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Recent eLetters

Displaying 1-10 letters out of 144 published

  1. Effect of diet and medicines on the serum iron and transferrin saturation

    I read this article with interest. I totally agree with the authors' statement that many requests for HFE mutation analysis are frequently ordered in the community without measuring serum iron and transferrin saturation (T-sat) first. While this report is intriguing, I am very much interested to know if the samples for serum iron and T-sat in this study were fasting samples or postprandial samples. The diet rich in iron can obviously increase the T-sat. Medications such as vitamin C, dietary supplement containing iron, multivitamins with iron and oral contraceptive pills (OCPs) and can increase the T-sat [1,2]. Another point to consider is that about half of the adults in the western countries take vitamins and other dietary supplements regularly and about three to three quarter million women in Britain take OCPs [3,4]. This means the results of the serum iron and T-sat obtained in the daily clinical practice can highly be influenced by the iron-rich diet, vitamins, dietary supplements and OCPs. I wonder how many patients in this current study are on those medications and how many samples were drawn postprandially. Provided those patients were excluded from this study, the actual number of the patients with T- sat > 50% would be decreased. This translates to further saving of money from unnecessary testing of HFE mutation analysis. Referring physicians should submit fasting blood samples for serum iron and T-sat. Patients who are on above-mentioned medications should avoid their medications for at least 24 hours prior to the fasting blood draw [2].

    Thein H. Oo, MD

    References: 1. Transferrin saturation test. http://www.cdc.gov/ncbddd/hemochromatosis/training/diagnostic_testing/testing_protocol.html Accessed May 8, 2015

    2. Transferrin saturation. http://emedicine.medscape.com/article/2087960-overview Accessed May 8, 2015

    3. Vitamins: How many Americans use them? http://www.huffingtonpost.com/2011/04/13/vitamin-use_n_848777.html Accessed May 8, 2015.

    4. Contraception: patterns of use fact use. http://www.fpa.org.uk/factsheets/contraception-patterns-use Accessed May 8, 2015

    Conflict of Interest:

    None declared

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  2. Authors Response: Histological grade in needle core biopsies of invasive carcinoma of the breast: the potential role of reduction of mitotic count threshold in improving agreement with grade in the surgical specimen

    Dear Sir / Madam,

    We are happy to address the points raised by Lee et al in their commentary on our paper [1] and thank them for their interest in it.

    Lee et al correctly note that our re-assessment was of the mitotic count in these specimens. To clarify, these were carried out by either of two observers (CAD, JL) blinded to the original core and excision grading. The other elements of the tumour grade (tubule formation and nuclear score) were not re-assessed, but were as per the original report, that is to say, as reported prospectively by the original reporting pathologist. Similar to Nottingham, in Edinburgh five pathologists with a specialist or subspecialist interest in breast pathology were involved in reporting these cases. The mitotic counts of cases in which our count on review would have assigned the case to a different mitotic score (M) category were reviewed jointly by both authors and a consensus count agreed. These represented just 7% of our cases. It is thus very unlikely that this had any significant effect on the assessment of grade between core and excision.

    Edinburgh is one of the largest breast cancer centres in the UK. We follow the NHSBSP guidelines in our handling of specimens and are aware of the potential difficulties of poor fixation. We do not however have this problem, as evidenced by the grade distribution of tumours in our department which is comparable to other centres on national audit.[2]

    Lee's main concerns however appear to be that our series is selective (presumably relating to our inclusion of breast conserving surgery tumours only) and the low proportion of grade 3 tumours (on excision) in our series, suggesting it would lower the potential impact of undergrading on core biopsy.

    We did not include tumours treated by mastectomy principally because the majority of these (117/170) would have been excluded on the basis of multifocal disease (56), having received neoadjuvant chemotherapy / systemic therapy (31), having a past history of breast cancer (20) or having had their core biopsy performed in another hospital and not available for review (10). Had the remaining 53 cases been included they would not have made a material difference to the outcome or conclusions of our study and they would only have increased our proportion of grade 3 cancers to 29% (120/412).

