Letter to the Editor – Journal of Clinical Pathology
We read with interest the invited editorial by Grealish et al. entitled “Standardisation of practice for Canadian pathologists' assistants.” First of all, we would like to congratulate the CAP-ACP Executive Committee on its accomplishments to date. Establishing a method for board certification of Canadian Pathologists’ Assistants (PAs) is an important achievement which promotes standardization and high quality anatomical pathology services.
However, our primary reason for writing is to address an error of omission. The editorial correctly notes that there are four two year long Master’s PA training programs in Canada; however, it should be also noted that these vary considerably in size with a ten-fold difference between the largest and the smallest based upon the number of students currently enrolled. The editorial then implies that Canadian training programmes are not accredited and are in need of some new mechanism to become accredited. The editorial states that “the pursuit of creating a ... Canadian accrediting body for PA training programme is ongoing.” We respectfully disagree. The two large Canadian training programmes, hosted by the University of Calgary and Western University, respectively have each been accredited by the National Accrediting Agency for Clinical Laboratory Sciences (NAACLS) (https://www.naacls.org/about.aspx ). NAACLS...
Letter to the Editor – Journal of Clinical Pathology
We read with interest the invited editorial by Grealish et al. entitled “Standardisation of practice for Canadian pathologists' assistants.” First of all, we would like to congratulate the CAP-ACP Executive Committee on its accomplishments to date. Establishing a method for board certification of Canadian Pathologists’ Assistants (PAs) is an important achievement which promotes standardization and high quality anatomical pathology services.
However, our primary reason for writing is to address an error of omission. The editorial correctly notes that there are four two year long Master’s PA training programs in Canada; however, it should be also noted that these vary considerably in size with a ten-fold difference between the largest and the smallest based upon the number of students currently enrolled. The editorial then implies that Canadian training programmes are not accredited and are in need of some new mechanism to become accredited. The editorial states that “the pursuit of creating a ... Canadian accrediting body for PA training programme is ongoing.” We respectfully disagree. The two large Canadian training programmes, hosted by the University of Calgary and Western University, respectively have each been accredited by the National Accrediting Agency for Clinical Laboratory Sciences (NAACLS) (https://www.naacls.org/about.aspx ). NAACLS is a highly coveted international standard that permits our graduates to write the American Society of Clinical Pathology (ASCP) board of certification (BOC) exam as well as the new Canadian Certification Council of Canada (CCCPA) exam and thus our graduates are able to practice on both sides of the border. Presently NAACLS accredits the eight PA training programs in the US (two more are in the final stages of approval) and the above named two in Canada (http://www.pathassist.org/?page=AboutUs_NAACLS); it also accredits training programs in a myriad of other technical arenas in the US and elsewhere. We would suggest that there is no need to create a redundant accreditation specific to Canada given that the two programs already represent the vast majority of Canadian trainees and given the undisputable standards of the NAACLS. Furthermore, nothing precludes other Canadian programmes from seeking and obtaining NAACLS accreditation. Grealish et al.’s suggestion that there should be a “Canadian accrediting body” to address four training programmes is not only unnecessary but would be costly and suffer from unavoidable conflicts of interest because of insufficient critical mass.
The appropriate ‘made in Canada’ solution was already found in the Canadian certification process. While there initially had been considerable enthusiasm in Canada for simply adopting the pre-existing American certification process, this approach did not address the needs of Canadian on-the-job trained (OJT) PAs, which as correctly noted in the editorial, began the profession in Canada and should be honoured. Therefore, separate certification examinations in Canada and the US were, unfortunately, unavoidable. However, having taken this approach to certification is not a good enough reason to start down the pathway of dual program accreditations. We would like to stress that North America-wide accreditation is the best solution for Canadian training programmes and their trainees. Quite simply, NAACLS accreditation is the gold standard and Canadians should not settle for anything less!
Reference:
Grealish M, Wolff A, Eastwood J, Lee D; PA Section of the CAP-ACP Executive Committee. Standardisation of practice for Canadian pathologists' assistants. J Clin Pathol. 2017 Dec;70(12):998-1000. Epub 2017 Sep 12.
We found the paper ‘Long QT syndrome and sudden unexpected infant death’ by Van Niekerk and colleagues to be comprehensive and interesting. We would like to point out that there appears to be a misunderstanding as the authors state that in Australia and New Zealand all sudden and unexpected deaths are mandated to undergo targeted post-mortem genetic testing. Guidelines published by TRAGADY (Trans-Tasman Response AGAinst sudden Death in the Young) advocate that material suitable for DNA extraction must be obtained as part of the best practice guidelines for investigation of sudden death of a young person (1). However, subsequent genetic analysis is not mandated. A policy on the genetic investigation of cause of death in coronial autopsy cases has been recently released by the Royal College of Pathologists of Australasia (RCPA) (2). It is likely this policy document was not available at the time Van Niekerk and colleagues were writing their paper. The RPCA policy states that genetic testing of the deceased is not endorsed in the absence of engagement of the family of the deceased with a genetic counselling service and confirmation of a family history compatible with a heritable disorder. Ideally, there should be identification in the living relatives of a putative genetic defect (or defects) or phenotype for which testing is available. For a number of reasons, some of which are outlined in the RCPA policy document, mandatory post-mortem genetic testing may not be benefic...
We found the paper ‘Long QT syndrome and sudden unexpected infant death’ by Van Niekerk and colleagues to be comprehensive and interesting. We would like to point out that there appears to be a misunderstanding as the authors state that in Australia and New Zealand all sudden and unexpected deaths are mandated to undergo targeted post-mortem genetic testing. Guidelines published by TRAGADY (Trans-Tasman Response AGAinst sudden Death in the Young) advocate that material suitable for DNA extraction must be obtained as part of the best practice guidelines for investigation of sudden death of a young person (1). However, subsequent genetic analysis is not mandated. A policy on the genetic investigation of cause of death in coronial autopsy cases has been recently released by the Royal College of Pathologists of Australasia (RCPA) (2). It is likely this policy document was not available at the time Van Niekerk and colleagues were writing their paper. The RPCA policy states that genetic testing of the deceased is not endorsed in the absence of engagement of the family of the deceased with a genetic counselling service and confirmation of a family history compatible with a heritable disorder. Ideally, there should be identification in the living relatives of a putative genetic defect (or defects) or phenotype for which testing is available. For a number of reasons, some of which are outlined in the RCPA policy document, mandatory post-mortem genetic testing may not be beneficial.
