Okay apologies everybody for the technical shenanigans. Yeah so I'm a pathologist working really closely with the Gynae Oncology Group here in Swansea and I just thought I'd give an overview really of what we do. So it's very a basic presentation just to give you an indication of what our role is in the MDT, what we can offer to help support our colleagues and patients for the health board. The slides are not moving on. Oh no there they are. Okay right I've got control that's good and that's covered here in this introductory slide. To illustrate the points that I'm going to make I've got a couple of cases just to show you. So just to outline a typical MDT for us incorporates three different health boards. We take referrals from HALDA and POW which are sites east and west of where we are here in Swansea and we all get together once a week to discuss our cases over a morning. Sometimes that runs into the afternoon if we've got particularly long lists and in that group are a number of individuals and there's no particular order given here but everybody has got an essential role in discussing these cases rather like we've just done with the case that we were discussing of the cervical cancer. In a typical meeting we'll have around 40 patients or so to review and I've based much of this presentation on an actual meeting that we had to look at the basic format of the kinds of discussions that we have. So they're split into separate parts for the health boards that are covered and we have specific oncology discussions and discussions that focus on pathology but the vast majority of the cases require review of radiology as you can see here. As part of the process of us looking at these cases to give a pathology opinion those that we don't have in our files we ask to be sent across to us for review of the glass slides and that can present quite a considerable workload when cases are coming from other centres if they're big resection cases with multiple trays of slides and multiple rounds of immunohistochemistry and there are pros and cons to this process and everybody has a different set of views. Some of my colleagues believe that reviewing reception specimens and post-operative cases rarely adds anything to the report and that really we should focus on looking at pre-operative diagnostic biopsies before surgical treatment has taken place. I have some sympathy with that view but then there are others who believe that we should review every single slide before we're able to give an opinion. I am aware that some centres in pathology review they really focus on relaying information from the reports and don't look at slides at all so I know that there's considerable variation across the UK as to how this should be done. I do believe that if I'm asked an opinion I need to see the material to know that what I'm saying is based on my perception and my opinion for it to be valid. It does allow for intimate discussion around the cases and for differences of opinion in the perception to come to light so there are three central pathologists here in Swansea that look at this material and we do discuss cases that are difficult between us to come to a consensus view where possible. It also allows for us to relay the message to our clinical patient-facing colleagues that pathology is not a matter of positive or negative. In a lot of cases it's an interpretive opinion based on the medical context and is subjective. It also allows where we're able to show slides in meetings to allow us to educate the medical students within the room and to provide some level of interprofessional teaching and the kinds of cases that we discuss often promote discussions that go on to develop into service development projects for improving our service for patients and potentially for research also. As I've said some of the case reviews are quite time consuming and one could argue that in a setting where pathology is short-staffed globally but particularly in the UK where 20% of our consultant posts are sitting vacant because a lack of qualified staff to fill them that reviewing specimens that are already reported can result in a degree of reduced productivity shall we say in reporting specimens that aren't yet reported. The British Association of Gynae Pathologists have also raised the point that sometimes MDT review can create conflict between pathologists where there's a disagreement about a diagnosis and that can be a negative impact but I'm happy to say that we don't suffer from that here in Swansea where we all get on and are quite willing to share ideas and have an open mind about diagnoses. To boil down the three main areas that I think we can offer value to the MDT it's in confirming and reviewing the diagnoses and specifics around the morphological assessment of pathological slides around performing additional IHC where that appears to be required and also offering a view on how it's interpreted and any further immunohistochemistry that might be warranted in a companion diagnostic setting to aid oncological treatments. In addition to those two things that are core business for us pathologists I think we can also add a general medical opinion about care of patients because we are all medics and have had spent considerable time on the wards before we went into pathology and in those instances where we're short-staffed in the MDT and we need to be chorus we can really help