    More importantly in relation to the potential impact of the proportion of grade 3 tumours in our series Lee at al fail to note that of our symptomatic cases 48% (72/150) were grade 3 on excision. Neither the whole symptomatic group nor the subset of 41 cases scored as (T3, N3, M1) within it showed benefit from application of the modification of the mitotic scores. Of the (T3, N3, M1) subset 14 would have been reclassified as grade 3* on core biopsy, only 6 of which were grade 3 on excision. As for all other subsets, in our experience there is a marginal increase in the sensitivity counterbalanced by a larger reduction in the specificity of cases designated as grade 3 on core biopsy using the modified scores.

    Finally, we do not seek to disprove the findings of Lee's group. They have shown their utility in their own population.[3] We demonstrate that they do not work in ours. Our conclusion remains that the current recommended mitotic count thresholds are appropriate and should be maintained. We agree that further studies could contribute to the debate, but note that the treatment of the breast cancer population is changing to include more cases receiving neoadjuvant therapy which may make repetition more difficult.

    References:

    1. Dhaliwal CA, Graham, C, Loane J. Grading of breast cancer on needle core biopsy; does a reduction in mitotic count threshold improve agreement with grade on excised specimens? J Clin Pathol 2014; 67:1106-8

    2. NHS breast screening programme and Association of Breast Surgery: An audit of screen detected cancers for the year of screening April 2012 to March 2013; Public Health England, May 2014.

    3. Lee A, Rakha E, Hodi Z et al. Re-audit of revised method for assessing the mitotic component of the histological grade in needle core biopsies of invasive carcinoma of the breast. Histopathology 2012; 60: 1166-7

    Conflict of Interest:

    None declared

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  3. Histological grade in needle core biopsies of invasive carcinoma of the breast: the potential role of reduction of mitotic count threshold in improving agreement with grade in the surgical specimen.

    Accurate histological grading of invasive carcinoma of the breast in needle core biopsies is important for patient management, for example for selecting patients for neoadjuvant chemotherapy. The grade in the core biopsy tends to underestimate the grade in the excision specimen, particularly due to underestimation of the mitotic count. We recently proposed a reduction in the threshold for the mitotic count which we found of particular value in tumours scored as T3, P3, M1 (less than 10% tubules, marked nuclear pleomorphism and few mitoses) and therefore grade 2 on the core biopsy.(1,2)

    Dhaliwal et al tested this approach in a 359 core biopsies in Edinburgh and found it to be of no value either in the whole series or in the T3, P3, M1 subset.(3) The two series of tumours show important differences. The histological grade of the Edinburgh carcinomas was on average lower: 27% of carcinomas were grade 3 in the surgical specimen compared with 40% in our series from Nottingham. Potential explanations for this difference include the high number of Edinburgh patients excluded because they received neoadjuvant chemotherapy (22% in Edinburgh compared with 4% in the older Nottingham series). Such patients often have grade 3 tumours. In addition the majority of Edinburgh cancers (58%) were detected by screening (such tumours tend to be of lower grade than symptomatic cancers as shown in tables 2 and 3 of the Edinburgh paper). Breast cancer resections in Nottingham are received fresh in the laboratory and incised immediately to ensure good fixation, which is important for accurate assessment of grade. Poorly fixed specimens tend to have lower grade including lower mitotic count. Were the specimens immediately incised in Edinburgh? Finally it is not clear why only tumours that were excised with breast conserving surgery were included.

    Dhaliwal achieved 79% agreement between grade in the core biopsy and the surgical specimen. As they state this is at the upper end of the range reported in the literature. The mitotic counts were assessed by two observers retrospectively and if there was a discordance with the original report the biopsy was reassessed. In the Nottingham study the core grade was assessed prospectively and independently by 5 different observers. Double reporting as performed in Edinburgh may improve the assessment of grade. The lower proportion of grade 3 tumours in Edinburgh reduces the potential impact of undergrading on the core biopsy.

    The Edinburgh study does not disprove the potential value of reducing the mitotic threshold as their series is selective with a low proportion of grade 3 tumours. Further studies including a good proportion of grade 3 tumours are needed to test whether reducing the mitotic threshold in the core biopsy is of value in assessing histological grade.

