lymph nodes , Mx mastectomy , WLE wide local excision Nineteen patients who had not had a diagnostic surgical excision had follow-up of at least 2 years -LRB- range 25 to 105 months -RRB- . None of these patients received radiotherapy to the breast . Malignancy was identified in seven women . In four , the malignancy was at the same site as the core biopsy -LRB- see Table 2 -RRB- , in one DCIS was found in a different quadrant of the same breast and two developed contralateral invasive carcinoma . Three women had no surgical excision and follow-up of less than 2 years . Neither of the two women with a previous history of contralateral invasive carcinoma developed carcinoma at the site of the core biopsy showing lobular neoplasia . No significant relationships were found between the diagnosis of malignancy -LRB- DCIS , pleomorphic LCIS or invasive carcinoma -RRB- at the site of the core biopsy and the following features : age of the woman , diagnosis of ALH or LCIS on the core biopsy , whether core biopsy or vacuum-assisted biopsy was performed and the method of guidance -LRB- freehand , ultrasound or stereotactic -RRB- . Pleomorphic LCIS on core biopsy Both patients with pleomorphic LCIS on core biopsy presented with calcification detected by mammographic screening . In both , calcification was seen histologically in association with the pleomorphic LCIS . Both had a diagnostic surgical excision , which showed cribriform DCIS in one and further LCIS in the other . Atypical intraductal epithelial proliferation/radial scar/papillary lesion Eight patients had atypical intraductal epithelial proliferation , radial scar or a papillary lesion in addition to lobular neoplasia on the core biopsy . All eight presented with abnormalities detected by mammographic screening : calcification in five , calcification and distortion in one , mass in one and distortion in one . Seven patients had a diagnostic surgical excision , and one patient had her lesion removed with vacuum-assisted mammotomy . DCIS was found in one of three women with core diagnosis of atypical intraductal epithelial atypia and in one of two with core diagnosis of radial scar . Papillary DCIS with a 3-mm focus of invasion was found after a core diagnosis of papillary lesion with atypical intraductal epithelial proliferation . One patient with a core diagnosis of radial scar with atypical intraductal epithelial proliferation and one with a papillary lesion had benign findings at excision . Discussion Relation between lobular neoplasia and calcification An important question in the management of lobular neoplasia on core biopsy is the relationship between lobular neoplasia and calcification . Lobular neoplasia is not typically associated with any specific clinical abnormality , and there are no characteristic macroscopic features . Early papers suggested that classical lobular neoplasia does not have any diagnostic mammographic features -LSB- 4 -RSB- . In the past , surgical biopsies containing lobular neoplasia were frequently performed for mammographic calcification , but pathologically , the calcification was mostly associated with fibrocystic change and identified within the lobular neoplasia in about 20 % -LSB- 4 , 11 , 24 , 55 -RSB- . Calcification is associated with the lobular neoplasia in between 8 % and 53 % of core biopsies containing classical lobular neoplasia in different studies -LSB- 1 , 3 , 14 , 20 , 41 -RSB- . Benign calcification is frequently seen close to invasive carcinomas in surgical specimens -LSB- 52 -RSB- . It is well recognised that malignancy may be an incidental discovery on a biopsy for calcification that is associated only with benign disease -LSB- 49 -RSB- . The present study confirms the association between lobular neoplasia and columnar cell change -LSB- 8 , 41 -RSB- . In older studies , the majority of surgical biopsies containing lobular neoplasia were performed for fibrocystic change -LSB- 30 -RSB- . In the present study , calcification was associated with lobular neoplasia in 15 % of core biopsies , but commonly was also seen in fibrocystic change as well . Calcification was associated with columnar cell change in 32 % of cores with lobular neoplasia . The association of calcification with columnar cell change is well recognised -LSB- 27 -RSB- . Our results support the view that , in biopsies containing lobular neoplasia , most of the calcification is associated with fibrocystic change , particularly columnar cell change . Importantly , the lobular neoplasia is incidental to the calcification in the majority of biopsies . A recent study of collagenous spherulosis found that 15 of 59 patients had associated LCIS -LSB- 48 -RSB- . In contrast , only one of the patients in the present study with lobular neoplasia had associated collagenous spherulosis . Relationship