"OK, let's hold that thought for a moment and see what Student I has to say". \n\nClick on [[Student I's response:]]\n\nYou can also take a closer look at the slide again.\n\n[[slide 10|https://limdp.org/slide-10/]] \nBack one tab to get to this panel\n\n\n\n\n\n\n

"Wait a minute! Now, I am really confused. I see malignant cells and I see that they have not penetrated the basement membrane. But this does not look like skin! I don't see a dark stratum granulosum. I don't see any strands of stratum corneum.\nDoes seem like a thickened epithelial layer but no acanthosis. No signs of viral inclusions. Doc, what is it?\n\n[[Professor Jones answers:]]

Start with the slide:\n\n[[Langhans Giant Cell|https://virtualpathology.leeds.ac.uk/slides/library/view.php?path=%2FResearch_4%2FSlide_Library%2FDarren_Collection%2FSet_3%2F31508.svs]]\n\n\n\n\nReturn to [[Where's Patho?]] for more challenges.\n\nHappy hunting!\n\n

HEADS UP: SORRY - MY SOURCE FOR THE DIGITAL IMAGES USED TO WORK BUT NOT AT PRESENT(Working on it). THE JOURNAL REFS WORK. PROCEED - IT'S STILL A GREAT STORY.\n\nThe sun was shining. But Dr. Rogers was frowning. He has a case of a 33 year old woman with a large mass in her right breast, painful, slowly growing for about a year. It showed a 13 x12 cm mass which was hypervascular by doppler sonography. Mammography also showed a diffuse dense area of about the same size.\n\nThe group started to doze in the warm sun streaming through the window. What was the problem? Breast cancer!\n\nCatching their falling into the trap, he added one more point. \n"A fine needle biopsy was done. The pathologist concluded: Benign Capillary Hemangioma".\n\nNow he had their attention.\n\nSmith called out: "Discrepancy! I call foul! The radiological results and the histological results don't match"\n\nResident Jones raised his hand. "It seems to me that we need a macro biopsy".\n\n"OK," said Rogers. "But can't do it. Too big. Too vascular. Too difficult". We have to do a mastectomy. I'll set it in motion. Let's convene [[next week]] and continue the discussion\n\n

Start with the slide:\n\n\n[[Giant Cell Tumor of the Tendon Sheath: Multinucleate Giant Cell|https://my.pathomation.com/share/slide/nHq86BATAKspneqqS9ZO]]\n\n\n\n\n\nReturn to [[Where's Patho?]] for more challenges.\n\nHappy hunting!

The use of Twine in Diagnostic Pathology:\nStatic images: a study of look-alikes\nVirtual Microscopy: Diagnose the case

Try your hand at the following:\n\n1. [[Can you find the mucin that's loose in the tumor?]]\n2. [[Keeping abreast of rare pathologies]]\n

\nYou can choose which Set of Cases you would like to look at.\nFollow the group discussion actively. Take note of the important lessons.\n\nThere are five subject areas in the set of exercises:\n\n1. [[Dermatopathology Cases]]\n2. [[Tumor Board Cases]]\n3. [[In-situ Hybridization Cases]]\n4. [[Where's Patho?]]\n5. [[International Cases]]\n\n\nClick on the one you want. Let the challenge begin!\n\nFor maximum benefit, pause and think carefully about how YOU would diagnose the slide - conclusion with reasons. It is easy to fly along with the story and jump to the answer. But in the end, YOU have to come up with the right diagnosis!\n\nPractical suggestion: Delete each newly opened tab (slide or journal, etc) to get back to the story and to avoid tab overload.\n\n\nTHIS SITE IS UNDER CONSTRUCTION. HOPEFULLY, MORE CASES WILL BE ADDED, ESPECIALLY AS NEW METHODOLOGIES ARISE. COLLABORATORS ARE ENCOURAGED AND INVITED.

Start with the slide:\n\n[[Rhabdomyosarcoma|https://my.pathomation.com/share/slide/ZXdOzhwEyimXCcGNNSdX]]\n\n\n\nReturn to [[Where's Patho?]] for more challenges.\n\nHappy hunting!