    1. O'Shea AM, Rakha EA, Hodi Z, Ellis IO, Lee AHS. Histological grade of invasive carcinoma of the breast assessed on needle core biopsy - modifications to mitotic count assessment to improve agreement with surgical specimen. Histopathology 2011;59:543-548 2. Lee AHS, Rakha EA, Hodi Z, Ellis IO. Re-audit of revised method for assessing the mitotic component of histological grade in needle core biopsies of invasive carcinoma of the breast. (Letter) Histopathology 2012;60:1166-1167 3. Dhaliwal CA, Graham C, Loane J. Grade of breast cancer in needle core biopsy: does a reduction in mitotic count threshold improve agreement with grade on excised specimens? J Clin Pathol 2014;67:1106-1108

    Conflict of Interest:

    None declared

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  4. Comment on: 'The value of autopsies in the era of high-tech medicine: discrepant findings persist." Kuijpers C.C.H.J. et al. J Clin Pathol 2014;67:512-519 doi:10.1136/jclinpath-2013-202122

    To the Editor: Without doubt the hospital-based autopsy is an effective quality assurance and learning tool. The study by Kuijpers et al. supports this.[1] However, autopsy is a time-consuming and expensive procedure which may sometimes cause distress to the deceased patient's family and be associated with complex consent issues. It is therefore important to ask how far reaching, beyond the pathologist and the referring clinician, is the learning impact of each individual autopsy?

    The clinician requesting the autopsy is interested in the bullet- point preliminary summary (based on the macroscopic findings) that is signed out immediately. But how often is the final detailed multi-page report followed up? Autopsies and the associated laboratory tissue- processing usually do not take priority in a busy diagnostic department. Final reports may not be verified for some time after the procedure, decreasing their learning impact.

    Frequency of minor diagnostic errors, as measured by the autopsy gold standard, is increasing over time.[1] Improper use of imaging investigations is contributing significantly to incorrect pre-mortem diagnosis.[1] Could it be that the main problem is that there has been a huge increase in the number of diagnostic investigations that can be requested during life? More investigations at our fingertips do not necessarily make things better for the doctor, or for the patient.[1] How do we learn how to optimally use these investigations to avoid misdiagnosis or alternatively to optimally learn from the inappropriate use of past investigations, so that errors are not repeated?

    Some of the current issues with use of diagnostic investigations are as follows: 1. Understanding the tests: a. Wrong test selected for the situation - whether it be imaging or diagnostic pathology. This results in false positives or false negatives; b. Sensitivity, specificity and positive/negative predictive value - these parameters of a particular imaging modality or pathology test may not be appreciated. Acting on the false result whether it is negative or positive may have significant detrimental clinical impact; c. With complex histopathology or imaging investigations, are the nuances in the body of the report skipped or overlooked by the treating clinician? 2. Communication: a. With immensely busy clinical loads, how often is the suitability of the investigation or the unexpected final result discussed with the radiologist or pathologist? In other words, how often do we practice in a vacuum because of time constraints? 3. Clinico-pathological and radio-pathological correlation: a. Were the radiologist or pathologist given any clinical information, and if not did they seek such information before reporting?

    Obviously selection and interpretation of diagnostic tests is often not clear-cut in the real world. Furthermore, with increasing numbers and complexity of diagnostic tests come increasing workloads for pathologists and radiologists. There is increased expectation from both patients and referring clinicians. Faced sometimes with extraordinary numbers of cases to report each day, the pathologist may fail to look for or may miss a vital component of the history that was provided to them by the radiologist or clinician. This is easy to do in an electronic era where most reports and referrals are scanned and it takes time to search. There will also always be cases where only a proportion of slides or images were viewed before issuing a report. Errors are part of the human condition. The key is to learn from errors and to not repeat them.

    In summary, autopsy has always been an excellent tool for quality assessment in diagnostic accuracy. But is it a teaching and quality assurance procedure that is time and cost-effective, with results that are easy to disseminate with maximum learning benefit? Focus on development and delivery of high impact and time-efficient continuing education modules (particularly online) regarding quality assurance errors and diagnostic and investigative medicine has already been demonstrated to be of value,[2] so such modules may represent an alternative solution to these issues.