References:
1. Skinner J, Duflou JA, Semsarian C. Reducing sudden death in young people in Australia and New Zealand: the TRAGADY initiative. Med J Aust. 2008;189:539 - 40.
2. Royal College of Pathologists of Australasia. Genetic investigation of cause of death in coronial autopsy cases. Sydney, Australia; 2017 [updated 2017; cited 2018 1 January]; Available from: https://www.rcpa.edu.au/getattachment/0b40e990-3778-4aca-aaeb-1ea1d42441....
El Jabbour T et al. (Jun 2017) described the association between immunohistochemical PD-L1 positivity and loss of MMR proteins in colorectal cancer. However, the evaluation of Mismatch Repair Deficiency (dMMR) as a immunotherapy predictive marker is lacking for Malignant Melanoma (MM) and other malignancies, such as genitourinary, prostate, bladder, head and neck cancers, that are treated with immune checkpoint inhibitors (ICPI).
We recently assessed dMMR in MM patients treated with anti-PD-1/PD-L1 during 2014-2016 at University of Modena and Reggio Emilia: 7% of primary melanoma and 13% of metastasis showed the dMMR. We report a patient whose primary MM and metastasis showed dMMR with immunohistochemical lack of MSH6 expression. Her complex history was characterized by the regression of the multiple cerebral and visceral metastases after anti-PD-L1 therapy, and an extraordinary progression-free survival (1150 days) and overall-survival (2646 days). At present, she is still alive and well, and had the longest response to anti-PD-L1 treatment.
Our results emphasize that the immunohistochemical assessment of MMR protein expression in MM patients represents a useful predictive marker, which may have crucial importance for the determination of the response of anti-PD-1/PD-L1 therapy for MM and potentially for other solid malignancies treated with ICPI therapy.
In their article considering the relationship between Articles 8 and 9 of the European Convention of Human Rights (ECHR) and coronial autopsies, Leadbeatter and James argue that recourse to invasive autopsy ought only to be made after an ‘issues based’ investigation establishes that this is necessary. This stands in stark contrast to current practice.
Whilst Leadbeatter and James write to report their own research findings and discuss the decision in R (Rotsztein) v HM Senior Coroner for Inner London North, I was prompted to consider whether they were too restrained in their conclusions. My primary concern is that whilst redress to the ECHR may be legally and rhetorically attractive, it means that outcomes are dependent on the still living taking action. This may, or may not, promote the deceased person’s preferred course of action.
Prior to addressing this point in more detail, however, a brief mention to the necessity of invasive autopsies where a death occurs in suspicious circumstances. Leadbeatter and James discuss this; I found their discussion of ‘injury’ (Box 2, Issue 4) particularly interesting. They give the example of road or train deaths, where their approach was to first review evidence from the scene, take toxicology samples and remove trace evidence. Another example might be where a person is shot in the head at close range, the events being caught on CCTV. These examples highlight that even in extreme circumstances evisceration of the body m...
In their article considering the relationship between Articles 8 and 9 of the European Convention of Human Rights (ECHR) and coronial autopsies, Leadbeatter and James argue that recourse to invasive autopsy ought only to be made after an ‘issues based’ investigation establishes that this is necessary. This stands in stark contrast to current practice.
Whilst Leadbeatter and James write to report their own research findings and discuss the decision in R (Rotsztein) v HM Senior Coroner for Inner London North, I was prompted to consider whether they were too restrained in their conclusions. My primary concern is that whilst redress to the ECHR may be legally and rhetorically attractive, it means that outcomes are dependent on the still living taking action. This may, or may not, promote the deceased person’s preferred course of action.
Prior to addressing this point in more detail, however, a brief mention to the necessity of invasive autopsies where a death occurs in suspicious circumstances. Leadbeatter and James discuss this; I found their discussion of ‘injury’ (Box 2, Issue 4) particularly interesting. They give the example of road or train deaths, where their approach was to first review evidence from the scene, take toxicology samples and remove trace evidence. Another example might be where a person is shot in the head at close range, the events being caught on CCTV. These examples highlight that even in extreme circumstances evisceration of the body may add little by way of useful information.
This leads to my more substantive concern. That is, that grounding the argument against routine invasive autopsy in the rights to freedom of religion and/or family life risks minimising wider sentiments felt regarding the treatment of deceased bodies. I have argued (see I Jones, A Grave Offence: Corpse Desecration and the Criminal Law (2017) Legal Studies (Online first)) that it is an objective moral wrong to act in a way that is disrespectful towards a cadaver. The objectivity here stems from the almost universal commitment to the deceased body as, to quote Feinberg, a ‘sacred symbol’ of the ante-mortem person. This transcends religious adherence, cultural mores and familial relationships. We only need look to the responses to the organ retention scandals to see that religion alone is not responsible for the feeling that an, albeit scientifically, mutilated body is one which has been irreparably desecrated.
Leadbeatter and James’ findings therefore prompt the question, does the current approach of regular recourse to invasive autopsy violate wider social norms? If, as they argue, many of these procedures are unnecessary (in the sense of enabling the Coroner to discharge his duty and/or obtaining evidence to facilitate an effective criminal investigation) then it strikes me that when these autopsies are carried out, there is a strong case that invasive autopsies constitute acts of disrespect. Thus, in such circumstances an easily avoidable moral wrong is being committed against both the living and the dead.
Without religious doctrine to fall back on, at a time of shock and grief, and in the face of medical and legal authority, many people will not feel able to challenge the decision to order an invasive autopsy. Leadbeatter and James’ results suggest that change can, and should, come from within the medical profession. My feeling is that this ought to happen sooner rather than later; pathology could do without further public outcry.
