In the last few months, starting from the late 2019 in the area of Wuhan, China, an enormous increase in the number of infections due to SARS-coronavirus-2 (SARS-CoV-2) has been witnessed worldwide.[1-2] So far, 16 April 2020, the Situation report of the World Health Organization (WHO) has reported 1,914,916 confirmed cases and 123,010 deaths, of which 84,607 in the European Region.[2] This data could be itself sufficient to testify the importance of the on-going pandemic, which is further confirmed by the uncertainties regarding the possibility of gaining a natural or vaccine-mediated lifelong immunity. It is a matter of fact that, until the discovery of a vaccination, and maybe beyond that, it is likely that the world will have to deal with the virus and its long-time consequences for years. This necessarily imply that measures to deal with SARS-CoV-2 in all aspects, from life until death and post-mortem examination, have to be figured out and put in place.
A growing issue regards the distinction between “died from” and died with” SARS-CoV-2, which would be fundamental in order to gain knowledge on several issues including lethality of the virus, trend of death rate, and to compare data from different countries and regions (e.g. higher SARS-CoV-2 death rate per 1,000 infections are reported for Italy, UK and Belgium, while it is very low in Germany, Turkey and South Korea.[3] A complete post-mortem examination is probably an irreplaceable mean of distinguishing bet...
In the last few months, starting from the late 2019 in the area of Wuhan, China, an enormous increase in the number of infections due to SARS-coronavirus-2 (SARS-CoV-2) has been witnessed worldwide.[1-2] So far, 16 April 2020, the Situation report of the World Health Organization (WHO) has reported 1,914,916 confirmed cases and 123,010 deaths, of which 84,607 in the European Region.[2] This data could be itself sufficient to testify the importance of the on-going pandemic, which is further confirmed by the uncertainties regarding the possibility of gaining a natural or vaccine-mediated lifelong immunity. It is a matter of fact that, until the discovery of a vaccination, and maybe beyond that, it is likely that the world will have to deal with the virus and its long-time consequences for years. This necessarily imply that measures to deal with SARS-CoV-2 in all aspects, from life until death and post-mortem examination, have to be figured out and put in place.
A growing issue regards the distinction between “died from” and died with” SARS-CoV-2, which would be fundamental in order to gain knowledge on several issues including lethality of the virus, trend of death rate, and to compare data from different countries and regions (e.g. higher SARS-CoV-2 death rate per 1,000 infections are reported for Italy, UK and Belgium, while it is very low in Germany, Turkey and South Korea.[3] A complete post-mortem examination is probably an irreplaceable mean of distinguishing between these classes of deceased, by providing a multidisciplinary study of all organs and an extensive sampling of tissues, and of lowering the risks of misdiagnosis.
Legal medicine is the field where “mors gaudet succurrere vitae” (literally, death founds pleasure in helping life), or “the dead can speak to livings”.[4] Post-mortem examinations might suggest a mechanism of health harm, prevent the spread of a novel disease, control medical quality, arise suspicion toward a sign and even hint for a specific treatment and a preventive role of post-mortem examinations has been long declared.[5-7]
For example, the identification of pulmonary thromboemboli at post-mortem examination of patients who died from SARS, together with occlusions and microthrombosis of lung vessels in SARS-CoV-2 lung dissection and D-dimer elevation in patients now suggest the possibility of a therapeutic role of anticoagulant, heparin and low molecular weight heparin (LMWH) against SARS-CoV-2 infection.[8-11] Data regarding the true mechanism leading to death with SARS-CoV-2 are lacking, and it is unknown if a major role is played by respiratory acute insufficiency, multi-organ failure, cytokine release syndrome or hyper-response of the immune system, by haematological abnormalities, triggered within a disseminated intravascular coagulation (CID) syndrome or by all these mechanisms, in a different time from the contagion.[12-14]
So far, clinical criteria, e.g. onset of relevant symptoms before the death, have been applied, limiting the postmortem examination to the only collection of tissues (e.g. lung biopsies) and biological fluids to confirm the occurred infection by SARS-CoV-2. [15] Indeed, it is fundamental to limit the risks for health care professionals. [15] However, this could be a bit limitative, since the mere presence of a SARS-CoV-2 in the body does not prove that the deceased actually died because of it, even though a certified infection is surely a strong hint. Additionally, it is not clear whether the sensitivity of swabs might be affected in the post-mortem period, if false negatives could occur, due to a death of SARS-CoV-2 when the host succumbs and the timing of this negativity with respect to the time of death.