    References 1. Kuijpers C.C.H.J., Fronczek J., van de Goot F.R.W., et al. J Clin Pathol 2014;67:512-519 doi:10.1136/jclinpath-2013-202122 2. Ritchie A., Jureidini E. and Kumar R.K. Educating Junior Doctors to Reduce Requests for Laboratory Investigations: Opportunities and Challenges. Med.Sci.Educ. 2014;24:161-163 DOI 10.1007/s40670-014-0041-2

    Conflict of Interest:

    None declared

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  5. Reply to Dr. G Stenhouse

    The correspondent points out that the RCPath standards of 2007 were written for a symptomatic population. This is not specifically stated in the standards, which were written just as the UK pilots of FOB screening were concluding. The current proposed standards (2014) are still in draft stage. It seems clear however that it will apply equally to all cancers. The issue of the effect of preoperative therapy on reporting of SI, EMVI and node number is important. Unfortunately in our retrospective audit the use of the prefix "y" in staging patients who have had preoperative therapy was not universally applied. It is also true that in many units, including our own, the pathologist is not always informed that the patient has been treated by an oncologist. A tighter prospective study is needed. It should be noted that the revised national standards do not make any allowance for the effect of chemotherapy and radiotherapy. The comment that the failure of some units to meet minimum standards "....is likely to have serious adverse consequences for patient care" is , we feel, justified. There is significant crossover in under-reporting as can be seen by inspection of the tabulated data. Unit 10 on our tables, for example, did not report serosal invasion in any rectal cancer, reports only 10% EMVI and has a mean node yield of 5 for rectum and 10 for colon. It is certain that this will have led to understaging and possibly to denial of treatment to patients who would have benefitted. I agree that electronic reporting systems would be a major asset. We would certainly hope to ask for documentation of preoperative treatment in our follow-up audit!

    Conflict of Interest:

    None declared

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  6. Comment on 'A Survey of colorectal cancer in Scotland: compliance with guidelines and effect of proforma reporting'.

    Dear Editor,

    I entirely agree with the authors of 'A Survey of reporting of colorectal cancer in Scotland: compliance with guidelines and effect of proforma reporting'1 that proforma reporting should be standard across Scotland for reporting colorectal caner excision specimens. Although obvious, I feel it should be stated the 2007 RCPath dataset standards 2 were issued for a symptomatic population and, as stated in the study, these audited cases were both screening and symptomatic. Also, in their conclusions they allude to the potential impact that neo-adjuvant therapy could play in Serosal Involvement (SI), Lymph node retrieval and extramural venous invasion (EMVI) but state that this aspect could not be accurately assessed in this study. All reported cases in our Health Board are staged using TNM5 and, as such, will be prefixed with 'y' to identify them as having had neo-adjuvant therapy. If this was not known prior to reporting, a supplementary report will be issued after the case has undergone MDT discussion when the patient history is reviewed. This may be unique to our health board but, as it is part of the RCPath dataset, it should also be recorded.

    I do find the wording used in 'What this paper adds', where it states that "....this is likely to have serious adverse consequences for patient care." hard to extract from the data presented and this claim is not reported in the article by the authors themselves. The data suggests that there may be a group of patients that are falsely node 'negative' due to insufficient nodal sampling and a further group in whom the EMVI or SI is not identified. However, it does not state the cross over between these groups or if the ones 'missing' the EMVI/SI are node positive patients. Taken together this suggests that a small percentage of patients may have been excluded the option of adjuvant therapy, but without looking at specific patient outcomes and the case slides is it fair to label this as 'serious adverse consequences for patient care'?

    I do look forward to the results of the repeat data collection which will, hopefully, show proformas being used across all NHS Scotland boards as well as an uplift in the percentage of boards reaching all the standards. Further investigation of a national electronic dataset would also be welcomed especially if the data required for such audits can be extracted easily and possibly centrally from this. Given the existence of one in Norway maybe we should be moving to access that and use it throughout Scotland? I am sure the follow up audit will also take into account the influences of neo-adjuvant therapies on the audited adverse factors in the rectum, a treatment which is an established local practice, but also the emerging use of neo-adjuvant therapy in advanced colonic cancers. These data could be collated to allow reporting of all cases together and in different cohorts (Treatment naive V's neo-adjuvant) to try to identify the changes attributable to therapy.

    Conflict of Interest:

    I report GI resection specimens in a health board in Scotland that provided raw data for this survey. (Our board median nodal count is above 17 for both colonic and rectal excisions including post treatment cases)

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  7. Re:Mucosal large cell neuroendocrine carcinoma of the head and neck regions:inconsistent data

    Answers to the letter Dear Dr. Sir. 1. We confirmed that the patient was 79 years-old man on case 2. As the mitosis index and the Ki-67 labeling index were estimated with newly prepared sections, the indices were a bit different. We confirmed that the tumor cells were focally positive for chromogranin-A, but negative for synaptophysin on case 2. 2. Certainly, at the writing step of the review article (ref.3), the prognosis of our series of M-LCNEC was relatively good, but the prognosis became worse one year after that time. We concluded that the prognosis of M-LCNEC was relatively worse, like the LCNEC of other organs, in this recent paper (ref. 1). Moreover, we confirmed that three cases of M-LCNEC were positive for thyroid transcription factor(TTF)-1. 3. We confirmed that the age ranged from 52 to 74 years old in our M-LCNEC series and that four patients were alive without disease (31 months, 18 months, 24 months and 90 months).