We are intrigued by, and sympathetic toward, Dr Jones’ argument; we had approached our argument from the existing case law rather than from the fundamental position that dissection without good reason is morally unacceptable. We can understand that that position is supported by the need for appropriate consent in circumstances outwith a coroner’s jurisdiction. We would agree that invasive dissection that serves no defined purpose cannot be consonant with autonomy, beneficence, non-maleficence and justice.
Dear Editor
RE: Atypical aspirates of the breast: a dilemma in current cytology practice. Shuang-Ni Yu, Joshua Li, Sio-In Wong, Julia Y S Tsang, Yun-Bi Ni, Jie Chen, Gary M Tse. J Clin Pathol 2017;0:1–9. doi:10.1136/jclinpath-2016-204138
We read with interest the findings of Shuang-Ni Yu et al regarding “Atypical aspirates of the breast: a dilemma in current cytology practice” first published on May 29 2017 in Journal of Clinical Pathology.
Breast fine needle aspiration (FNA) utilisation has been in decline for some time and there are several reasons for the drop in the uptake of cytology in the investigation of breast diseases. Although the main sited reason is increased demand for ancillary tests, greater subjectivity of cytology when compared to histology which is generally regarded as the gold standard, and the unpreparedness of pathologists to provide unequivocal diagnoses not only in the borderline lesions but also in low grade malignancies. The need to provide a consistently high quality service to engender confidence in our speciality has never been greater.
The probabilistic approach to reporting FNA based on the 5 tier categories (C1 unsatisfactory; C2 benign; C3 atypical/indeterminate; C4 suspicious; and C5 malignant) does provide reliable accurate diagnoses for all categories except C1 unsatisfactory and C3 atypical/indeterminate categories. The C1 category highlights a failed FNA procedure whilst a C3 result indicates some diagnostic un...
Dear Editor
RE: Atypical aspirates of the breast: a dilemma in current cytology practice. Shuang-Ni Yu, Joshua Li, Sio-In Wong, Julia Y S Tsang, Yun-Bi Ni, Jie Chen, Gary M Tse. J Clin Pathol 2017;0:1–9. doi:10.1136/jclinpath-2016-204138
We read with interest the findings of Shuang-Ni Yu et al regarding “Atypical aspirates of the breast: a dilemma in current cytology practice” first published on May 29 2017 in Journal of Clinical Pathology.
Breast fine needle aspiration (FNA) utilisation has been in decline for some time and there are several reasons for the drop in the uptake of cytology in the investigation of breast diseases. Although the main sited reason is increased demand for ancillary tests, greater subjectivity of cytology when compared to histology which is generally regarded as the gold standard, and the unpreparedness of pathologists to provide unequivocal diagnoses not only in the borderline lesions but also in low grade malignancies. The need to provide a consistently high quality service to engender confidence in our speciality has never been greater.
The probabilistic approach to reporting FNA based on the 5 tier categories (C1 unsatisfactory; C2 benign; C3 atypical/indeterminate; C4 suspicious; and C5 malignant) does provide reliable accurate diagnoses for all categories except C1 unsatisfactory and C3 atypical/indeterminate categories. The C1 category highlights a failed FNA procedure whilst a C3 result indicates some diagnostic uncertainty. This uncertainty is reflected in the heterogeneous mix of pathological outcomes found within C3 aspirates, ranging from benign to malignant lesions.
Yu et al study has identified potentially helpful quantitative, cytomorphological and background features to predict the risk of malignancy within the C3 category. These findings may translate to changed clinical management decisions.
They confirm our work and their study supports our previously published results 1-3. In our earlier study we used a comprehensive range of morphological criteria and eliminated those that did not reach statistical significance in predicting either a malignant or a benign proliferative outcome within C3. We created an algorithm to predict the probability of malignancy based on 180 consecutive C3 cases using five significant criteria (cystic background; cohesiveness; presence of myoepithelial cells or bare bipolar nuclei; papillary fragments; and tubules). This algorithm was then applied to a subsequent 182 consecutive C3 cases and the accuracy of the model was evaluated with logistic regression and receiver operating characteristic (ROC) curves. By applying this algorithm based upon the presence or absence of our key criteria we were able to stratify the risk of malignancy within C3. An upper cut-point was established, above which a case with a high probability of malignancy could be upgraded to C4.
Our work and the current study by Yu et al support and cross validates the challenges presented by the C3 category. The similarity in the approach of both studies provides well-defined criteria with strong discriminating values and reveals the complex nature of C3. Indeed, this platform of evidence based knowledge may contribute to the review of the structured breast FNA reporting guidelines proposed by the International Academy of Cytology.
The decline in FNA use is not evidence based but rather due to lack of expertise and confidence. With robust, objective studies delving into the grey areas of FNAs, coupled with a renewed well-defined structured reporting system, FNA of the breast may see a resurgence of popularity. FNA is a less invasive procedure when compared to core biopsy, is cost effective, amenable to rapid onsite evaluation including triaging for ancillary tests and has a quick turnaround time which benefits patients and their treating clinicians.
Julie Weigner & Ibrahim Zardawi
1. Weigner. J, Zardawi. I, Braye. S. The True Nature of Atypical Breast Cytology. Acta cytologica. 2013;57(5):464-472.
2. Weigner. J, Zardawi. I, Braye. S, McElduff. P. The Microscopic Complexities of C3 in Breast Cytology. Acta cytologica. 2014;58(4):335-346.
3. Weigner J., Zardawi I., Braye S., McElduff P. The Conundrum of Papillary Breast Lesions within the C3 Category. Acta cytologica. 2015;59(4):289-297.
We were pleased to read the correspondence ‘Stage II patients can benefit from OSNA molecular lymph node staging’ from Cuatrecasas et al. and grateful for the authors’ interest and comments. Our study with one-step nucleic acid amplification (OSNA) for patients with colorectal cancer (CRC) primarily aimed to evaluate the accuracy of the test as compared with the standard care approach of a single H&E microscopic examination. We hoped to share with readers our experiences of working with this technology and highlight the challenges other centres will need to consider before introducing the service.[1]
While we acknowledged the concern raised by Cuatrecasas et al. that our study cohort of 19 patients is small, we emphasise that we tested 82 lymph nodes with OSNA and feel our results show a fair indication of the concordance of the assay with routine histology. It is also important to point out that initially more patients were recruited for the study but several specimens had to be excluded due to faecal contamination, sealed perforation or macroscopic serosal (T4) disease – all of which could arguably lead to false positive results by OSNA. The significance of our data is that to our knowledge this was the first time OSNA had been fairly compared with routine histology rather than intensive work-up of multiple levels, immunohistochemistry (IHC) and conventional molecular methodologies. We agree that there is insufficient convincing evidence that intensive interrog...