Finally, post-mortem examination of patients affected by SARS-CoV-2, healed and later died might provide an opportunity to ass long-time effects of the virus on lungs, hearts and other tissues.
For the above-mentioned reason, we would like to remark the importance of performing post-mortem examinations in this era of SARS-CoV-2 pandemic spread, provided that guidance to limit the risks for workers are respected and appropriate precautions put in place.[16]
Given the importance of a homogenization process regarding the death numbers due to SARS-CoV-2, borrowing a concept used in forensic toxicology for novel psychoactive substances (the scientific knowledge of which, as in the case of SARS-CoV-2 is still limited),[17] we would also like to suggest the adoption of a shared scale in the evaluation of the role of SARS-CoV-2.
In the evaluation the following factors are suggested:
1. Presence and severity of the infection by SARS-CoV-2, as assessed by in vivo data, including swabs, clinical records, radiological imaging, and post-mortem samples, including once again swabs, blood lower respiratory tract or any other sample.[15] When available, in vivo data are useful to assess if the victim has been infected, possessed risk factors for mortality and was suffering from symptoms suggestive of SARS-CoV-2 or not.[18] Post-mortem examinations on the other hand might provide insights on tissues not accessible in livings and multiple samples. [15, 19]
2. Presence and severity of previous diseases. These could have a role in facilitating the accidental contact between SARS-CoV-2 and the victim, as in the case of a hospitalized person who came in tight contact with an infected patient and acquired the infection in this setting, or of an immune-depressed patient. The latter is not only characterized by a facilitated contagion, in comparison with a healthy subject, but also a different natural history of the SARS-CoV-2 infection, been on one hand less prone to an abnormal physiological response, on the other extremely more exposed to the direct harm caused by the pathogen.
3. Circumstances of the death. These are of paramount importance, especially for the exclusion of SARS-CoV-2 as a cause of death, as in road traffic fatal accidents, gunshot-wounds, asphyxia, burns etc. It is clear that an external traumatic event, occurred after the contraction of the virus, could break the chain of the even, or better substitute itself, leading to death in an independent manner with respect to CoV-2. Is this the extreme case of an infected asymptomatic patient which is struck by a vehicle or shot to dead by military forces, as recently occurred in Africa due to curfew violation.[20]
Suicides should be evaluated carefully, since they do not automatically exclude a contribution of SARS-CoV-2, even though in an indirect way. For examples, it has been reported by the news that suicides occurred due to the fear of having infected other people. Circumstances are also fundamental in order to ascertain the risk of contagion, as in the case of people in close contact with patients because co-inhabitants or due to professional setting, as for doctors. A high index of suspect should be always maintained in the latter case, given the likelihood of an infection.[21]
4. Post-mortem radiology. Especially when in vivo imaging is not disposable, chest X-ray or, even better, post-mortem computerized tomography (PMCT) or a “virtopsy” approach could facilitate the retrieval of typical features of SARS-CoV-2. Of course, the decision to submit a suspected CoV-2 victim to an expensive and time-consuming (considering the pre-scan and post-scan necessities, as to disinfect the room) PMCT should be evaluated case-by-case and is not mandatory. Most importantly, its execution should not negatively impact clinical routine and the necessities of living patients.
5. Pathologic macroscopic and microscopic findings. Lungs and respiratory airways appear as the primary target of the infection and certainly their analysis should be as accurate as possible. Some data has already been published on persons with certified infection and could be useful to assess a compatibility of cases to the described features. [15, 19, 22-24]. Though, iatrogenic damage due to medications or devices, as in the case of alveolar hyper-insufflation in the course of mechanical ventilation, is possible and should be considered carefully. Moreover, myocardial, liver and multi-organ failure has been described.[23, 25]
6. Toxicological evaluation. A toxicological screening of common drugs of abuse could be important to exclude acute intoxications. Moreover, in the cases of patients prescribed multiple drugs, an evaluation of concentrations could be useful to assess if levels were within therapeutic ranges or exceeded them, suggesting a potential overdose.