between simple classical lobular neoplasia and carcinoma In this study , 44 women with simple classical lobular neoplasia on core biopsy had surgical excision or follow-up of at least 2 years . Twenty-five women had immediate surgical excision , which showed invasive carcinoma , DCIS or pleomorphic LCIS in nine -LRB- 36 % -RRB- . In the majority , the core biopsy was judged to have missed the clinical/radiological lesion . This emphasises the importance of clinico-pathological review and further investigation of any discordance . Most of the missed lesions occurred in the early part of the study , suggesting that the accuracy of radiological localisation of core biopsies may have improved later in the series . A smaller number of carcinomas occurred after lobular neoplasia on core biopsy apparently incidental to the clinical or radiological lesion . This raises the question of whether excision biopsy should be considered after all core biopsy diagnoses of lobular neoplasia . The frequency of malignancy if the patients with radiological -- pathological discordance are excluded is 11 % -LRB- 2/18 -RRB- . Four of 19 patients with at least 2 years follow-up developed carcinoma at the site of the core biopsy . In one , the carcinoma was mammographically occult , although it was clinically palpable , in one the original mammogram was dense and two women had calcification apparently adequately sampled by the core biopsy . Definite comment can not be made , but the clinical histories suggest that it is possible that the carcinoma may have been identified earlier in some of these patients if they had had an immediate surgical biopsy . If these women are added to those without radiological -- pathological discordance in the above paragraph , the frequency of malignancy is 16 % -LRB- 6/37 -RRB- . Previous published studies of simple lobular neoplasia on core biopsy were reviewed -LSB- 1 -- 3 , 6 , 9 , 10 , 12 , 14 , 16 -- 18 , 20 , 21 , 23 , 25 , 26 , 31 , 33 , 36 , 37 , 39 , 41 -- 43 , 46 , 47 , 51 , 54 , 58 , 59 -RSB- . The data in most studies are not representative . Probably the major bias is that only about half of the lesions had a surgical biopsy and it is not clear how patients were selected for excision biopsy . Furthermore , most studies only report image-guided or stereotactic biopsies . A surgical biopsy was performed in 561 patients with a core biopsy diagnosis of lobular neoplasia with invasive carcinoma found in 50 or 49 and DCIS in 32 or 33 -LRB- 82 -LSB- 15 % -RSB- in total -RRB- . It is ` impossible to know if some of the reported cases are those in which the targeted lesion has been missed and re-excision was done for failure to successfully sample the target ' -LSB- 15 -RSB- . In reviewing the previous studies , we have assumed that sampling was adequate for core biopsy performed for calcification if calcification was present in the core biopsy . Of those 52 malignancies with details available , 25 -LRB- 48 % -RRB- had a radiological -- pathological discordance -LRB- missed mass in 22 and missed calcification in 3 -RRB- , and 27 had apparently adequately sampled calcification . One hundred four patients who did not have immediate surgical excision had reported follow-up . The only four patients -LRB- 4 % -RRB- with invasive carcinoma or DCIS on follow-up at the site of core biopsy are the four patients described in the present study . The absence of subsequent malignancy in other studies is very surprising given that lobular neoplasia is a well-established risk factor for later carcinoma . Nevertheless , the low rate suggests that the chance of invasive carcinoma or DCIS is lower in those not having immediate surgical excision . It is difficult to estimate the chance of finding invasive carcinoma or DCIS if all patients had an excision biopsy . The 15 % rate found in the subset of patients who had immediate excision biopsy is probably an overestimate . If the cases with radiological -- pathological discordance are excluded , the risk is probably about half of this , approximately 8 % . If one assumes that half of the patients who did not have an immediate excision did not have invasive carcinoma or DCIS at the core site , this gives an estimate of about 4 % . This represents an estimate of the lower limit of risk . Some studies suggest that the risk of finding invasive carcinoma or DCIS is a little higher if the core biopsy shows LCIS rather than ALH -LSB- 13 -RSB- . In view of the subjectivity of this distinction on core biopsy , it is probably of limited use in routine practice . It is clearly appropriate to investigate patients with simple classical lobular neoplasia on core biopsy that does not explain the clinical or radiological abnormality . If a definitive diagnosis can not be made with further core biopsy , then an excision biopsy