Dear Editor, We read with interest the comprehensive review on IgG4-related disease (IgG4-RD) by Drs Culver and Bateman [1], and wish to add on IgG4-RD in synovial tissue. A previous report suggested that up to 10% of patients with IgG4-RD have arthritis [2]. Two reports of arthropathy by Umekita K et al and Shinoda K et al showed evidence of infiltration of IgG4-positive plasma cells in the synovium [3, 4]. It is therefore interesting to speculate if specific biomarkers of tissue IgG4-RD exist either in the plasma or clinically relevant tissue filtrate (i.e., CSF, synovial fluid etc) that is similar to the authors' concept of examining clinically non- involved tissues for IgG4-RD.

Synovial fibroblasts or fibroblast-like synoviocytes in rheumatoid arthritis use B-cell activating factor (BAFF) and TLR3 to promote immunoglobulin class switch [5], that is evidence of perpetuation of autoimmunity in non-lymphoid tissue and possibly similar to what happens in IgG4-RD. Ugo Fiocco and colleagues from Italy have tried to identify candidate synovial biomakers in psoriatic arthritis, and showed that synovial fluid interleukin-6 (SF- IL-6) and SF-IL-1b levels along with synovial tissue (ST)-CD45+ and ST-CD31+ levels were altered significantly as well as disease activity after anti-TNF therapy [6]. A new report now suggests that basophil-TLR and basophil/B cell-BAFF interaction may lead to the development of IgG4-RD [7]. It is certainly not the end of the road for this intriguing disease.

Conflict of interests: None declared

Authors: Sujoy Khan, Consultant Allergy & Immunology, Apollo Gleneagles Hospital, Kolkata, India; Ratnadeep Ganguly, Consultant Histopathologist, Apollo Gleneagles Hospital, Kolkata, India

References: 1. Culver EL, Bateman AC. IgG4-related disease: can non-classical histopathological features or the examination of clinically uninvolved tissues be helpful in the diagnosis? J Clin Pathol. 2012;65:963-9.

2. Masaki Y, Dong L, Kurose N et al. Proposal for a new clinical entity, IgG4-positive multiorgan lymphoproliferative syndrome: analysis of 64 cases of IgG4-related disorders. Ann Rheum Dis 2009; 68; 1310-5.

3. Umekita K, Kaneko Y, Yorita K et al. Arthropathy with infiltrate IgG4-positive plasma cells in synovium. Rheumatology (Oxford). 2012;51:580 -2. 4. Shinoda K, Matsui S, Taki H et al. Deforming arthropathy in a patient with IgG4-related systemic disease: Comment on the article by Stone et al. Arthritis Care Res 2011; 63: 172.

5. Alsaleh G, Fran?ois A, Knapp AM et al. Synovial fibroblasts promote immunoglobulin class switching by a mechanism involving BAFF. Eur J Immunol. 2011;41:2113-22.

6. Fiocco U, Oliviero F, Sfriso P et al. Synovial biomarkers in psoriatic arthritis. J Rheumatol Suppl. 2012;89:61-4.

7. Watanabe T, Yamashita K, Sakurai T et al. Toll-like receptor activation in basophils contributes to the development of IgG4-related disease. J Gastroenterol. 2012 Jun 29. [Epub ahead of print]

Conflict of Interest:

None declared

'High risk medicolegal autopsies: is a full post-mortem examination necessary?'

Comment on the article by Fryer et al, J Clin Pathol 2013, 66:1-7

The article by Fryer et al raises several critical issues - I do not agree with them on all points - and leads to an important overall conclusion for the future prosecution of autopsies in the UK.

The piecemeal introduction of cadaveric imaging for non-homicide cases in (currently) a few centres in England is probably unstoppable, and has the backing of government (although not the central funding). As stated in their article, it is intended to avoid performing an open autopsy examination in a proportion of cases where a coroner has commanded a post-mortem examination. Interestingly whilst this article, and other publications like it, discuss replacing open autopsy with imaging, in public educational fora when presentations by pathologists and radiologists are made, the emphasis is more on imaging as an adjunct than a replacement for autopsy. What is not widely discussed anywhere is how the useful contribution of cadaveric imaging is critically dependent on clinical case-mix.