7. Additional analyses should be performed whenever suggested by circumstantial, clinical or necroscopic data.
A possible SARS-CoV-2 significance score or CSS could be classified in four-points, in order to provide a fast assessment tool, which could be used in order to help establishing the cause of death for the Judicial Authority, as follows:
• 0 when SARS-CoV-2 was merely an occasion, but does not upsurge to the role of cause of death. An occasion is classified by its insignificance with respect to the death, exchangeability, ineffectiveness, non-indispensability.[26] An example is that of a old victim, with multiple increasing episodes of acute pulmonary edema due to cardiac chronic decompensation in the last stage, whose conditions are so severe that he succumbed to the mere rhinitis manifestations of SARS-CoV-2 and would have died even in the presence of usually well-tolerated pathogens.
• 1, i.e. low, when SARS-CoV-2 was present and a causative role cannot be excluded, even though an alternative leading cause of death is likely. An example could be that of a victim with multi-organ failure due to failed transplant, who suffers of multiple opportunistic infections, including low symptomatic SARS-CoV-2.
• 2, i.e. medium SARS-CoV-2 has likely contributed to death, even if additional factors might have had a prominent role. An example could be that of a victim with past history of haemorrhages and a poor haemostatic balance, who receives LMWH or other similar medications due to massive SARS-CoV-2-induced CID and dies of cranial hemorrhage.
• 3, i.e. high: SARS-CoV-2 with all probability was the leading cause to death.
A CSS could remain U= unclassified/unclear, when not enough data is disposable, until the execution of additional analyses, e.g. of swabs or microscopical analysis, or even after that, when the role of SARS-CoV-2 is unclear.
The so-presented scale tends to over-aestimate the role of SARS-CoV-2, though this seems necessary at this historic moment due to its diffusion and to the lack of knowledge regarding time course, natural history and mechanisms of injury.
Moreover, CSS should not be intended as a mathematic simplification of the process of post-mortem evaluation, a self-explanatory and sufficient response to a complex issue. Though CSS contains several elements of judgement and could lower the inhomogeneities in forensic evaluation of SARS-CoV-2, it is to be considered as an additional concise tool to be placed side by side with full medico-legal evaluation and discussion.
6. Byard RW. Preventive pathology revisited. Forensic Sci Med Pathol 2014;10(2):155-6. doi: 10.1007/s12024-014-9534-y. Epub 2014 Jan 23.
7. Buschmann CT, Tsokos M, Kleber C. Preventive pathology: the interface of forensic medicine and trauma surgery for pre-hospital trauma management. Forensic Sci Med Pathol 2015;11(2):317-8. doi: 10.1007/s12024-014-9603-2.
8. Chong PY, Chui P, Ling AE, et al. Analysis of deaths during the severe acute respiratory syndrome (SARS) epidemic in Singapore: challenges in determining a SARS diagnosis. Arch Pathol Lab Med 2004;128(2):195-204.
9. Fox SE, Aibek A, Harbert JL, et al. Pulmonary and Cardiac Pathology in Covid-19: The First Autopsy Series from New Orleans. medRxiv 2020.04.06.20050575. doi: https://doi.org/10.1101/2020.04.06.20050575
10. Luo W, Yu H, Gou J, et al. Clinical Pathology of Critical Patient with Novel Coronavirus Pneumonia (COVID-19). Preprints 2020, 2020020407.
11. Thachil J. The versatile heparin in COVID-19. J Thromb Haemost 2020. doi: 10.1111/jth.14821. [Epub ahead of print]
12. Henderson LA, Canna SW, Schulert GS, et al. On the alert for cytokine storm: Immunopathology in COVID-19. Arthritis Rheumatol 2020. doi: 10.1002/art.41285. [Epub ahead of print]
13. Tang N, Bai H, Chen X, et al. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost 2020. doi: 10.1111/jth.14817. [Epub ahead of print]
14. Shi Y, Wang Y, Shao C, et al. COVID-19 infection: the perspectives on immune responses. Cell Death Differ 2020. doi: 10.1038/s41418-020-0530-3. [Epub ahead of print]
15. Hanley B, Lucas SB, Youd E, et al. Autopsy in suspected COVID-19 cases. J Clin Pathol 2020. pii: jclinpath-2020-206522. doi: 10.1136/jclinpath-2020-206522.