We were pleased to read the correspondence ‘Stage II patients can benefit from OSNA molecular lymph node staging’ from Cuatrecasas et al. and grateful for the authors’ interest and comments. Our study with one-step nucleic acid amplification (OSNA) for patients with colorectal cancer (CRC) primarily aimed to evaluate the accuracy of the test as compared with the standard care approach of a single H&E microscopic examination. We hoped to share with readers our experiences of working with this technology and highlight the challenges other centres will need to consider before introducing the service.[1]
While we acknowledged the concern raised by Cuatrecasas et al. that our study cohort of 19 patients is small, we emphasise that we tested 82 lymph nodes with OSNA and feel our results show a fair indication of the concordance of the assay with routine histology. It is also important to point out that initially more patients were recruited for the study but several specimens had to be excluded due to faecal contamination, sealed perforation or macroscopic serosal (T4) disease – all of which could arguably lead to false positive results by OSNA. The significance of our data is that to our knowledge this was the first time OSNA had been fairly compared with routine histology rather than intensive work-up of multiple levels, immunohistochemistry (IHC) and conventional molecular methodologies. We agree that there is insufficient convincing evidence that intensive interrogation of lymph nodes to identify micrometastases or single tumour cells is of clinical benefit in terms of predicting survival or identifying those Stage I/II patients who will experience recurrence, nor is there good evidence that upstaging histologically node-negative patients and exposing them to potentially harmful chemotherapy would improve their survival. There is certainly no such evidence for this to be carried out routinely via OSNA testing. Given this, even if a test such as OSNA was shown to be more sensitive than current methods we see no reason for a change in practice at this stage. The reported accuracy data for ONSA have actually been mixed though[2-6] and in addition, as Cuatrecasas et al. say, any new method of lymph node analysis will be costlier than traditional approaches and so any such expenditure must be fully justified. In breast cancer it seems that OSNA is not cost-effective,[7] but in colorectal cancer a full economic analysis has yet to be performed. We definitely do not deny though that the use of OSNA in some contexts, including in conjunction with new surgical techniques, may potentially be of benefit in the future; the data in our original correspondence were later included in the manuscript of a wider surgical trial published elsewhere.[8]
The authors commented that our lymph node yield for OSNA testing was low in most cases but this does not reflect the overall lymph node sampling for each patient. The total lymph node count was 355 from 19 patients (range 9 to 32 nodes per patient, median 18). We also wish to emphasize that in our study we have used comparable inclusion and exclusion criteria for OSNA, In addition, after standard fixation, further small lymph nodes were often identified during dissection of the specimen and by submitting additional fatty tissue in search of lymph nodes. Extra care and diligence were taken to achieve a minimum of 12 lymph nodes recommended by the Royal College of Pathologists.[9] However, the aim of the study was to assess the ability of OSNA to detect metastases, not to evaluate how OSNA may affect staging and we do not feel this is a true limitation of our results. We too found that pooling lymph nodes does help to overcome processing limitations and to bring down costs – this does however potentially pose a difficulty with accurately determining the N stage if there is a positive OSNA result.[9] This also leaves no tissue for future investigation, clinical or research. It is also important to bear in mind that tumour deposits or circumscribed nodules of extramural venous invasion located in the soft tissue can be mistaken for lymph nodes at fresh dissection which itself poses significant challenges on histology to classify soft tissue tumour deposit as vascular invasion or nodal metastasis. If unable to tell on histology, this will be staged as ‘pN1c’. This issue has caused much debate in the 6th to 8th Edition of the AJCC Cancer Staging Manual and UICC TNM for CRC.[10-12] Without histology, we will never know if we truly have submitted lymph node or soft tissue deposit resulting from venous invasion for OSNA. Refrigeration of the specimen until a convenient time for dissection is a possible solution to overcome one of the logistical issues we encountered. This would of course require considerable additional fridge space and proper validation of histology and immunohistochemistry acquired following this change of protocol.
We share the authors’ view that the future of molecular testing in CRC is probably going to change traditional histological practice and we welcome such advancement. We also recognise that a single H&E section represents a small proportion of a lymph node and follow with interest the concept of total tumour load in CRC. However, for the foreseeable future, the UK uses TNM and RCPath guidelines for reporting CRC which in turn are based on the best current available evidence for predicting behaviour in these patients.[9-12] We hope and expect the evidence base to continue to grow and are confident that future staging systems will adapt accordingly.
Conflict of Interest
None declared
References
1. Colling R., Yeung T., Hompes R., Kraus R., Cahill R., Mortensen N. and Wang L.M. OSNA testing for lymph node staging in colorectal cancer. J Clin Pathol, 2017. 70(7): p. 638-639.
2. Croner R.S., Geppert C.I., Bader F.G., Nitsche U., Spath C., Rosenberg R., Zettl A., Matias-Guiu X., Tarragona J., Guller U., Sturzl M. and Zuber M. Molecular staging of lymph node-negative colon carcinomas by one-step nucleic acid amplification (OSNA) results in upstaging of a quarter of patients in a prospective, European, multicentre study. Br J Cancer, 2014. 110(10): p. 2544-2550.
3. Croner R.S., Schellerer V., Demund H., Schildberg C., Papadopulos T., Naschberger E., Sturzl M., Matzel K.E., Hohenberger W. and Schlabrakowski A. One step nucleic acid amplification (OSNA) - a new method for lymph node staging in colorectal carcinomas. J Transl Med, 2010. 8: p. 83.