is indicated . The management of simple classical lobular neoplasia on core biopsy with no radiological -- pathological discordance is less straightforward . As discussed above , the literature suggests that the risk of malignancy is in the range of 4 % to 8 % . This risk is comparable to that associated with radial scar or papillary lesion with no epithelial atypia -LSB- 7 , 34 , 35 , 40 , 53 -RSB- . Both radial scars and papillary lesions are excised in many centres according to current guidance -LSB- 19 -RSB- . The major difference with lobular neoplasia , however , is that both are usually clearly defined lesions on radiological examination and therefore easy to excise . There is a need for prospective studies with surgical excision of all lesions so that an unbiased assessment of the risk of simple classical lobular neoplasia on core biopsy can be made . Careful radiology -- pathology correlation is essential . It may be possible to stratify the risk within this group using clinical , radiological or pathological features . Lobular neoplasia associated with radial scars , papillary lesions and atypical intraductal epithelial proliferations Most centres excise radial scars , papillary lesions and atypical intraductal epithelial proliferations diagnosed on core biopsy . In the present study , carcinoma was found on excision of three of the eight lesions with these lesions in combination with lobular neoplasia . This supports the practice of excising such lesions . Pleomorphic LCIS In the present study , both cores with pleomorphic LCIS had associated calcification . In contrast to the controversial nature of the association between calcification and classical LCIS , the literature suggests that there is a clear relationship between calcification and pleomorphic LCIS -LSB- 29 , 50 -RSB- . There are limited data on the significance of pleomorphic LCIS on core biopsy . One of the two patients in the present study had DCIS in the excision specimen . Three of the six patients described in the literature -LSB- 5 , 20 , 37 -RSB- had invasive carcinoma on excision , but radiology showed a density in one and an architectural distortion in another . Although the follow-up data are limited , we believe that , until there is further evidence , it is prudent to recommend that pleomorphic LCIS is managed as DCIS because of the morphological similarity of pleomorphic LCIS to high-grade DCIS . The present study may underestimate the frequency of pleomorphic LCIS , as E-cadherin immunohistochemistry was infrequently performed early in the study period and some cases may have been diagnosed as high-grade DCIS . Some lobular neoplasia shows features overlapping with DCIS and is difficult to classify even with E-cadherin immunohistochemistry -LSB- 32 , 38 -RSB- . Lobular neoplasia with comedo necrosis , but without marked nuclear pleomorphism , has recently been described -LSB- 22 -RSB- . The clinical significance of these rare clinico-pathological scenarios is uncertain . Until there is more evidence , it would be prudent to recommend surgical biopsy of such lesions because of the overlap of features with DCIS . Mass forming lobular neoplasia can occur rarely -LSB- 56 -RSB- , but is an example of clinico-pathological discordance , so surgical biopsy is prudent . In conclusion , we recommend excision after a core biopsy diagnosis of lobular neoplasia in the following circumstances : Discordance of clinical or radiological findings with the pathological changes -LRB- this includes mass-forming lobular neoplasia -RRB- Lobular neoplasia with atypical histological features including pleomorphic LCIS , lobular neoplasia with necrosis , and when it is not possible to exclude DCIS despite E-cadherin immunohistochemistryIf there is an associated risk lesion , such as atypical intraductal epithelial proliferation , radial scar or papillary lesion . We suggest that further studies are needed to guide the management of simple classical lobular neoplasia , as the data on the risk of associated carcinoma remain unclear in this group of patients .

O O O B I O O O O O O B O O O O O O O O B I O O O O O O O O O O O O O O O B I O O O O O O B I I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O B I I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O B O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I 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O O O O O O O O O O B I O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O B I O O O O O O O B I O O O B I O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O B I O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O B I O B I O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O

lobular neoplasia
lobular carcinoma in situ
breast

atypical lobular neoplasia
pleomorphic lobular carcinoma in situ
needle biopsy