16. Osborn M, Lucas S, Stewart R, et al. The Royal College of Pathologists. Briefing on COVID-19 Autopsy practice relating to possible cases of COVID-19 (2019-nCov, novel coronavirus from China 2019/2020). Available from: https://www.rcpath.org/uploads/assets/d5e28baf-5789-4b0f-acecfe370eee622... Access date: 18 April 2020
17. Elliott S, Sedefov R, Evans-Brown M. Assessing the toxicological significance of new psychoactive substances in fatalities. Drug Test Anal 2018;10(1):120-126. doi: 10.1002/dta.2225.
18. Li X, Xu S, Yu M, et al. Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan. J Allergy Clin Immunol 2020. pii: S0091-6749(20)30495-4. doi: 10.1016/j.jaci.2020.04.006. [Epub ahead of print]
19. Barton LM, Duval EJ, Stroberg E, et al. COVID-19 Autopsies, Oklahoma, USA. Am J Clin Pathol 2020;aqaa062. doi: 10.1093/ajcp/aqaa062
21. Zhan M, Qin Y, Xue X, et al. Death from Covid-19 of 23 Health Care Workers in China. N Engl J Med 2020. doi: 10.1056/NEJMc2005696. [Epub ahead of print]
22. Xu Z, Shi L, Wang Y, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med 2020;8(4):420-422. doi: 10.1016/S2213-2600(20)30076-X. Epub 2020 Feb 18.
23. Tian S, Xiong Y, Liu H, et al. Pathological study of the 2019 novel coronavirus disease (COVID-19) through postmortem core biopsies. Mod Pathol 2020. doi: 10.1038/s41379-020-0536-x.
24. Tian S, Hu W, Niu L, et al. Pulmonary Pathology of Early-Phase 2019 Novel Coronavirus (COVID-19) Pneumonia in Two Patients With Lung Cancer. J Thorac Oncol 2020. pii: S1556-0864(20)30132-5. doi: 10.1016/j.jtho.2020.02.010. [Epub ahead of print]
25. Yang F, Shi S, Zhu J, et al. Analysis of 92 deceased patients with COVID-19. J Med Virol 2020. doi: 10.1002/jmv.25891. [Epub ahead of print]
26. Puccini C. Istituzioni di Medicina Legale. Casa Editrice Ambrosiana 2003.
given the spread of Covid-19 infection with its serious consequences and given that the phenomenon has taken on partly unexpected epidemic dimensions which have required drastic Italian government restrictive measures to counteract its spread, in Our opinion it is legitimate to think of a reclassification of the risk category to which the pathogen Covid-19 belongs.
As it is known, Covid-19 is a viral pathogen of relatively recent acquisition in the human species which in its changed forms has presented over time health problems of growing social impact in different parts of the world and currently in Italy.
The SARS-1 (SARS-CoV, 2002, China) and MERS (2012, Saudi Arabia) forms have relatively little interest in Europe while the SARS-CoV-2 (China, Wuhan, 2019; Covid-19) has importantly spread in Italy.
So far beta-coronaviruses capable of causing disease in humans have been classified by WHO in the Risk Group (RG) 3: ”viral agent with high individual risk, but with a risk of collective spread assessed as low-moderate”.
So, the probability of propagation in the community of this virus was assessed as "moderate".
Also the NIH Guidelines defines the risk groups 3 as “high risk to an individual but a low risk to the community”
Furthermore, RG3 (NIH and WHO) is defined as to have efficient therapeutic approaches .
However, the present experience has led us to realize that Covid-19 has a very hig...
given the spread of Covid-19 infection with its serious consequences and given that the phenomenon has taken on partly unexpected epidemic dimensions which have required drastic Italian government restrictive measures to counteract its spread, in Our opinion it is legitimate to think of a reclassification of the risk category to which the pathogen Covid-19 belongs.