"Let's put it together".\nHere we have a young man from China. A disease unexpected for his age. None of the internal known causes. Suggests an external cause. Early onset might suggest an intoxication. It is well known that in China one of their delicacies is Shark Fin Soup. Very expensive. But the history describes him as well-to-do. So let's assume that he has shark fin soup, probably often.\n\nSo - the cyanobacteria produce the neurotoxin, the neurotoxin works its way up the food chain and gets into the shark fins and into the soup. He eats the soup. The BMAA get into his brain. Into his neuronal proteins. That unusual and irregular protein causes tangles and clumps. The result is amyotrophic lateral sclerosis, ALS, or Lou Gehrig's Disease."\n\nNice story. \n\nNice detective work. Of course, we have to get back to them, to verify. They have to detect the BMAA in his brains cells"\n\nThe group jumped up. "Then what?! Is there a cure?"\n\n"No, not exactly. [[Riluzole|https://en.wikipedia.org/wiki/Riluzole]] is the only drug on the market for ALS but that only addresses the genetic issues. Of course, we can advise that he stop having shark fin soup. But how to untangle the tangles - that is the big challenge. I don't want to throw cold water on your ideas. But, then again, maybe I should throw cold water on your heads, for a price, and maybe the funds raised would help find that needed cure.\n\nGood job, guys."\n\n[Go back to the [[Opening Page|Start]] to try another case].\n

Start with the slide:\n\n[[Langhans Giant Cell|\n\n[[Langhans Giant Cell|https://my.pathomation.com/share/slide/KHzVeTdOXzsPWgJbhfdp]]\n\n\n\n\nReturn to [[Where's Patho?]] for more challenges.\n\nHappy hunting!\n\n\n\n\n\n

Try your hand at the following:\n\n1. [[The sin of occupying false premises]]\n

"I think that it is not melanoma. I think that these cells are too light to be melanocytes. More like keratinocytes, to me. I would say that this is Squamous Cell Carcinoma-in-situ. You see that it has not penetrated the basement membrane. No evidence of bulky growth. But clearly malignant cells. No mass in the dermis. No horn pearls".\n\n[[Professor Jones replies:]]

Here are two cases in which an initial diagnoses of renal tumor turned out to be an Echinococcal cyst:\n\n\n\n[[Case 1:|http://www.ncbi.nlm.nih.gov/pubmed/25031471]]\n\n[[Case 2:|http://www.ncbi.nlm.nih.gov/pubmed/25911040]]\n\n\nWork-in-progress: I plan to contact the authors to obtain a digital image to accompany this discussion.\n\nReturn to the [[Middle East|The Middle East]] to see more cases.\n\n

Dr. Chan called the group together for an important discussion.\n\n"I have a case that was directed to me from our friends in China. Not your typical histopathology analysis but a puzzle that he has been wrestling with. He asks for our help."\n\n"OK," said Resident A. "What is the case".\n\n"It's a case of Lou Gehrig's Disease. In this room we can can properly call it amyotrophic lateral sclerosis. The famous Stephen Hawkings had it. Of course, Lou Gehrig had it. It's rare in the population but devastating to those who are afflicted. Progressive muscle weakness, loss of speech and eventually a fatal paralysis of the diaphragm. \n\nIt usually affects people 60 and over. The puzzle is that here we have a case of a 30 year old guy, well-off, healthy, active, in the prime of his life, suddenly struck down with this disease.\n\nResident B chimed in: "What is the background? What have they done so far".\n\n"Well here's the thing. They have ruled out just about everything. No physical trauma. None of the genetic markers. What could have triggered it?"\n\nThe group [[discussed]] the possibilities for a while.\n\n\n\n\n\n

"One other thing. I have been browsing the literature while we were talking. Look what I found". \nHe sent everyone the [[link|http://jcp.bmj.com/content/early/2014/10/28/jclinpath-2014-202629]] and they all took a look at the abstract.\n\n\n"Good man, Marco".\n\n"Yes. Sullivan and coworkers at Emory add two important observations to our analysis of this case:\n"1) CD31 seems to correlate much more strongly with angiosarcoma than CD34. We would not have known that from our observations on this one case. Good to have in mind.\n2) ERG can also be used. Targets nuclear proteins while CD31 targets membrane proteins. Good to keep in mind, to add to our toolbox of possible stains to rule in and rule out. With sarcomas, you can never be too careful or thorough.\n\nGood job, guys. See you next week! \n\n[Go back to the [[Opening Page|Start]] to try another case].