We would all agree that having imaging data prior to commencing a standard autopsy, whether the imaging was done under hospital care prior to death or done just prior to the autopsy as with deaths in the community, is valuable. It focuses attention to relevant clinical pathologies to be examined, and provides negative information for some organs (such as the brain in ?intracranial haemorrhage). An unintended and underused consequence of pre-autopsy imaging is enabling feedback to radiologists, particularly in the in-hospital setting, of their diagnostic performance. They necessarily receive plentiful such information in cancer multi-disciplinary meetings, but do not regularly obtain information on their diagnostic hits and misses when it comes to the moribund. Like all diagnosticians they are fallible.

High risk cases Fryer et al suggest that in cadavers of patients with suspected illicit drug intake, and known 'high-risk infection' (specifically Hazard Group category 3 infections, including HCV, HBV, HIV), an external examination plus blood sample toxicology can remove the need for autopsy in more than half the cases. The results, presented in % terms, are indeed persuasive. Toxicology alone provided the cause of death in 78% of cases, and CT scan alone in 25%. In the validation group (suspected drug abuse but no infection), the toxicology provided the cause of death in 87%.

The arguments presented for avoiding open autopsy on high risk cases include expense, disruption to busy mortuary work, and health risk to staff. Interestingly, the authors state that some pathologists in their centre are reluctant to perform autopsies on such cases. But these general statements do not stand up to scrutiny. And crucially the data arise from only a small numbers of cases examined.

In the 15 years covered by the study, only (my italics) 70 cases happened, ie 4.6 a year. Most were HCV+ve, 3 HIV+ve and one HBV+ve; the latter should really be excluded from the list of high risk infection in practice, since all NHS exposure-prone staff have to be successfully vaccinated against HBV and thus this poses no risk. I would contrast this very low cadaver infection rate with what happens at St Thomas' Hospital mortuary, where we see 1-2 HCV and/or HIV+ve cases a week, and have had no problems in performing them safely. Joint compilation of protocols for all eventualities by both anatomical pathology technologists (APTs) and pathologists ensures smooth, safe and efficient practice. I would suggest that the reported reluctance to perform such autopsies depends on unfamiliarity.

With the implementation of universal precautions for all autopsies, the true risks of high risk autopsy practice is minimal. When such infections are common, they do not disrupt the work flows, since all bodies are essentially treated the same, and they do not engender more expense. Let us not forget that in the recent times of good safe working practice, the likelihood of acquiring such an infection at work is vastly less than the risk to life of travelling to and from the workplace.

What are the consequences of reducing open autopsy practice by such minimal invasive techniques, and what are the opportunity costs? The focus here is on persons suspected of drug abuse with HCV or HIV.

Refinement of causes of death I am pleased that in Table 1, autopsies were indeed done to identify the alcoholic ketoacidosis syndrome and co-morbid infections. These variants of toxic pathology cannot be addressed without tissue samples, and preferably open autopsy examination of the relevant organs. But how much other important and/or interesting pathology might be missed by not doing open examinations? Table 1 lists a good number of lesions that may not be seen with CT: heart valve vegetations, tuberculosis (a public health notifiable infection), asthma, and cirrhosis (a disease of public health concern, and not reliably identified by imaging even in the living).

From my own observations I could add three generic scenarios: * The complicated and often critical contribution of co-morbidities, eg chronic lung and heart disease, to death from drug toxicity; it is much easier to evaluate the concepts of borderline toxicity and drug tolerance in individual cases when the whole pathology is known. * The contribution of sepsis from the IV injection habit pe se, both acutely with septic shock, and chronically through amyloidosis and renal failure. * The importance of considering the timing of a drug-related death, such as with evidence of aspiration pneumonitis, and addressing the questions of distressed relatives at inquest - for which there can be much evidence from the autopsy pathology.

Pathology education (or lack of) This is what disturbs me most about these trends towards imaging-only post -mortem examinations. Where and how are we going to teach the next generations of pathologists in the difficult arts of dissection and, even more importantly, histological examination? The current human tissue regulations already impact badly here, and removing yet more case work (drug-related deaths are indeed interesting and have significant internal pathologies that could become unfamiliar) takes away even more opportunity. Whilst some would argue that much of this type of examination is a waste of time, I hold that it provides practice in technique and interpretation, so that when a truly difficult and nuanced case emerges, it can be addressed with experience and reason.