As it is known, Covid-19 is a viral pathogen of relatively recent acquisition in the human species which in its changed forms has presented over time health problems of growing social impact in different parts of the world and currently in Italy.
The SARS-1 (SARS-CoV, 2002, China) and MERS (2012, Saudi Arabia) forms have relatively little interest in Europe while the SARS-CoV-2 (China, Wuhan, 2019; Covid-19) has importantly spread in Italy.
So far beta-coronaviruses capable of causing disease in humans have been classified by WHO in the Risk Group (RG) 3: ”viral agent with high individual risk, but with a risk of collective spread assessed as low-moderate”.
So, the probability of propagation in the community of this virus was assessed as "moderate".
Also the NIH Guidelines defines the risk groups 3 as “high risk to an individual but a low risk to the community”
Furthermore, RG3 (NIH and WHO) is defined as to have efficient therapeutic approaches .
However, the present experience has led us to realize that Covid-19 has a very high propagation ability in the community as it spreads very easily from one individual to another, this is also reflected into the containment measures issued urgently by a number of National European governments.
In addition, for Covid-19 effective and validated therapies are not currently known and there is no vaccine available against it.
It should also be considered that validated serological diagnostics for Covid-19 infection are currently unavailable.
It therefore seems necessary to review the classification of the risk associated with Covid-19 infection and with it, it seems necessary to review the consequent safety levels (bio-containment), for laboratories that have to handle potentially infected material (WHO Laboratory biosafety manual, 2004, III edition).
The topic is of considerable importance as regards the autopsy activity on subjects with Covid-19 infection or with suspected Covid-19 infection.
This activity, prudently, should be carried out in safe environments and with procedures corresponding to those relating to the safety levels suitable for the biocontainment of RG4 agents, rather than those corresponding to the containment level for RG3.
Guidelines are urgently needed to help pathologists operate in the safest way, also contributing to harmonizing approach at European level.
It is proposed to ensure that:
1. in case of an ascertained death for SARS-CoV-2 (i.e. with a positive test for Covid-19) post-mortem autopsy should be avoided, unless the procedure is performed in environment and in ways appropriate for diagnostic activities at RG4 level;
2. in each hospitalized patient, molecular assessment (nasopharyngeal swab test) should be performed to determine Covid-19 presence;
3. when this first test is negative, a second diagnostic test should be carried out in the following 24 hours as recommended by the WHO;
4. when a person dies (irrespective if hospitalized or not), in the absence of documented molecular verification on Covid-19 presence, a nasopharyngeal swab should be performed just after having ascertained the death with the usual procedures;
5. in any case, when a documented valid verification on Covid-19 presence in the subject is absent, post-mortem invasive assessments and procedures should be carried out only with the precautions indicated for RG4;
6. in any case, based on the available medical documentation, in the present Covid-19 epidemic context the pathologist should be free to decide unquestionably whether to perform a complete autopsy or to perform a minimally invasive autopsy on selected areas of the body.
It is essential to remember that the goal of clinical pathology laboratory testing is not the acquisition of information itself, but to improve patient outcome through the promotion of proper laboratory test utilization, namely an appropriate test request and result utilization [1]. Given that pathology laboratory testing is reported to play a crucial role in 70% of clinical decisions and that the overall mean rate of inappropriate over-utilization is around 20% [2], innovations that rationalise and guide appropriate testing are welcome. Mahe et al are to be commended on defining an algorithm to determine which patients to test for the myeloproliferative neoplasm (MPN)-associated JAK2 V617F mutation [3]. Such an approach is particularly pertinent given that identification of this mutation has shifted from a confirmatory test for a relatively uncommon group of diseases to an advance screening test in the initial work up of patients in whom the numerous secondary causes that result in haematological indices similar to that of MPN have not been excluded. Also, the recent revision of World Health Organization classification of myeloid neoplasms lowered the threshold of haemoglobin level for considering a diagnosis of the MPN polycythaemia vera (PV) with a subsequent perceived and real impact on the level of JAK2 V617F testing [4, 5]. Using simple complete blood count (CBC) indices, Mahe et al found that application of their JAK2-tree algorithm to a historical dataset would hav...