make sure that there's enough balance of opinion for the team as a whole. In addition to that we can also offer guidance as to where the best place for biopsy is likely to be and I'm thinking one would want to avoid taking bone biopsies for metastatic disease where there's an unknown primary and an indication for immunohistochemistry because decalcifying a biopsy can interfere with the antigen retrieval for that process. We can offer guidance about the best sort of fixative mediums for specimens and pre-analytic considerations for genetic testing further down the line. So just to go into a bit more depth there that when I talk about as being able to offer value in terms of morphology that's confirming the diagnosis and the histotype of malignancy because in the setting of ovarian cancer for example ovarian cancer is not one disease it's many different types and there are five major common types of epithelial malignancy for example so there's often discussions about the subtype between us when we're discussing cases for review. We can offer value in grading specimens additional items from the minimum data set as set out by the Royal College and for those of you who aren't aware there are minimum data sets for reporting pathological specimens that are published by the Royal College of Pathologists and they're freely available on their website under publications and anyone in the world can access those for supporting reporting. We also take in certain circumstances for example in endometrial malignancies we'll look at lymphobascular space invasion because we know that's a critical point for determining ongoing treatment. And as I've said interpretation additional immunohistochemistry highlighting companion diagnostics where appropriate and classifying malignancies according to their molecular signature are things that we can also bring to the table. And I think we've talked about this already really being able to give additional medical One thing that we are required to do for genomic testing downstream is to highlight areas of malignancy on glass slides to be able to guide macro dissection so if there is only a small area of malignancy on a slide that's available for DNA or RNA extraction we'll highlight that laboratory where our molecular testing is performed can actually just take off the region of interest to enrich their extraction process for malignant nuclei. So we assess the tumor nuclear contents of our specimens to help inform that process and get the best results that we can for patients. So we assess the tumor nuclear contents of our specimens to help inform that process and get the best results that we can for patients. An example of where we've added value in diagnosis and this was in the last MDT that I reviewed slides for there was a case of a woman who'd had a cervical loop excision at the age of 45 years with a history of severe dyskaryosis in a smear that was performed following high risk HPV identification as part of our national screening program and this is the slide that you can see here you can see that there's a hyperchromatic area here and here this is the surface squamous epithelium with a with a small ulnus area here and you can see that the epithelium is detached from the underlying stroma and that you've got an endo cervical gland here with with some mucus. This is diathermy artifact from the cervical loop excision process and really this is very densely packed and at low power it wouldn't be possible to make a diagnosis in my opinion one needs to get down at higher power which we'll come to shortly. This is another area similar very dense inflammatory infiltrate with lymphoid follicles and and some ulceration of the surface. Other sections were devoid of malignancy or inflammatory infiltrate. So at higher power you can see that there are indeed some cells here that look atypical with really quite pleomorphic hyperchromatic nuclei within a dense bed of inflammatory cells these small round blue nuclei are lymphocytes and the original reporting pathologist performed some histochemistry on these difficult areas to see if they can highlight cytokeratin positivity that might indicate an underlying carcinoma and this is what these look like. We've got broad spectrum cytokeratin expression here within that dense lymphoid infiltrate and that this is highly suggestive of an invasive carcinoma. P40 expression highlights squamous differentiation so this is a poorly differentiated squamous carcinoma and p16 here in the center is a block diffuse expression which would support an HPV driven malignancy. So in the original section that I showed you it appeared that the infiltrate extended to the deep margin and this was supported by p40 staining in that larger section where you can see that the diethylamine specimen margin runs through that p40 positive region and this is how it was reported by the original reporting pathologist from elsewhere and I agreed with everything that had been said in that report but in addition to that I was able to consider what the third dimension of the malignancy might be and add that into my review. So it's worth remembering that when these loop specimens are received they're three-dimensional pieces of tissue and what we have on a slide is a two-dimensional representation of what is a three-dimensional structure. In each of the cassettes that we place tissue sections in they measure three