Research opportunities Coronial autopsies are not intended for research but, basically, to determine whether a cause of death is natural, and an inquest may be dispensed with, or actually or potentially unnatural and so needs more investigations and inquiry. That said, because they provide >95% of adult autopsy work in the UK, they inevitably have a surveillance and potential research role. The epidemiology of diseases, including infections, changes constantly, and the autopsy provides one mode of monitoring and reporting on this.

The prime common example (I omit transmissible spongiform encephalopathies deliberately) is HIV disease. Much of what we know of the clinico-pathological cadence of HIV disease and results of new treatments (beneficial and adverse) comes from autopsy work. And it is published as such, although the commissioning coroners are probably not aware of that.

Coronial autopsies make a significant contribution to our understanding of cardiovascular disease in HIV-infected persons. Those not familiar with HIV may not realise the large clinical research, treatment and pharma interest into whether HIV per se and/or its anti-retroviral therapies do, or do not, activate endothelial cells and so augment arteriosclerosis, affecting the heart and brain in particular. HIV-infected suspected drug abusers thus contain within themselves at least two interesting pathological aspects (what is HIV doing and what are the drugs doing to that person), where a full autopsy can provide unique and cumulative evidence, to the ultimate benefit of public health.

Requirement for minimal invasive post-mortem examinations As Fryer et al state, the minimal invasive system requires two robust processes in place. First rapid toxicology, and they indicate one week as satisfactory. I would argue that this is not fast enough, since bodies do decompose even whilst refrigerated and important histopathological information is lost. More practically, in London, none of the laboratories offering services performs even that fast. That should be remediable, if the paymasters (the coroners) exercised their power to force the laboratories to turn over tests within, say, 3 working days.

Secondly, available imaging, particularly CT scanning. This is in practice impossible without proper funding; I pass over the availability of interested pathologists. At present, such non-forensic imaging is funded from now rather old government grants, or from individual initiatives such as jewish or moslem communities, or even interested radiologists with some surplus monies in their educational funds. But these are not appropriate for a nation-wide roll-out of cadaveric imaging - whether as replacement or (I would argue) as adjunct to open autopsy. These post-mortem examinations are done at the behest of coroners, and unfortunately they are not centrally but locally funded, with all that implies for variation in service provision.

So is there a future plan? The NHS has recently issued a large post- consultation document on cadaveric imaging {ref}, written by Prof Guy Rutty in Leicester and colleagues, with input from many other relevant specialities. I do encourage all autopsy-active pathologists (and coroners) to read it.

It provides the first realistic estimates of the actual costs of autopsies, with or without imaging costs, which alone make enlightening and disturbing reading for those involved in the economics of autopsy practice. But its main plank is the plan for future mortuary provision in England. Essentially, it is proposed that all mortuaries have attached dedicated CT scanners; that there need be only 30 such facilities in England (only 3 in London, the rest outside). And that all bodies are scanned prior to autopsy. The optimal funding for such an integrated pathology-radiology service is central government, not local source.

Conclusion There is much controversial material in this NHS document to discuss, but I certainly endorse the significant reduction of active mortuaries, with provision of imaging facilities on-site, and the resulting concentration of expertise in such places. As well as cases I still perform myself, I review many autopsies done by others and am frequently disturbed by their suboptimal or frankly dreadful quality. It is inevitable that experience, insight and - crucially - constant audit by, and consultation with, peers does sharpen and maintain practice standards. And so with autopsies: we should be doing them as a speciality interest practice, with similarly interested colleagues, in centres that do a lot of them very well. Which brings me back to the start of this Comment: in such facilities, 'high risk infections' will pose no problems for practitioners, who will be very familiar with them and their wrinkles. So isolating that category of cases for a qualitatively different approach to post-mortem examination from all the other cases will not be necessary.

Whether the NHS plan is rolled out as proposed, or through other exigencies the number of active mortuaries declines, the end result of fewer, but properly specialised facilities is appropriate. Pre-examination imaging will find it right place and 'high risk' cases will be optimally prosected.