4. Guller U., Zettl A., Worni M., Langer I., Cabalzar-Wondberg D., Viehl C.T., Demartines N. and Zuber M. Molecular investigation of lymph nodes in colon cancer patients using one-step nucleic acid amplification (OSNA): a new road to better staging? Cancer, 2012. 118(24): p. 6039-45.
5. Yamamoto H., Tomita N., Inomata M., Furuhata T., Miyake Y., Noura S., Kato T., Murata K., Hayashi S., Igarashi S., Itabashi M., Kameoka S. and Matsuura N. OSNA-Assisted Molecular Staging in Colorectal Cancer: A Prospective Multicenter Trial in Japan. Ann Surg Oncol, 2016. 23(2): p. 391-6.
6. Vogelaar M.F.J., Reimers M.M.S., der L.R.L.A.v., Linden M.J.C.v.d., PhD, Smit M.V.T.H.B.M., PhD, Lips M.D.J., PhD, Velde M.C.J.H.v.d., PhD, Bosscha M.K. and PhD. The Diagnostic Value of One-Step Nucleic acid Amplification (OSNA) for Sentinel Lymph Nodes in Colon Cancer Patients. Annals of Surgical Oncology. 21(12): p. 3924-3930.
7. Huxley N., Jones-Hughes T., Coelho H., Snowsill T., Cooper C., Meng Y., Hyde C. and Mujica-Mota R. A systematic review and economic evaluation of intraoperative tests [RD-100i one-step nucleic acid amplification (OSNA) system and Metasin test] for detecting sentinel lymph node metastases in breast cancer. Health Technol Assess, 2015. 19(2): p. v-xxv, 1-215.
8. Yeung T.M., Wang L.M., Colling R., Kraus R., Cahill R., Hompes R. and Mortensen N.J. Intraoperative identification and analysis of lymph nodes at laparoscopic colorectal cancer surgery using fluorescence imaging combined with rapid OSNA pathological assessment. Surg Endosc, 2017.
9. Royal College of Pathologists. Standards and datasets for reporting cancers: Dataset for colorectal cancer histopathology reports. 2014: Royal College of Pathologists.
10. Quirke P., Williams G.T., Ectors N., Ensari A., Piard F. and Nagtegaal I. The future of the TNM staging system in colorectal cancer: time for a debate? Lancet Oncol, 2007. 8(7): p. 651-7.
11. Nagtegaal I.D., Tot T., Jayne D.G., McShane P., Nihlberg A., Marshall H.C., Pahlman L., Brown J.M., Guillou P.J. and Quirke P. Lymph nodes, tumor deposits, and TNM: are we getting better? J Clin Oncol, 2011. 29(18): p. 2487-92.
12. Nagtegaal I.D., Knijn N., Hugen N., Marshall H.C., Sugihara K., Tot T., Ueno H. and Quirke P. Tumor Deposits in Colorectal Cancer: Improving the Value of Modern Staging-A Systematic Review and Meta-Analysis. J Clin Oncol, 2017. 35(10): p. 1119-1127.
We have read with interest and concern the correspondence letter published in the July issue of your journal “OSNA testing for lymph node staging in colorectal cancer”.
Although the authors state on the letter “We aim to provide unbiased data on the diagnostic accuracy of OSNA in detecting CRC nodal metastases and feedback the practicalities of running such a service in a National Health Service (NHS) cellular pathology department”, we think the information given in their article is somehow incomplete. Their conclusions are based on the analysis of 99 lymph nodes (LNs) from a small cohort of 19 cases, with only 5.2 LNs examined per patient. Current guidelines, including the guidance of The Royal College of Pathologists, recommend that at least 12 LNs should be assessed to ensure an adequate specimen evaluation and a reliable pathologic staging.[1] In contrast, several studies using colon cancer OSNA lymph node analysis have assessed 12 or more LNs.[2–4]
We agree with their statement that intraoperative OSNA detection of LN metastasis does not have a role in CRC surgery, mainly because regional lymphadenectomy is invariably included with the colectomy specimen. But this is not the target of molecular lymph node assessment in CRC. The most important clinical application of molecular LN analysis in CRC is that it enables a more precise staging in early CRC than the one obtained with conventional H&E analysis, especially useful for stage II pa...
We have read with interest and concern the correspondence letter published in the July issue of your journal “OSNA testing for lymph node staging in colorectal cancer”.
Although the authors state on the letter “We aim to provide unbiased data on the diagnostic accuracy of OSNA in detecting CRC nodal metastases and feedback the practicalities of running such a service in a National Health Service (NHS) cellular pathology department”, we think the information given in their article is somehow incomplete. Their conclusions are based on the analysis of 99 lymph nodes (LNs) from a small cohort of 19 cases, with only 5.2 LNs examined per patient. Current guidelines, including the guidance of The Royal College of Pathologists, recommend that at least 12 LNs should be assessed to ensure an adequate specimen evaluation and a reliable pathologic staging.[1] In contrast, several studies using colon cancer OSNA lymph node analysis have assessed 12 or more LNs.[2–4]
We agree with their statement that intraoperative OSNA detection of LN metastasis does not have a role in CRC surgery, mainly because regional lymphadenectomy is invariably included with the colectomy specimen. But this is not the target of molecular lymph node assessment in CRC. The most important clinical application of molecular LN analysis in CRC is that it enables a more precise staging in early CRC than the one obtained with conventional H&E analysis, especially useful for stage II patients. The OSNA assay has been validated for CRC lymph node analysis. Its sensitivity and diagnostic accuracy for LN tumor burden detection is greater than that of HE.[2,3,5] Clinicians face the problem of recurrence in up to 20% of stage II CRC patients within 5 years after a curative-intended surgical resection. They have little or no objective and reliable data for decision making on stage II CRC patients, nor can they foresee that a patient has an increased risk of disease recurrence or poor survival. In addition, several meta-analysis have demonstrated that the presence of nodal micrometastases in CRC detected by molecular methods is a prognostic factor, associated to poor survival rates.[6] Nevertheless, no survival studies have been published so far determining the amount of tumor burden detected with OSNA that has clinical significance.[3]
We have recently published three different articles addressing some of the aspects that Dr Colling and his colleagues bring up. In the first one we demonstrated that molecular positivity found in LNs by the OSNA assay correlated with other classical risk factors in CRC, such as male gender, high grade areas or signet ring cell histology.[7] Our second paper was centered on the analysis of those LNs that drain the tumor. Pre-surgical endoscopy tattoo of early CRC not only maps out the tumor LN drainage, but also enhances LN harvesting and identifies those LNs that are more prone to harbor tumor burden, detected with the OSNA assay.[8] The third paper faces one of the most important problems this letter brings up, the high cost of molecular determinations.[9] Conventional pathological LN analysis is very cheap but its sensitivity is low, since it analyzes less than 1% of the LN. It has been useful in the pre-molecular, pre-CRC-screening era. The actual scenario of early-stage CRC detection has revealed the deficiencies of the classical histology method of LN evaluation. The introduction of any method of LN analysis other than H&E results costlier, but diagnostic accuracy leads to patient’s correct management and it has an inherent prognostic information. We designed the pooling method, which allows to analyze all the LNs from CRC patients in a median of 2 determinations per case, saving 85% of time, costs and personnel. [9] With the pooling method, all LNs from the colectomy specimen are analyzed together. Combining LNs for molecular determinations solves the problem of those LNs that do not fulfill the weight criteria for single OSNA analysis. The pooling method obtains the amount of tumor burden present in the LN compartment, or total tumor load (TTL), which gives a valuable information of how much tumor has escaped from the primary tumor to the nodal compartment.