It is essential to remember that the goal of clinical pathology laboratory testing is not the acquisition of information itself, but to improve patient outcome through the promotion of proper laboratory test utilization, namely an appropriate test request and result utilization [1]. Given that pathology laboratory testing is reported to play a crucial role in 70% of clinical decisions and that the overall mean rate of inappropriate over-utilization is around 20% [2], innovations that rationalise and guide appropriate testing are welcome. Mahe et al are to be commended on defining an algorithm to determine which patients to test for the myeloproliferative neoplasm (MPN)-associated JAK2 V617F mutation [3]. Such an approach is particularly pertinent given that identification of this mutation has shifted from a confirmatory test for a relatively uncommon group of diseases to an advance screening test in the initial work up of patients in whom the numerous secondary causes that result in haematological indices similar to that of MPN have not been excluded. Also, the recent revision of World Health Organization classification of myeloid neoplasms lowered the threshold of haemoglobin level for considering a diagnosis of the MPN polycythaemia vera (PV) with a subsequent perceived and real impact on the level of JAK2 V617F testing [4, 5]. Using simple complete blood count (CBC) indices, Mahe et al found that application of their JAK2-tree algorithm to a historical dataset would have reduced testing for this mutation by 15%, a considerable impact on workload [3]. Co-incidentally, another group have reported a similar attempt to refine JAK2 V617F testing for suspected PV by incorporating the immature platelet fraction into a CBC-based algorithm [6]. These two studies from Canada and New Zealand suggest that JAK2 V617F over-requesting is a widespread issue.
Given the specificity of the JAK2 V617F mutation for the MPN and the distinct haematological and clinical characteristics of these malignancies, it is disappointing to realise that similar to previous studies [7], Mahe et al note that the majority of JAK2 V617F requests had no clinical details provided. While obtaining CBC data for 95% of their historical cohort it should be mentioned that not all laboratories performing JAK2 V617F mutation studies might have access to corresponding CBC results, e.g. centralised genetic or molecular diagnostic facilities. Other (uncommon) instances that preclude application of this algorithm are when a bone marrow aspirate is provided for molecular analysis or in the acknowledged clinical scenario where splanchnic vein thrombosis unveils a haematologically latent MPN [8].
For other providers of a similar molecular diagnostic service it would be valuable for the authors to discuss how they actually intend to implement this algorithm prospectively and to educate users of their service. A review after a period of operation would reveal any issues regarding barriers to adherence and provide welcome evidence for reducing unnecessary JAK2 V617F testing in a real-world setting.
REFERENCES
1. Salinas M, López-Garrigós M, Flores E, et al. Managing inappropriate requests of laboratory tests: from detection to monitoring. Am J Manag Care 2016;22:e311-6.
2. Zhi M, Ding EL, Theisen-Toupal J, et al. The landscape of inappropriate laboratory testing: a 15-year meta-analysis. PLoS One 2013;8:e78962.
3. Mahe E, Mønsted Pedersen K, Çolak Y, et al. JAK2-tree: a simple CBC-based decision rule to guide appropriate JAK2 V617F mutation testing. J Clin Pathol 2019;72:172-6.
4. Sandes AF, Gonçalves MV, Chauffaille ML. Frequency of polycythemia in individuals with normal complete blood cell counts according to the new 2016 WHO classification of myeloid neoplasms. Int J Lab Hematol 2017;39:528-31.
5. Langabeer SE. An increase in diagnostic JAK2 V617F mutation testing: is masked polycythaemia vera the explanation? Eur J Intern Med 2018;52:e37-8.
6. Johnson S, Baker B. A CBC algorithm combined with immature platelet fraction is able to identify JAK2 V617F mutation-positive polycythaemia vera patients. Int J Lab Hematol 2019, Epub ahead of print, doi: 10.1111/ijlh.12967.
7. Langabeer SE. Referral centre variation in requesting JAK2 V617F mutation analysis for the investigation of a myeloproliferative neoplasm. J Clin Pathol 2012;65:1149-50.