Echinococcus: hydatid cysts mimicking tumors\nAn alert to telepathologists in-sourcing from that troubled part of the world.\n\nEchinococcus granulosis in found in many regions of the world, including the Middle East.\n\nRecent papers indicate that it can be/has been misinterpreted as being a tumor in numerous tissues. \n\nAlso, in some cases, what was taken to be a tumor turned out to be a hydatid cyst.\n\nHere are some sample papers:\n\n1. [[kidney]]\n2. [[liver]]\n3. [[lung]]\n4. [[pancreas]]\n\n\nWork-in-progress: I plan to contact the authors to obtain a digital image to accompany this discussion.\n\n[Go back to the [[Opening Page|Start]] to try another case].\n

Dr. Jones welcomed the group to the Dermatopathology Lab's weekly conference. He put up a slide on the Power Wall. \n\n[On the Web, when you have finished looking at the slide go back to the previous tab]\n\n"Let's take a close look at [[slide 10|https://limdp.org/slide-10/]] \n\n\nJust to orient you, notice that the slide is presented upside-down; the surface epithelium is at the bottom. \n\nNow, what is your diagnosis?\n\n[[Student G's response:]]\n\n\n\n

Start with the slide:\n\n[[Hodgkins Disease: Reed-Sternberg Cell\n|https://my.pathomation.com/share/slide/8PVqT3LGJhDcxwHTo4Q8]]\n\n\nReturn to [[Where's Patho?]] for more challenges.\n\nHappy hunting!

"Well, looking at the appearance of the hyperchromatic nuclei and the overall dark staining appearance of the tissue, I would say Superficial Spreading Malignant melanoma, Clark Level I. This is supported by the observation of mitotic figures and the observation that the tumor cells have not penetrated the basement membrane".\n\n[[Professor Jones comments:]] \n\n

Staining done. Slides loaded. Group back in place.\n\n"Well, Jose, how about you present. What did you find?"\nBut just show us the results. Everybody work on it first.\n\nHe showed the [[CD31 slide|http://diagnosticpathology.slidepath.com/dih/webViewer.php?snapshotId=13699057396334]] first.\n\n"What do you think?"\n\nEveryone shouted at once. "Definitely stained for CD31. Definitely shows the stain color that we would expect".\n\n"Good. Now, Jose, show us the [[AE1/AE2 slide|http://diagnosticpathology.slidepath.com/dih/webViewer.php?snapshotId=13699057638253]]. Study it carefully.\n\n"What are your observations?"\n\nNo staining. Rules out a tumor of epithelial cells. The other slide rules in endothelial tissue as the tumor tissue.\n\n"Good job. Now, I have some [[homework]] for you."\n

\nChallenge: \n\nCan you find the following diagnostically significant cell types?\n\n\n[[Giant Cell Tumor of the Tendon Sheath: Multinucleate Giant Cell]]\n\n[[Tuberculosis: Langhans Giant Cell 1]] \n[[Tuberculosis: Langhans Giant Cell 2]]\n\n[[Rhabdomyosarcoma: Brick Red Tumor Cell]]\n\n[[Hodgkins Disease: Reed-Sternberg Cell]]\n\n\n\n[Go back to the [[Opening Page|Start]] to try another case].\n

\nSorry. \n\nThis page is under construction.\n\nBut I have great plans: \n Stories involving\n\n FISH, CISH\n Multiplexing\n TILs\n Maybe AI\n Maybe 3D\n Maybe In vivo\n\nLots of new developments to get to. Hopefully.\n\n\n[Go back to the [[Opening Page|Start]] to try another case].