Prof Sebastian Lucas Dept of Histopathology St Thomas' Hospital London SE1, UK [email protected] 28th Jan 2013

Reference "Can Cross-Sectional Imaging as an Adjunct and/or Alternative to the Invasive Autopsy be Implemented within the NHS?" Report from the NHS Implementation Sub-Group of the Department of Health Post Mortem, Forensic and Disaster Imaging Group (PMFDI). October 2012. The document can be downloaded from the East Midlands Forensic Pathology Unit. The full website address is: http://www2.le.ac.uk/departments/emfpu/Can%20Cross- Sectional%20Imaging%20as%20an%20Adjunct%20and- or%20Alternative%20to%20the%20Invasive%20Autopsy%20be%20Implemented%20within%20the%20NHS%20 -%20FINAL.pdf

Conflict of Interest:

None declared

Your recently published paper entitled: "Composite Intestinal Adenoma -microcarcinoid Clues to Diagnosing an Under-recognized Mimic of Invasive Adenocarcinoma", by Dr. Salaria, et al., (1) immediately reminded me of a non-cited paper that I co-wrote in 1985 (2) about 3 recto-sigmoid carcinomas that presented with hepatic metastases; two patients died within a year, while one had progressive disease. A 26-year-old homosexual, likely with HIV/AIDS had a 4-cm polypoid posterior rectal mass that on subsequent excision was an ulcerated small cell undifferentiated carcinoma (SCUC). A 78-year-old-woman had a 4-cm mass 8 cm from the anal sphincter that showed a nesting, trabecular, carcinoid type SCUC associated with a gland-forming infiltrating adenocarcinoma. A 51-year- old woman had a 3-cm sessile adenomatous polyp, 20 cm from the anal sphincter that contained both infiltrating adenocarcinoma and SCUC; a liver biopsy was of a neuroendocrine carcinoma with dense core granules (DCG). The three varied histologically and ultrastructurally, as well as in the appearance of their neuroendocrine (NE) cells and size and abundance of NEG; they resembled both carcinoid and SCUC tumors. At the ultrastructural level, GI adenocarcinomas can have an unsuspected neuroendocrine component and a variable behavior. This suggests the possibility that there a spectrum, from a serendipitously discovered combined adenoma with a locally invasive/infiltrating carcinoid (1) through a highly aggressive adeno-endocrine lesion, with a metastatic neuroendocrine component. Both endodermal components are likely derived from the same crypt stem cells. Similar combinations are found by TEM in adenocarcinomas of the lung. In both cases, the behavior doesn't necessarily parallel the light and ultrastructural appearance, e.g., carcinoid versus "oat cell" (2). Thus, care must be taken when analyzing GI adenomas, not just looking for an adenocarcinomatous component, but also for a SCUC/carcinoid component; if either feature is identified, the liver and lymph nodes (patient #3) may be involved and there may be other lesion in the patient (307). 1) Salaria SN, Abu Alfa AK, Alsaigh NY, et al. Composite Intestinal Adenoma-microcarcinoid Clues to Diagnosing an Under-recognized Mimic of Invasive Adenocarcinoma. J Clin Pathol 2013 66:302-6. 2) Schwartz AM, Orenstein, JM. Small-cell undifferentiated carcinoma of the rectosigmoid colon. Arch Pathol Lab Med 1985;109:629-32.

Conflict of Interest:

None declared

Dear Editor

I read with interest the recent article by Cook et al. and do agree that examination of breast reduction specimen is beneficial since incidental malignancy/high risk lesions are well documented.The problem has often been one of examination of relatively large breast reduction specimens with attendant time and resource constraints, often requiring random sampling.

Specimen mammography (SM) offers an efficient and potentially less time consuming method of examining the breast reduction specimen.The use of SM is currently limited to a few units. A recent survey (in-press) of Plastic Surgeons of UK and Ireland however revealed that only 5 % of a total of 260 surgeons request SM routinely, 7% occasionally do while 88% never request SM.[1]

Only one study has addressed the role of mammography in breast reduction; Ozmen et al in a relatively small case series of forty women investigated the potential benefits of specimen radiography in detection of breast pathologies in breast reduction tissue,they found the use of SM useful specifically in guiding the histopathologist to high risk areas to examine.[2] Thus the question of SM is one that needs to be addressed , especially from a cost-benefit viewpoint.

References

1) Iwuagwu OC, Platt AJ, Drew PJ Reduction Mammoplasty in UK & Ireland- current trends. In Press BJPS.

2) Ozmen S, Yavuzer R, Latifoglu O, Ayhan S ,Tuncer S ,Yazici I, Atabay K. Specimen radiography: an assessment method for reduction mammaplasty materials. Aesth. Plast. Surg. Vol. 25: 432-435,2001.