The authors also question fresh LN dissection. Fresh LN harvesting does not have to be performed immediately. It may be postponed a few hours if the colectomy specimen is kept in the refrigerator at 4ºC, immediately after surgical excision. It needs coordination between the surgical and pathology departments, accordingly to the best fitting work up at each center. The OSNA assay for CRC lymph node analysis has its indications; it is intended for early-stage CRC with high probability to have negative LNs with H&E. Exclusion criteria are fresh specimens that are received open, surgical specimens received fixed in formalin, rectal tumors treated with neoadjuvant therapy and T3 cases with extensive fat infiltration. As for T4 cases, only antimesenteric tumors could be included. As for contamination by fecal matter, the surgical specimen must be received closed. LN harvesting is performed after separation of the mesocolon fat from the colon wall. With this simple procedure, contamination should not be an issue.
The OSNA technique may force pathologists and clinicians to change their current concepts in colon cancer staging. Instead of a more precise or sharpened version of the classical pN staging, the TTL provides a continuous variable of tumor load in the nodal copartment, which may have an implicit risk of recurrence, yet to be defined with upcoming follow up data. It may enable to shift treatment decisions defined by recurrence risks obtained not only by TTL cut offs, but also from well stablished risk factors such as tumor grade, molecular profile and patient’s factors. Such an ambitious goal must be supported by ongoing studies with adequate patient data and follow up.
1 Langman G, Loughrey M, Shepherd N, et al. Association of Coloproctology of Great Britain & Ireland (ACPGBI): Guidelines for the Management of Cancer of the Colon, Rectum and Anus (2017) - Pathology Standards and Datasets. Color Dis 2017;19:74–81. doi:10.1111/codi.13708
2 Croner RS, Geppert C-I, Bader FG, et al. Molecular staging of lymph node-negative colon carcinomas by one-step nucleic acid amplification (OSNA) results in upstaging of a quarter of patients in a prospective, European, multicentre study. Br J Cancer 2014;110:2544–50. doi:10.1038/bjc.2014.170
3 Yamamoto H, Tomita N, Inomata M, et al. OSNA-Assisted Molecular Staging in Colorectal Cancer: A Prospective Multicenter Trial in Japan. Ann Surg Oncol 2015;:1–6. doi:10.1245/s10434-015-4880-x
4 Aldecoa I, Atares B, Tarragona J, et al. Molecularly determined total tumour load in lymph nodes of stage I-II colon cancer patients correlates with high-risk factors. A multicentre prospective study. Virchows Arch Published Online First: 22 July 2016. doi:10.1007/s00428-016-1990-1
5 Yamamoto H, Sekimoto M, Oya M, et al. OSNA-based novel molecular testing for lymph node metastases in colorectal cancer patients: results from a multicenter clinical performance study in Japan. Ann Surg Oncol 2011;18:1891–8. doi:10.1245/s10434-010-1539-5
6 Rahbari NN, Bork U, Motschall E, et al. Molecular detection of tumor cells in regional lymph nodes is associated with disease recurrence and poor survival in node-negative colorectal cancer: a systematic review and meta-analysis. J Clin Oncol 2012;30:60–70. doi:10.1200/JCO.2011.36.9504
7 Aldecoa I, Atares B, Tarragona J, et al. Molecularly determined total tumour load in lymph nodes of stage I–II colon cancer patients correlates with high-risk factors. A multicentre prospective study. Virchows Arch 2016;469. doi:10.1007/s00428-016-1990-1
8 Aldecoa I, Montironi C, Planell N, et al. Endoscopic tattooing of early colon carcinoma enhances detection of lymph nodes most prone to harbor tumor burden. Surg Endosc Other Interv Tech Published Online First: 2016. doi:10.1007/s00464-016-5026-3
9 Rakislova N, Montironi C, Aldecoa I, et al. Lymph node pooling: a feasible and efficient method of lymph node molecular staging in colorectal carcinoma. J Transl Med 2017;15:14. doi:10.1186/s12967-016-1114-3
I just want to put out a typo in figure (1) : the sokal score formula should be : exp(0.0116*(age - 43.4 ) + ... and not exp(0.0116*(age - 4.34 ) +... .
If you use 4.34 all you patients will be in "High Risk Group".
In a previous issue of this journal, we presented problems of using
Bouin’s fixative for immunohistochemical and nuclear morphometric assays
on prostatic biopsies(1). We agree with the important comment offered by
Berney that Bouin’s fixative could increase the sensitivity for detection
of high grade prostatic intraepithelial neoplasia (HGPIN) and prostate
cancer. Furthermore, we agree that increa...