Resident Susan Green thought.."what do I think? I think I'd rather be with my fiance right now.. but hold on, got to stay focused.."\n\nShe said "I see lots of hyperchromatic nuclei in the lining cells, and mitotic figures. Looks malignant to me. And pretty seriously."\n\n"Right," said Dr. Rogers. Here. Take a look at this sample from that slide that I pulled out. Just a static image but you can clearly see the nuclear changes that Susan was describing. \nHe puts the [[sample slide|http://image.wikifoundry.com/image/3/a15b4ba12be3caec1668fc1b0d934546]] on screen for all to see.\n\nNow, what do we need to do to nail down that this is a tumor of vascular tissue.\n\nMatt jumped in: "How about histochemical staining?"\n\n"Great idea! What do you suggest?\n\nMatt responded before he thought. "Breast tumor. Let's go for [[HER2 stain]]".\n\n

"Hold on!"\n"Take a look at this paper by [[Hwang, et al|https://doi.org/10.5858/arpa.2013-0179-OA]]\n\nThey show that TTF-1 really does not differentiate well between ADC and LCC. You really need to keep up with the literature. Your thinking was good, to try to do additional staining. Observations are easy. Interpretations are usually much harder.\n\nSee you all next week!\n\n[Go back to the [[Opening Page|Start]] to try another case].

Your assignment is to read the paper that this exercise was based on. It is [[Bennani et al|http://www.diagnosticpathology.org/content/8/1/66]]\n\nLots more detail, more background. It is part of your work on this case.\n\nOne last question: "Why did I bring up this case? Answer: it is such a rare case. Bennani quotes Desbiens, et al who indicate that there are only 17 cases of angiosarcoma in the breast per one million women. \n\nSusan chimed in: "Even we almost missed it. It we would have stopped at the level of the needle biopsy we would have sent her home. And then - sent home with a malignant tumor and a note saying "Don't worry" how long would she have lived...?"\n\nRight. When something is so rare, you want to be doubly sure that you do everything you can to be certain of your diagnosis".\n\nMarco raised [[his hand]].

"Okay, I, you are making an important observation. And you are absolutely right - it is not skin."\n\n"But this is a Derm Path Lab", he shouted. "What do you mean that this is not skin".\n\n"Hold on," said Professor Jones. Let's get everyone [[together]] and we'll see what is going on with this slide".\n\n

"I agree. Same observation".\n\n"Anyone else want to chime in?" \nA number of hands went up, all in agreement. \nExcept [[Resident C]].

"I came late. Just walked in. Missed the earlier discussion but I read up on the case and I asked the lab for a TTF-1 stain of the slide".\nHe takes out a thumb drive and plugs it into the computer to project for the group.\n\n[[Slide 13 H&E Stain|http://goo.gl/J7iMv7]]\n\nAnd now...\n\n[[Slide 14 Immunohistochemical staining for \nTTF-1|http://goo.gl/h5Iqj2]]\n\nJust to make my point, I made a slide for you to look at, of a selected, matched area, nicely stained.\n\nYou see, the lung tissue stains for TTF-1, proving that it is Adenocarcinoma.\n\n[[Professor Chan responds:]]

"BMAA is Beta-Methyl-Amino-L-Alanine. Not naturally found in proteins but one of hundreds that exist in nature. Cyanobacteria are found in the oceans of the world. They get into the food chain, get into shark meat and fins and then into people."\n\n"Then what?"\n\n"Well, it has been found that these unusual amino acids can get into human, especially brain, proteins. That causes misfolding and tangles, just as we see in Alzheimer's Disease and ALS." See [[this abstract|http://www.sciencedirect.com/science/article/pii/S0014488613003762]]. There are also a number of pathological changes inducible by [[BMAA|http://www.ncbi.nlm.nih.gov/pubmed/26002186]].\n\nResident F added: "I was reading a similar story about the outbreak of neurodegenerative disease amongst the Chamorros in Guam. They eat flying squirrels. The flying squirrels eat cycad plants and the plants have these same cyanobacteria on their roots. Probably a similar story."\n\n[[Dr. Chan summed up:]]

Here is a paper indicating that liver tumors and Echinococcal cysts share similar features and can be misdiagnosed:\n\n[[liver|http://www.ncbi.nlm.nih.gov/pubmed/22075370]]\n\n\nWork-in-progress: I plan to contact the authors to obtain a digital image to accompany this discussion.\n\nReturn to the [[Middle East|The Middle East]] to see more cases.

