I have very eloquently gone over a lot of the contents that I had intended to. So this is really an emergency trimmed down version, which really is primarily aimed at my pathology colleagues, but I don't know how many of them are on here. So I might just skip through some of the initial introductory slides that, as a junior pathologist when I first started doing this, a lot of the terminologies that my gynae-onc and medical oncology colleagues were so familiar with were like an alphabet soup, really, because I didn't really understand a lot of the terminology. So I thought I'd go over it. But I think if there aren't many pathologists, shall I just skip over this, Asima? What do you think? No, please carry on. It's going to be too basic for you all, so it's going to be a bit embarrassing. I actually have some pathologists that said they couldn't join and would like to hear more of this case. So they wanted me to report it. Oh, all right. Okay. I'll go ahead then. But I would ask my surgical and oncology colleagues present here to please bear with me. So my name is Angela Ralte. I graduated from St. John's Medical College in Bangalore, continued with my MD pathology in Ames, New Delhi, and carried on with my training at the Royal Victorian Firmary in Newcastle, where I attained my fellowship with the Royal College of Pathologists. I'm currently the lead gynaecological pathologist for the Northern Gynaecological Oncology Centre and the lead cytopathologist for the North Eastern Yorkshire Cervical Screening Centre based at South of Tyne and Wear Pathology Centre in Gateshead, North East England. There are two main treatment options for high-grade, high-stage ovarian epithelial cancers. The first option is surgery first, called primary debulking surgery, followed by a platinum-based chemotherapy. The second option is where the patient receives chemotherapy first, called neoadjuvant chemotherapy, followed by surgery, called interval debulking surgery. This is usually undertaken when optimal primary debulking is not technically feasible and is designed to decrease tumour size prior to surgical resection to increase the rate of optimal cytoreduction. The definition for optimal cytoreduction has changed over the years, and correct me if I'm wrong, but I understand that the current definition is when there is no macroscopically visible tumour. That's correct. I think for the optimal, we say the GCIG criteria is still less than one centimetre, but we love that to be actually less than 2.5 millimetres to say optimal. Yeah, okay. Thanks, Oshima. And this interval debulking surgery is usually undertaken after three to four cycles of chemotherapy. Chemotherapy is usually in the form of carboplatin and paclitaxel, but with the advent of HRT testing, patients now are eligible for bevacizumab and or PARP inhibitors if the tumour is shown to be homologous recombinant deficient or have tumour bracker mutation. At the Northern Gynaecological Oncology Centre in Gateshead, the standard of care is primary debulking surgery, where optimal cytoreduction appears achievable in patients with good performance status. Where this is not achievable, three randomised controlled trials have shown that interval debulking surgery produces progression-free survival and overall survival equivalent to those of primary debulking surgery, and this is from the Canadian and European studies. This is slightly controversial. I'm not going to go into this because sometimes we can have quite a lively discussion at the MDTs as well, so this is really out with the remit of this talk. But as pathologists, really, because of the increasing trend towards new adjuvant chemotherapy, and although the selection criteria and the approach differs between different centres and different countries, our job is really to assess the chemotherapy response in the specimens derived from this interval debulking surgery, which is really the subject of this short didactic. Until recently, there was no uniform consensus regarding the histopathological grading system for response to new adjuvant chemotherapy. Bohm et al proposed a simple reproducible system for scoring and grading the response of tubo-ovarian high-grade serous carcinoma to new adjuvant chemotherapy based on histopathologic assessment of tissues removed at IDS. Now in this paper, the lovely professor of pathology, Professor Navina Singh, was the senior author, and they reported that the three-tiered chemotherapy response score of omental tissues showed a significant association with progression-free survival and overall survival in their validation cohort. And this has actually been validated by a number of papers, and they have independently assessed the CRAs and they've validated it. However, it is developed in a single centre and it has not been validated in a prospective multi-centre setting. In spite of this, the International Collaboration on Cancer Reporting has recommended the use of CRS system for grading of new adjuvant chemotherapy response in ovarian carcinomas. This is a departure from other solid cancers like breast and colorectal cancers in which new adjuvant chemotherapy response is assessed on the primary tumour. This is mainly because the authors felt that the peritoneal disease is a critical determinant of survival in these tumours and is therefore more prognostically relevant site for new adjuvant chemotherapy assessment. The authors also found that adnexal disease after NACT was difficult to assess and less reproducible to score, and it did not correlate significantly with the outcome, although most studies are needed to confirm this. There is a recent paper by an Italian group, Santoro et al, I think, Manisha, you mentioned that article in your talk, where they have found that adnexal disease did correlate with outcome, but as I said earlier, more studies are needed. So coming on to the