In a previous issue of this journal, we presented problems of using
Bouin’s fixative for immunohistochemical and nuclear morphometric assays
on prostatic biopsies(1). We agree with the important comment offered by
Berney that Bouin’s fixative could increase the sensitivity for detection
of high grade prostatic intraepithelial neoplasia (HGPIN) and prostate
cancer. Furthermore, we agree that increased sensitivity could occur at
the cost of decreased specificity, as is the case for most diagnostic
assays.
Bouin’s fixation was used as a routine fixative for prostatic
biopsies at our institution owing to the better nuclear detail offered by
this fixative, making the diagnosis of HGPIN easier. Diagnosis of HGPIN
assumed greater importance in the ‘sextant biopsy era’, as men with HGPIN
had a higher chance of being diagnosed with cancer on repeat biopsies (2).
The relevance of finding HGPIN has now decreased owing to extended
prostatic biopsy sampling (3). At our institution, there has been switch
to formalin for fixing prostatic biopsies for the above two reasons —
i.e., decreased predictive value of HGPIN on biopsies, and difficulties
with various molecular assays following fixation in Bouin’s fluid. We
have noticed a decrease in the prevalence of HGPIN on biopsies following
this switch, though a formal analysis has not been performed.
The radical prostatectomy specimens at our institution continue to be
fixed with formalin, as they have always been. We agree that using a
discrepant fixative such as Bouin’s on biopsies could lead to different
patterns of agreement between biopsy and surgical specimens. It indeed
would be interesting to analyze the correlation between formalin and
Bouin’s fixed specimens to gain a better understanding of how these
fixative differences affect the likelihood of diagnosing both HGPIN and
cancer.
References
1. Ananthanarayanan V, Pins MR, Meyer RE, Gann PH.
Immunohistochemical assays in prostatic biopsies processed in Bouin's
fixative. J Clin Pathol 2005;58(3):322-4.
2. Keetch DW, Humphrey P, Stahl D, Smith DS, Catalona WJ.
Morphometric analysis and clinical followup of isolated prostatic
intraepithelial neoplasia in needle biopsy of the prostate. J Urol
1995;154(2 Pt 1):347-51.
3. Moore CK, Karikehalli S, Nazeer T, Fisher HA, Kaufman RP, Jr.,
Mian BM. Prognostic significance of high grade prostatic intraepithelial
neoplasia and atypical small acinar proliferation in the contemporary era.
J Urol 2005;173(1):70-2.
Letter to the Editor – Journal of Clinical Pathology
We read with interest the invited editorial by Grealish et al. entitled “Standardisation of practice for Canadian pathologists' assistants.” First of all, we would like to congratulate the CAP-ACP Executive Committee on its accomplishments to date. Establishing a method for board certification of Canadian Pathologists’ Assistants (PAs) is an important achievement which promotes standardization and high quality anatomical pathology services.
However, our primary reason for writing is to address an error of omission. The editorial correctly notes that there are four two year long Master’s PA training programs in Canada; however, it should be also noted that these vary considerably in size with a ten-fold difference between the largest and the smallest based upon the number of students currently enrolled. The editorial then implies that Canadian training programmes are not accredited and are in need of some new mechanism to become accredited. The editorial states that “the pursuit of creating a ... Canadian accrediting body for PA training programme is ongoing.” We respectfully disagree. The two large Canadian training programmes, hosted by the University of Calgary and Western University, respectively have each been accredited by the National Accrediting Agency for Clinical Laboratory Sciences (NAACLS) (https://www.naacls.org/about.aspx ). NAACLS...
Show MoreWe found the paper ‘Long QT syndrome and sudden unexpected infant death’ by Van Niekerk and colleagues to be comprehensive and interesting. We would like to point out that there appears to be a misunderstanding as the authors state that in Australia and New Zealand all sudden and unexpected deaths are mandated to undergo targeted post-mortem genetic testing. Guidelines published by TRAGADY (Trans-Tasman Response AGAinst sudden Death in the Young) advocate that material suitable for DNA extraction must be obtained as part of the best practice guidelines for investigation of sudden death of a young person (1). However, subsequent genetic analysis is not mandated. A policy on the genetic investigation of cause of death in coronial autopsy cases has been recently released by the Royal College of Pathologists of Australasia (RCPA) (2). It is likely this policy document was not available at the time Van Niekerk and colleagues were writing their paper. The RPCA policy states that genetic testing of the deceased is not endorsed in the absence of engagement of the family of the deceased with a genetic counselling service and confirmation of a family history compatible with a heritable disorder. Ideally, there should be identification in the living relatives of a putative genetic defect (or defects) or phenotype for which testing is available. For a number of reasons, some of which are outlined in the RCPA policy document, mandatory post-mortem genetic testing may not be benefic...
Show MoreEl Jabbour T et al. (Jun 2017) described the association between immunohistochemical PD-L1 positivity and loss of MMR proteins in colorectal cancer. However, the evaluation of Mismatch Repair Deficiency (dMMR) as a immunotherapy predictive marker is lacking for Malignant Melanoma (MM) and other malignancies, such as genitourinary, prostate, bladder, head and neck cancers, that are treated with immune checkpoint inhibitors (ICPI).
We recently assessed dMMR in MM patients treated with anti-PD-1/PD-L1 during 2014-2016 at University of Modena and Reggio Emilia: 7% of primary melanoma and 13% of metastasis showed the dMMR. We report a patient whose primary MM and metastasis showed dMMR with immunohistochemical lack of MSH6 expression. Her complex history was characterized by the regression of the multiple cerebral and visceral metastases after anti-PD-L1 therapy, and an extraordinary progression-free survival (1150 days) and overall-survival (2646 days). At present, she is still alive and well, and had the longest response to anti-PD-L1 treatment.
Our results emphasize that the immunohistochemical assessment of MMR protein expression in MM patients represents a useful predictive marker, which may have crucial importance for the determination of the response of anti-PD-1/PD-L1 therapy for MM and potentially for other solid malignancies treated with ICPI therapy.
In their article considering the relationship between Articles 8 and 9 of the European Convention of Human Rights (ECHR) and coronial autopsies, Leadbeatter and James argue that recourse to invasive autopsy ought only to be made after an ‘issues based’ investigation establishes that this is necessary. This stands in stark contrast to current practice.