to four millimeters of thickness and so it's possible if you've got multifocal disease in more than one section to be able to estimate a third dimension if you assume that the full thickness of that tissue block is infiltrated and I also added in to the review report the depth of invasion that I could see and gave an idea of provisional Vigo staging but obviously with that being in completely excised that's an at least comment on the report. Further to that I made a comment about lymphovascular space invasion which I did not identify, neither did I see a high grade CGIN nor stratified mucinous intrapithelial lesion. I talked about the need to correlate with the clinical and radiological features which is something I frequently do and just to remind people that we don't report alone we everything that we report is in the context of the wider medical setting. I did wonder about whether there may be a role for PDR1 in this setting and really that relies on the MDT discussion again and an understanding about whether there's metastatic disease present. So moving on to the second illustrative case to look at immunohistochemistry and where we were able to bring additional value. This was a biopsy taken from an 83 year old woman who had a past medical history as given on the request form of ovarian cancer 10 years previously. So the biopsy was of a right inguinal nodular mass and had the appearance that you can see here. So we've got fibrous tissue with this more hyperchromatic cohesive lesion that appears to be forming glandular spaces and also papillary areas as well. There's also necrosis present in this biopsy and these features really are those of a metastatic carcinoma and highly suggestive of an adenocarcinoma because of the papillary and the glandular morphology. The immunohistochemistry that was sent along with this specimen reported p53 as being negative and generally speaking the guidance from the British Association of Gynaepathologists, the BAGP, indicates that p53 should be reported as mutant or wild type in its expression pattern and this can be an area of difficulty where we see as in this case a null pattern of expression. So this reflects an underlying truncating mutation where there's an inserted stop codon as a result of the mutation and that the protein that's expressed is not long enough to be picked up by the antibody specific for p53. So you get this diffuse but complete nuclear absence of p53 staining. Now in normal tissues there is always a certain degree of p53 expression because it's a key molecular guardian of the genome. It governs the cell cycle and whether to push cells into apoptosis if there's been a problem in the cell cycle. So one would usually expect to see some positivity. There is some positivity in the background lymphocytes that you can see the fibrocells and the stroma and that's good for us to be able to know that the immunohistochemical stain has worked. So we turn that an internal positive control and I was able to say that this pattern is best regarded as null pattern and reflects a mutant p53 status in the tumour. So the original report was given as metastatic carcinoma of genital tract origin and given the null pattern p53 and the clinical history I entirely agree with that. Additional markers of WT1 and Pax8 support a genital tract origin and WT1 expression is often seen in high-grade serous carcinomas of tuberovarian or primary peritoneal origin. But further understanding of that clinical history of ovarian cancer revealed a history of carcino-sarcoma. So it's important for me to be clear about what the histotype is of previous malignancies with as great a detail as possible and in this case I concluded that it was just the epithelial component or the epithelial appearing component of the carcino-sarcoma in the previous lesion that had metastasized to this inguinal lymph node and that the immunohistochemistry was in keeping with that. So carcino-sarcoma is best regarded as a really very poorly differentiated carcinoma where the sarcomatous differentiation really represents a de-differentiation of what is overall an epithelial tumor. So what was I able to add on top of reviewing the previous diagnosis? Well we performed ER and PR to help guide any potential future hormonal treatments and suggested BRCA testing and HRD testing, homologous recombination deficiency testing, to guide further treatment also. So I hope you can see from both the cases that I've illustrated in the way that I've tried to group the value we can bring to NDT that there's multiple roles that we can play but in essence they fall into three categories really. Those based on the morphology of the H&E and a pattern recognition for diagnosis including the subtype of malignancy that's present if there's malignancy present at all. We can offer expertise around immunohistochemistry, both choice, interpretation and suggestions for future requests and also just give general guidance so that we can give the best reports and answers for our patients based on the clinical setting that they find themselves in. So at that point I'll stop there and just thank you very much for your attention and invite any questions or general comments that people might have and reflecting on the practice where they are. Thank you.

pathologist

Gynae Oncology Group

multidisciplinary team (MDT) meetings

pathology slides

immunohistochemistry

expertise