chemotherapy response score, it is a three-tier numerical code. CRS1 is where there is no or minimal tumour response with abundant viable tumour with minimal tumour regression, and in some cases, it is difficult to decide between tumour regression due to chemotherapy and tumour-associated desmoplasia or inflammatory infiltrate, and here is one such example. This is a chemotherapy response score of one, where you can see these islands of tumour cells surrounded by an inflammatory desmoplastic reaction. So this is a CRS score of one, but if you just looked at this image on its own without knowledge of the history, you could very well interpret this as inflammatory desmoplastic response of the tumour rather than chemotherapy response. Chemotherapy response score two is where there is appreciable tumour response, but with viable tumour that is readily identifiable, and the viable tumour is regularly distributed throughout, and here is an example. You can see there is abundant desmoplastic response to the tumour. However, the tumour is easily identifiable. Here is another example of chemotherapy response score of two. There is very good response. However, the tumour nodules exceed more than two millimetres. Another example of chemotherapy response score of two, and the difficulty with chemotherapy response score of two that Manisha alluded to, is really related to, in my opinion, sampling. Like for instance, if you took this specimen, this is a very low bird's-eye view of the omentum. Now, if you sampled just this area, you would call it chemotherapy response score of one, whereas if you sampled this area alone, it would be a chemotherapy response score of two. Therefore, I think with interpretative specialties or interpretative where there is a difference in the sampling and the interpretation, there lies a problem with the scoring because it is really dependent on the areas and the amount you sample. This is an example of a CRS score of three, which is defined as complete or near-complete response with no or minimal residual tumour, but scattered tumour islands that should be less than two millimetres in maximum size. And you really should have mainly fibroinflammatory response, but just scattered tumour cells. And it is also advised to record whether there is no residual tumour or residual microscopic tumour is present. Here is another example of CRS score of three, where the omentum shows just inflammatory fibroblastic response, but no visible tumour. There is a little island of chronic inflammatory infiltrate here, but otherwise there is no visible tumour. In some instances, rather than a fibroinflammatory response, you get these sheets of filmy histiocytes with these abundant pale cells with abundant pale cytoplasm and scattered inflammatory infiltrate. I just want to show an example of an omentum with the CRS score. I will not tell you what the CRS score is at this point, but really the omentum looks quite normal on external examination. And what I tend to do is I sequence, I bread loaf the omentum at two to three millimetre intervals and lay them out and assess each of these slices and sample as much as is practicable. If the omentum is thin, you can roll it into a Swiss roll and take two to three millimetre thick sections because some of them can be quite subtle. So this is an area where it's really difficult to assess whether this is residual tumour or a fibroinflammatory response. And if it's difficult for you at surgery, it's difficult for us in pathology as well. And therefore judicious extensive sampling is really the answer to getting the most accurate CRS score as possible. This is another high power view showing these little streaks of pale white areas which could either be desmoplastic chemotherapy response or it could be residual tumour. Now this is a section from that, sorry, section from the case that I just trimmed. You can see that most of it is actually inflammatory, sorry, inflammatory fibroblastic response tumour regression with tumour, viable tumour that measures just over two millimetres. So again, with the sampling, you could either miss this completely because it is not immediately obvious on gross examination which area is residual tumour and which area is chemotherapy response. And this is a section of the ovary and sometimes rather than the grey-white area, you get these yellowish deposits which are on microscopy sheets of foamy histiocytes as a response to tumour, as a response to chemotherapy. So really the practical problems, I've just mentioned three main practical problems is the CRS score is great, but it really doesn't account for cases of high-stage disease with no mental involvement where metastasis is via hematogenous route rather than the transleucelomic route. And what if there is no tumour bed in the omentum to assess for chemotherapy response? So I had a case, I mean, I had like five debulks, two of them primary and about three interval debulks this week. And one of them had a completely normal omentum, but the pelvic peritoneal biopsy showed areas of fat necrosis and the creamy yellow areas, which clearly was a response to chemotherapy. So how do you assess the omentum when there is no tumour bed to assess? You know, if it's just fat, if there was no tumour to begin with, you might be giving a falsely high CRS score of three, when actually there may be viable tumour elsewhere that is not, that is, if you, if we were given a score, a CRS score for ovary or diaphragm would be a CRS score of one. So in these instances, what I do is I comment on the response in other structures. I don't give it a formal score, and I just say there is no tumour in the omentum to formally assess or to formally give a CRS score. And what if CRS score three is in the omentum and other tissues show minimal response? I think I've just mentioned that. I give the omental score as recommended and