8. Goulding C, Uttenhal B, Foroni L, et al. The JAK2 (V617F) tyrosine kinase mutation identifies clinically latent myeloproliferative disorders in patients presenting with hepatic or portal vein thrombosis. Int J Lab Hematol 2008;30:415-9.
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.
In the last few months, starting from the late 2019 in the area of Wuhan, China, an enormous increase in the number of infections due to SARS-coronavirus-2 (SARS-CoV-2) has been witnessed worldwide.[1-2] So far, 16 April 2020, the Situation report of the World Health Organization (WHO) has reported 1,914,916 confirmed cases and 123,010 deaths, of which 84,607 in the European Region.[2] This data could be itself sufficient to testify the importance of the on-going pandemic, which is further confirmed by the uncertainties regarding the possibility of gaining a natural or vaccine-mediated lifelong immunity. It is a matter of fact that, until the discovery of a vaccination, and maybe beyond that, it is likely that the world will have to deal with the virus and its long-time consequences for years. This necessarily imply that measures to deal with SARS-CoV-2 in all aspects, from life until death and post-mortem examination, have to be figured out and put in place.
Show MoreA growing issue regards the distinction between “died from” and died with” SARS-CoV-2, which would be fundamental in order to gain knowledge on several issues including lethality of the virus, trend of death rate, and to compare data from different countries and regions (e.g. higher SARS-CoV-2 death rate per 1,000 infections are reported for Italy, UK and Belgium, while it is very low in Germany, Turkey and South Korea.[3] A complete post-mortem examination is probably an irreplaceable mean of distinguishing bet...
Dear Editor,
given the spread of Covid-19 infection with its serious consequences and given that the phenomenon has taken on partly unexpected epidemic dimensions which have required drastic Italian government restrictive measures to counteract its spread, in Our opinion it is legitimate to think of a reclassification of the risk category to which the pathogen Covid-19 belongs.
As it is known, Covid-19 is a viral pathogen of relatively recent acquisition in the human species which in its changed forms has presented over time health problems of growing social impact in different parts of the world and currently in Italy.
The SARS-1 (SARS-CoV, 2002, China) and MERS (2012, Saudi Arabia) forms have relatively little interest in Europe while the SARS-CoV-2 (China, Wuhan, 2019; Covid-19) has importantly spread in Italy.
So far beta-coronaviruses capable of causing disease in humans have been classified by WHO in the Risk Group (RG) 3: ”viral agent with high individual risk, but with a risk of collective spread assessed as low-moderate”.
So, the probability of propagation in the community of this virus was assessed as "moderate".
Also the NIH Guidelines defines the risk groups 3 as “high risk to an individual but a low risk to the community”
Furthermore, RG3 (NIH and WHO) is defined as to have efficient therapeutic approaches .
However, the present experience has led us to realize that Covid-19 has a very hig...
Show MoreIt is essential to remember that the goal of clinical pathology laboratory testing is not the acquisition of information itself, but to improve patient outcome through the promotion of proper laboratory test utilization, namely an appropriate test request and result utilization [1]. Given that pathology laboratory testing is reported to play a crucial role in 70% of clinical decisions and that the overall mean rate of inappropriate over-utilization is around 20% [2], innovations that rationalise and guide appropriate testing are welcome. Mahe et al are to be commended on defining an algorithm to determine which patients to test for the myeloproliferative neoplasm (MPN)-associated JAK2 V617F mutation [3]. Such an approach is particularly pertinent given that identification of this mutation has shifted from a confirmatory test for a relatively uncommon group of diseases to an advance screening test in the initial work up of patients in whom the numerous secondary causes that result in haematological indices similar to that of MPN have not been excluded. Also, the recent revision of World Health Organization classification of myeloid neoplasms lowered the threshold of haemoglobin level for considering a diagnosis of the MPN polycythaemia vera (PV) with a subsequent perceived and real impact on the level of JAK2 V617F testing [4, 5]. Using simple complete blood count (CBC) indices, Mahe et al found that application of their JAK2-tree algorithm to a historical dataset would hav...
Show MoreLetter 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...
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