Whilst Leadbeatter and James write to report their own research findings and discuss the decision in R (Rotsztein) v HM Senior Coroner for Inner London North, I was prompted to consider whether they were too restrained in their conclusions. My primary concern is that whilst redress to the ECHR may be legally and rhetorically attractive, it means that outcomes are dependent on the still living taking action. This may, or may not, promote the deceased person’s preferred course of action.
Prior to addressing this point in more detail, however, a brief mention to the necessity of invasive autopsies where a death occurs in suspicious circumstances. Leadbeatter and James discuss this; I found their discussion of ‘injury’ (Box 2, Issue 4) particularly interesting. They give the example of road or train deaths, where their approach was to first review evidence from the scene, take toxicology samples and remove trace evidence. Another example might be where a person is shot in the head at close range, the events being caught on CCTV. These examples highlight that even in extreme circumstances evisceration of the body m...
Show MoreWe are intrigued by, and sympathetic toward, Dr Jones’ argument; we had approached our argument from the existing case law rather than from the fundamental position that dissection without good reason is morally unacceptable. We can understand that that position is supported by the need for appropriate consent in circumstances outwith a coroner’s jurisdiction. We would agree that invasive dissection that serves no defined purpose cannot be consonant with autonomy, beneficence, non-maleficence and justice.
Dear Editor
Show MoreRE: Atypical aspirates of the breast: a dilemma in current cytology practice. Shuang-Ni Yu, Joshua Li, Sio-In Wong, Julia Y S Tsang, Yun-Bi Ni, Jie Chen, Gary M Tse. J Clin Pathol 2017;0:1–9. doi:10.1136/jclinpath-2016-204138
We read with interest the findings of Shuang-Ni Yu et al regarding “Atypical aspirates of the breast: a dilemma in current cytology practice” first published on May 29 2017 in Journal of Clinical Pathology.
Breast fine needle aspiration (FNA) utilisation has been in decline for some time and there are several reasons for the drop in the uptake of cytology in the investigation of breast diseases. Although the main sited reason is increased demand for ancillary tests, greater subjectivity of cytology when compared to histology which is generally regarded as the gold standard, and the unpreparedness of pathologists to provide unequivocal diagnoses not only in the borderline lesions but also in low grade malignancies. The need to provide a consistently high quality service to engender confidence in our speciality has never been greater.
The probabilistic approach to reporting FNA based on the 5 tier categories (C1 unsatisfactory; C2 benign; C3 atypical/indeterminate; C4 suspicious; and C5 malignant) does provide reliable accurate diagnoses for all categories except C1 unsatisfactory and C3 atypical/indeterminate categories. The C1 category highlights a failed FNA procedure whilst a C3 result indicates some diagnostic un...
We were pleased to read the correspondence ‘Stage II patients can benefit from OSNA molecular lymph node staging’ from Cuatrecasas et al. and grateful for the authors’ interest and comments. Our study with one-step nucleic acid amplification (OSNA) for patients with colorectal cancer (CRC) primarily aimed to evaluate the accuracy of the test as compared with the standard care approach of a single H&E microscopic examination. We hoped to share with readers our experiences of working with this technology and highlight the challenges other centres will need to consider before introducing the service.[1]
Show MoreWhile we acknowledged the concern raised by Cuatrecasas et al. that our study cohort of 19 patients is small, we emphasise that we tested 82 lymph nodes with OSNA and feel our results show a fair indication of the concordance of the assay with routine histology. It is also important to point out that initially more patients were recruited for the study but several specimens had to be excluded due to faecal contamination, sealed perforation or macroscopic serosal (T4) disease – all of which could arguably lead to false positive results by OSNA. The significance of our data is that to our knowledge this was the first time OSNA had been fairly compared with routine histology rather than intensive work-up of multiple levels, immunohistochemistry (IHC) and conventional molecular methodologies. We agree that there is insufficient convincing evidence that intensive interrog...
Dear Sirs,
We have read with interest and concern the correspondence letter published in the July issue of your journal “OSNA testing for lymph node staging in colorectal cancer”.
Show MoreAlthough the authors state on the letter “We aim to provide unbiased data on the diagnostic accuracy of OSNA in detecting CRC nodal metastases and feedback the practicalities of running such a service in a National Health Service (NHS) cellular pathology department”, we think the information given in their article is somehow incomplete. Their conclusions are based on the analysis of 99 lymph nodes (LNs) from a small cohort of 19 cases, with only 5.2 LNs examined per patient. Current guidelines, including the guidance of The Royal College of Pathologists, recommend that at least 12 LNs should be assessed to ensure an adequate specimen evaluation and a reliable pathologic staging.[1] In contrast, several studies using colon cancer OSNA lymph node analysis have assessed 12 or more LNs.[2–4]
We agree with their statement that intraoperative OSNA detection of LN metastasis does not have a role in CRC surgery, mainly because regional lymphadenectomy is invariably included with the colectomy specimen. But this is not the target of molecular lymph node assessment in CRC. The most important clinical application of molecular LN analysis in CRC is that it enables a more precise staging in early CRC than the one obtained with conventional H&E analysis, especially useful for stage II pa...
Good Morning,
I just want to put out a typo in figure (1) : the sokal score formula should be : exp(0.0116*(age - 43.4 ) + ... and not exp(0.0116*(age - 4.34 ) +... .
If you use 4.34 all you patients will be in "High Risk Group".
source : Sokal JE, Cox EB, Baccarani M, Tura S, Gomez GA, Robertson JE, et al. Prognostic discrimination in « good-risk » chronic granulocytic leukemia. Blood. 1 avr 1984;63(4):789‑99.
http://www.bloodjournal.org/content/63/4/789.long?sso-checked=true
Sincerely
Jim Canet
Dear Editor
In a previous issue of this journal, we presented problems of using Bouin’s fixative for immunohistochemical and nuclear morphometric assays on prostatic biopsies(1). We agree with the important comment offered by Berney that Bouin’s fixative could increase the sensitivity for detection of high grade prostatic intraepithelial neoplasia (HGPIN) and prostate cancer. Furthermore, we agree that increa...
Pages