    Dr. Kimihide Kusafuka, D.D.S., Ph.D. Pathology Division, Shizuoka Cancer Center Hospital and Research Institute

    Conflict of Interest:

    None declared

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  8. To the Editor

    To the Editor:

    In their review article "Challenges and controversies in the diagnosis of mesothelioma: Part 1. Cytology-only diagnosis, biopsies, immunohistochemistry, discrimination between mesothelioma and reactive mesothelial hyperplasia, and biomarkers", Henderson et al.1 describe and illustrate "rod-like or cylindrical crystalloids as seen in numerous mesothelial cells in the pleural effusion of a malignant mesothelioma". The authors state "so far as we are aware they have been reported only in epithelioid malignant mesothelioma (MM)". In an effort to clarify/correct the impression that these inclusions are specifically associated with epithelioid MM, I report a series of 16 benign pleural fluids and 1 benign pericardial fluid each containing mesothelial cells with these rod-like or crystalloid inclusions (Figure 1,2). None of the 17 patients had a diagnosis of MM and none developed MM during follow-up (range from 1 to 7 yrs). The patients (13 males, 4 females) ranged from 13 to 91 years in age (median 78.5 yrs.) at thoracentesis/ pericardiocentesis. Clinical diagnoses included congestive heart failure, chronic renal disease, end stage liver disease, pneumonia, and CLL. Three of the 17 patients had a diagnosis of carcinoma (endometrioid endometrial, renal clear cell, and cutaneous squamous cell); none of these tumors involved the effusion. Others have also reported similar appearing crystalloids within mesothelial cells in effusions in a variety of benign conditions. 2, 3

    References: 1. Henderson DW, Reid G, Kao SC, et al. Challenges and controversies in the diagnosis of mesothelioma: Part 1. Cytology-only diagnosis, biopsies, immunohistochemistry, discrimination between mesothelioma and reactive mesothelial hyperplasia, and biomarkers. J Clin Pathol 2013;66:847-853. 2. Zaharopoulos P, Wen JW, Wong J. Membranous lamellar cytoplasmic inclusions in histiocytes and mesothelial cells of serous fluids. Acta Cytol 1998;42:607-613. 3. Lang E, Uthman M. Pseudo-Gaucher cells in peritoneal fluid: An uncommon manifestation of extramedullary hematopoiesis. Diagn Cytopathol 1999;20:379-381.

    Please note Figs 1,2 (jpgs) have been emailed to Mr. Rinon along with a copy of this letter.

    Conflict of Interest:

    None declared

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  9. Re:About uncertainty in IBD histological diagnosis