Here is a case of what seemed to be an Echinococcal hydatid cyst turned out to be a Large Cell Carcinoma of the Lung:\n\n[[lung|http://www.ncbi.nlm.nih.gov/pubmed/19067256]]\n\n\nWork-in-progress: I plan to contact the authors to obtain a digital image to accompany this discussion.\n\nReturn to the [[Middle East|The Middle East]] to see more cases.\n\n\n

Challenges in Digital Pathology\n\n

Dr. Chan was holding forth at the weekly Tumor Board meeting. He had half a dozen residents in Pathology around him, ready for the first case.\n\nHe presented the background. The charge was to find differences between pulmonary large cell carcinomas without squamous differentiation and solid subtype adenocarcinomas. This was a challenge. Hwang et al (ref at the end) had published a study in which they observed very few differences between the two and suggested that they be classified as one entity. They zero in on mucin production as a differentiating feature, proposing that nonsquamous nonneurendocrine LCCs with undifferentiated morphology can justifiably be recategorized as mucin poor solid adenocarcinomas.\n\n"So," he addressed the group, "what I would like you to do is look at these two slides".\n\nOne is LCC (Large Cell Carcinoma) and the other is ADC (Adenocarcinoma). Using only mucicarmine staining as a differentiating criterious, can you find the staining of the mucin in the cytoplasm and thereby tell me which is which on that basis? Mucin-positive is ADC. Mucin-negative is LCC.\n\nI'll give you a clue: Here is the pink-staining mucin. As you can see, it is very subtle. \n[[Fixed image:|https://www.labce.com/spg949468_mucicarmine_diagnostic_applications.aspx#:~:text=The%20mucicarmine%20staining%20procedure%20is,originating%20from%20the%20gastrointestinal%20tract.]]\n\nNow here are the two slides:\n\n[[Slide 11:|http://goo.gl/NlPGuF]] \n\n[[Slide 12:|http://goo.gl/Zh2mY8]]\n\nAlright! Go for it.\n\nAfter scanning the entire slide at high power for while, they reported their conclusions.\n\n[[Resident A says:]]\n\n

\nHere is a case of a cyst originally taken to be tumor:\n\n[[Pancreas|http://www.ncbi.nlm.nih.gov/pubmed/24906281]]\n\nWork-in-progress: I plan to contact the authors to obtain a digital image to accompany this discussion.\n\n\nReturn to the [[Middle East|The Middle East]] to see more cases.

Susan was all into it now. "No, that is for other tumor markers, other tumor types. We need something specific for endothelial tissue".\n\n"What do you suggest?" \n\nResident Jose Ramos suggested: "I know. Let's stain for CD31 and CD34. They are specific for endothelial cells. That will tell us if the proliferationg tissue is vascular".\n\nGood! Let's ask the the lab to do that. \nBut we also need a control stain. What will rule out epithelial tissue?\n\nThis gave them pause for a moment. Then Jose, the group's histochemical stains man, jumped in again. Let's stain with cytokeratin AE1/AE2. That will tell us if it is an epithelial cell proliferation of some other sort, not vascular.\n\nLet's stain and [[reconvene]]".

Background: Mrs. X came to my office with vaginal bleeding and pain. I took a sample of cervical epithelium, 3x2 cm and sent it to the GYN Path Lab for diagnosis.\n\nClinical Impression: Cervical Intraepithelial Neoplasia [CIN].\n\nBack to [[together]]

"I would say that Slide 11 is negative for mucin. I could not find any indications of mucicarmine staining. But I did find lots in Slide 12. Not even so subtle".\n\nProfessor Chan replies:\n"OK, very good. Let's hear what [[Resident B]] says".

The group was back in the Path Lab Conference Room, each in his or her accustomed seat.\n\nMrs. Rabinowitz had her right breast removed, for her own safety. Proper histological sampling was done. Dr. Rogers was ready to present the findings.\n\nHe first presented to the group the H&E results.\n\n"As indicated by the radiology, we find lots of vascularity..."\nBefore he finished, Resident Larsen interjected: "So, sounds like hemangioma".\n\n"If all we looked at was the presence of vascular tissue, maybe. But look at the slide, look all over, and tell me what you think".\n\nEach one brought up the slide on his laptop and [[studied it|http://diagnosticpathology.slidepath.com/dih/webViewer.php?snapshotId=13699058238941]] [Double click on the slide to see the virtual WSI] [Then click on previous tab]\n\n[[Now what do you think?]]