comment that other tissues show minimal response, but I don't give it a specific numerical score. The Italian group gave a score of zero and one, but obviously that's not widely accepted as of yet. So I'm just going to give you a few examples. This is from 2019, in a 53-year-old woman who presented with change in bowel habits and bloating. She had a significantly raised CA125, other tumour markers were normal. On imaging, she was found to have a stricturing erectile lesion and a six-centimetre bilateral solid ovarian masses, and the radiologist and everybody else was convinced that this was a primary erectile cancer with Krukenberg metastasis to both ovaries, but it was referred to Rottgeil MDT. I don't know, Ashima, if you were around for this. Do you remember this case? I think I showed the picture at the meeting. Because the CA125 was markedly raised, she was referred to our MDT. Pre-op biopsies with erectile lesion were really non-diagnostic as they were mostly necrotic and therefore, guess what, they decided to have to do a frozen section. And this is the fresh ovary of right and left ovary. As you can see, both ovaries, solid, lobulated, firm, less than 10 centimetre, typical Krukenberg's appearance, and you can see the fallopian tube actually looks normal. This is a cut surface showing this lobulated, firm mass. So I do touch imprint cytology on all my frozen sections. It's just I find it a lot easier because it prevents all the artefacts associated with the frozen section. So anyway, the intraoperative diagnosis was, I was fairly confident that this was a high-grade serious carcinoma. Bearing in mind this, all this history I got later, so I didn't know this entire history. I just got this ovary and I was told to say, you know, is it primary or is it secondary? Because it looked odd. Isn't it, Ashima? Do you give us the history? No, I don't. I know. Right? Save the embarrassment. Yeah. Anyway, so this was papillary and I was fairly confident I had no problem favouring a guy in your origin, high-grade serious carcinoma. This was the fixed specimen, lobulated, firm mass. And then I get this rectosigmoidectomy, smooth mesorectal plane with a positive high-tie node. And then I, you know, I can feel beads of sweat. Oh my goodness. I have incorrectly interpreted this as frozen section. This is a metastatic colorectal cancer and this woman is going to die because I have incorrectly interpreted her frozen section report. So obviously when I got it, I trimmed it. I grossed it like I would a colorectal where we longitudinally slice the colon. And as I'm slicing more beads of sweat because I can see a luminal necrotic lesion invading the full thickness of the bowel wall, going into the mesorectum and involving the mesorectal fat, mesorectal lymph nodes, and almost extending into the mesorectal resection margin. But this was indeed a high-grade serious carcinoma, which involved both ovaries, fallopian tube, uterine myometrium, and almost all the lymph nodes that were in the mesorectum was involved by this tumor, including the paraitic and pelvic nodes. The omentum was negative for tumor. So really this is a stage four disease, but with a negative omentum. And it is these cases that I think we will have difficulty interpreting the chemotherapy response scope because the chemotherapy response is not present in the omentum because there is no tumor there to begin with. So I think in these instances, it is important to assess all the other structures and give perhaps not a formal score, but give at least a comment to say extensive response or minimal, the wordings that are used for the chemotherapy response score. And hopefully in the fullness of time, when more studies are done, we will be able to assess the chemotherapy response in these types of tumors. This is another case of a complete chemotherapy response. You really need to see the tumor bed. You need to see the fibroplasia. You need to see the inflammatory infiltrate. Just having fat with no tumor, I think is not correct to assess for chemotherapy response because we don't know if there was tumor there to begin with. So sorry, I forgot about this. So this is a case where the chemotherapy response score was three on the omentum, but actually this is a section of the ovary. There was very little response in the ovary. So does this matter? You know, yes, there is less reproducibility, but I think this really needs more studies before we can, or before we, you know, before we come to the conclusion that adnexal disease does not affect outcome. So again, this is both tubes and ovaries. You can see this is the fallopian tube. There is really very little tumor response to chemotherapy. And this particular patient had a cervix. This is a section of the cervix, and this is P53 highlighting the mutated type overexpression in this cervix deposit. So she had tumor in both ovaries and in the cervix showing minimal response, but with excellent response within the omentum. Obviously these cases are just fairly recent, a few weeks old, so we don't know the outcome yet. So the CRS system is really the only method that is currently recommended in the ESMO ESGO guidelines for ovarian cancer patients to predict survival. It is simple, free, and easy to use. Its reproducibility and accuracy has been validated in various studies. And in fact, omental response to NACT with this scoring system has been reported to be more important than debulking status for prognosis, and it will have an impact on patient care and future research into better chemotherapeutic options, especially for patients with chemo-resistant disease. And that is the end of my talk. Thank you for listening. Thank you, Angela. I mean, that was really brilliant.

chemotherapy response score

CRS system

ovarian carcinomas

neoadjuvant chemotherapy

primary debulking surgery

high-grade ovarian epithelial cancers