    Firstly, Dr Canavese and colleagues' interest in the guideline document is much appreciated. Before responding specifically, it is worth noting that there are two main diagnostic decisions to make when a patient presents with suspected chronic idiopathic inflammatory bowel disease (IBD): distinguishing IBD from other causes of inflammation; and classifying IBD as ulcerative colitis (UC) or Crohn's disease (CD). Even with full clinical details, comprehensive sampling, and assessment by a well-informed pathologist there will be a significant minority of IBD biopsies that cannot be classified confidently as UC or CD.[1, 2] There will also be a number that cannot even be categorised as IBD or non-IBD. However, I agree entirely that several other factors beyond the pathologist's control may also contribute to diagnostic uncertainty. Indeed, the proven importance of adequate clinical details and of thorough sampling are often noted in clinical guidelines.[1, 3-8] For example, limited sampling within and between sites may be one of the reasons why histopathologists are apparently less successful at diagnosing CD than diagnosing UC.[7-9] I also agree that pathologists have a responsibility to convey the level of diagnostic certainty as clearly as possible to the clinical teams. Proposed categories for the conclusion of an IBD biopsy report have been included in the BSG guideline ("PAID" scheme, Table 14).[10] The suggested terminology represents a consensus view on the best way to express probability. Accordingly, its adoption is recommended. Similarly, vague terms such as "in keeping with" are best avoided or used sparingly (Table 13).[10] Dr Canavese and colleagues' suggested solutions are helpful. I agree that the pathologist should insist on a minimum standard of clinical input. Indeed, provision of the endoscopy report to the pathologist will be recommended strongly in a forthcoming guideline for clinicians.[11] Similarly, identifiable deficiencies in the process should be noted by the pathologist interpreting the biopsies, especially if they interfere with assessment. Also, a statement in a histology report that repeat endoscopy and sampling might be informative would oblige the clinician to consider this option. However, enforcement of minimum clinical standards can be difficult. Overall, better communication between pathologists and clinicians, ideally in the setting of a regular clinicopathological meeting, is an excellent way to enhance diagnostic accuracy.[4, 10, 12] On a more general note, the scope and quality of IBD services and the reasons for suboptimal management may vary within and between countries. Attempts are being made to remedy the inconsistencies. Reassuringly, a UK services standards document for IBD includes guidance on the use of histopathology services and is cognisant both of the value of biopsy assessment and of the importance of interaction between pathologists and clinicians.[13]

    Yours sincerely,

    Professor R M Feakins

    Conflict of Interest:

    None declared

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  10. About uncertainty in IBD histological diagnosis

    Dear Prof. Feakins,

    First of all we wish to express our congratulations for your excellent reporting guidelines about the diagnosis of IBD on biopsies published in JCP, September 2013.

    About this important matter, we would like to make some comments based on our personal experience. Regarding the terminology in the histological diagnosis of IBD, it was stated (section "Probability" in the paragraph "Terminology") that "unfortunately, there are no universal agreed of terms to describe the various levels of certainty or uncertainty encountered by the histopathologists and the clinicians, unless the diagnosis is definite". In this meaning, the "level of uncertainty" of diagnosis defines the category of cases that do not satisfy the conventional criteria for a definite diagnosis of IBD or non IBD colitis, due to inadequate clinical information, as well as to inadequate number and quality of biopsies or unclear microscopic pattern (absence of IBD -specific lesions). This group of histological diagnoses with a significant level of uncertainty is relevant in IBD management for various reasons:

    1) It represents a large portion of the patients that underwent endoscopy with a clinical suspicion of IBD, given the frequent inadequacy of the prerequisites of diagnosis in clinical practice, as stated in your recent paper, published in this journal. We confirmed this trend in a recent study of our group, based on the evaluation the clinical/endoscopic information, the sampling procedures and the histological characteristics of 353 histological reports collected from 13 of the most representative gastroenterological centres in Piedmont (Italy), that evidenced a low rate of adequacy (5% adequate clinical/endoscopic information, 13% adequate sampling and no case with a correct orientation of the samples). (The first results will be presented at the Congress of the Italian Pathologists Society - SIAPEC Rome October 2013 and then published).

    2) The nomenclature of this category of cases is still heterogeneous, as well described in your paper, and often equated with a definite diagnosis in clinical practice.

    3) There is no clear indication about the management of patients with this typology of histological diagnosis. In our opinion, the effect of these anomalies is often inappropriate treatment for these patients, with the consequent modifications of the endoscopic pattern, that reduces the chance of a further diagnostic setting. Moreover, these diagnoses may be misleading in the case studies. Thus, we think it might be useful to consider this item in the management of IBD patients and to improve the quality of the histological diagnosis in the first evaluation of patients with clinical/endoscopic pattern suggestive of IBD (see also our letter to the editor [World J Gastroenterol 2013 January 21; 19(3): 426-428]) by:

    1. implementing a minimum mandatory set of clinical information and histological sampling that could fit with an appropriate diagnostic process in histology and using an univocal nomenclature for histological diagnosis that does not meet these requirements, with the goal of reducing the number of inconclusive or inappropriate diagnoses.

    2. adopting the repetition of the endoscopy (after a brief discussion with the clinical staff) for all the cases with a significant "level of uncertainty" in histological diagnosis.

    We hope that you agree with the need to obtain a more definite diagnosis for the patients, and we are strongly interested in your opinion about this topic. Thank you for your attention.

    We look forward to your kind response,

    Yours

    Conflict of Interest:

    None declared

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