Resident C wanted to know more about his background. A thirty year old, active, well-to-do. Reminds me of the [[Frates|http://espn.go.com/boston/story/_/id/11366772/in-als-fight-pete-frates-message-loud-clear-ice-bucket-challenge]] story. Another guy, American, about 30, also active, not a candidate for ALS but there it was. Instead of freaking out or giving up, he threw himself into finding a cure. That needs a lot of funding. Not simple for such a rare disease. He (and family and friends) came up with the [[Ice Bucket Challenge|https://en.wikipedia.org/wiki/Ice_Bucket_Challenge]]. Went viral and this year brought in about $140 million dollars.:\n\nResident D interjected. "Yes, I remember the story. Not sure if it was he that first came up with the Challenge idea but he sure made it focused and profitable."\n\nDr. Chang brought the group back to their own challenge. "What can we say about this particular case.\n\nResident A started off. "I have been doing some literature research in an area of interest of mine - the role of bacterial toxins as they work their way up the food chain and can affect people. They have discovered that cyanobacteria produce a neurotoxin, [[BMAA|https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3295368]], that can cause neurodegerative diseases."\n\nResident D added: "Yes, and Dr. [[Mash|http://www.ncbi.nlm.nih.gov/pubmed/24755394]], at the University of Florida recently discovered that this neurotoxin finds its way into shark fins.\n\n[[Resident E]] continued:\n\n

Now, listen carefully, everybody. You all heard each other's comments. Student I was right on. This is not skin. I would have hoped that all of you would have picked up on that. \nThis leads me to make an important point: Every slide comes with a report from the clinician. Read it. First. Here it is.\nSee [[Clinician C's report]].\n\nIn other words - check and double check. Don't take anything for granted. Now, obviously, there is a problem. What IS a GYN slide doing in the DERM PATH Lab. But, you know, mistakes happen (and I will surely look into this mixup with the proper people). But your job is to be open to possibilities. \nFirst, be attentive to details (like read the paperwork that comes with the slide).\nSecond, always be open to the possiblility of human error.\nThird, be attentive to all the details of the slide. You were so focused on this being skin pathology, and you did see malignant cells in a surface layer, so, of course you said melanoma or Bowen's Disease. But if you don't see signs that it really is skin, think of other cases, where you have malignant cells in superficial tissue, above the basement membrane. Like CIN. Always be careful not to occupy false premises.\n\nHave a great day, everybody. See you next week.\n\n[Go back to the [[Opening Page|Start]] to try another case].\n

\n\n\n\n\n\n\n\nCase 1: [[Did Lou Gehrig eat shark fin soup?|Case 1:]]

"OK, let's hold that thought for a moment and see what Student H has to say". \n\nClick on [[Student H's response:]]\n\nYou can also take a closer look at the slide again.\n\n[[slide 10|https://limdp.org/slide-10/]] \nBack a tab to get back to this panel

Zev Leifer, Ph.D.\nPresident and Chief Research Officer\nThe Leifer Institute for Molecular and Digital Pathology\n\n[[http://www.limdp.org]]\n\nProfessor of Microbiology and Pathology Emeritus\nNew York College of Podiatric Medicine\n[[http://www.nycpm.edu]]

[[Casas test|http://qumulus.mikroscan.com/live/anonymous-project/8vYBM1lHFc8JYHEeZzk8Cns1/?name=Users%2Fqscan%2Fab1132a1-ca4e-472e-9622-0ba6d0ea0e83]]

Many laboratories in the United States have arrangements with foreign countries to diagnose, via telepathology, pathology slides that they are unable to process. For the most part, this is due to a lack for qualified pathologists for the population, for various reasons.\n\nThere are case histories and pathologies, peculiar to those countries, that might not be familiar to pathologists in the U.S. Some examples might be helpful.\n\n[[China]]\n\n[[The Middle East]]\n\n

Enjoy!