The Farmer Who Removed His Skin Cancer With A Pocket Knife

Casey is a 45 year old man presenting to the emergency room with status epilepticus nurses pharmacologically terminate his seizure with bolus lorazepam his wife Jennifer tells the admitting nurse that over the past few days Casey had developed a left hemiparesis with recurrent persistent headaches he reported feeling as if someone were pushing from inside his skull against his eyes the whole family acknowledged a severe personality change in Casey over the past few months there was something wrong happening to him Casey was a farmer from rural middle America several weeks ago Casey presented to a different emergency room at physical examination their neurologic signs were found he had ataxic gait a meeting without and taxi a-- referring to order gate being his walk his walk was disorderly and uncoordinated but the findings overall were inconclusive emergency staff were to refer Casey to outpatient radiology at discharge but he never followed up more immediately an erythema dismiss three and a half centimeters in diameter in his right axilla was found accompanied by a poorly healed scar on his right arm the mass appeared to be affecting multiple lymph nodes an infection was suspected the antibiotic clindamycin was started at discharge pain resolved the swelling persisted and Casey's hemiparesis worsened conscious now in this hospital Casey is coherent he recounts the attending physician the last few events in his memory he was struggling to work on the farm fatigued and tired he was standing in the Sun as the last thing he could remember before falling unconscious at Casey's initial workup in this emergency room doctors immediately find the right axillary mass to be four and a half centimeters in diameter no other palpable adenopathy s were present his blood pressure was a little high 145 over 97 oxygen saturation normal on ambient air blood glucose was 70 milligrams per deciliter complete blood count normal liver function test normal creatinine or measure of kidney function normal his electrolytes protein albumin and globulin were all normal everything seemed to be fine with Casey except for the mass in his right armpit along with a really strange looking scar on his right arm doctors asked Casey hey man what's going on here with the scar on your arm and his eyes immediately light up ah you'll be proud of me I took this one out myself he said as he pulled out his phone he scrolled to a picture that he landed on and told the doctors I chopped it out myself with a pocketknife about six months ago on the screen was an ulcerated asymmetrical pigmented lesion with irregular borders as the doctors were looking at what seemed to be skin cancer Casey said without any hesitation it was surprising to me how thick it was I don't want to get into the gory details but I definitely needed a big band-aid for this afterwards with what looked like a melanoma skin cancer that was on his right arm a growing mass in his right armpit and a 15-minute status epilepticus seizure doctors start to realize what's going on here Casey's visit to the other emergency room weeks ago probably wasn't a bacterial infection it was likely a cancer that had been spreading all throughout Casey's body despite the fact that he cut out that primary tumor on his right arm with a pocketknife further evaluation was performed by radiology and pathology pet and CT scans revealed hypermetabolic lymph nodes in his right axillary mass fine needle aspirate from an axillary mass lymph node tested positive for s100 and Mellon a both melanocytic amino markers the malignant epithelial proliferation in the sample was consistent with metastatic melanoma meaning it wasn't just skin cancer that had spread to his lymph nodes it was melanoma which is the deadliest kind of skin cancer these cells are likely the same ones that came from the cancer that he cut out of his arm but if it grew on the skin then how did it make it to his axillary lymph nodes this brings us to the idea of tumor thickness as melanomas grow there's two directions that they can take they can go wide but they can also go deep as the disease progresses it's the deep direction that becomes dangerous the deeper the tumor grows into the skin the closer that it gets to the blood supply once it in Travis eights into the blood supply parts of it can break off and start to circulate around in the body and as the blood drains into the first lymph nodes into the axilla a couple of those cancer cells can start to grow there okay so why cancer the body cells can usually break off and drain into the lymph nodes in normal function this never causes a problem why would the cancer cells be any different a biopsy of the primary lesion was not possible because of KC's self excision but a lymph node biopsy from the right axillary mass was performed paraffin-embedded tissue from this metastatic focus was used for extraction of genomic DNA PCR was used to perform a B raft sequence analysis with the use of primers spanning bier F axon 15 a substitution of thymine for adenine was detected at nucleotide 1799 corresponding to a substitution of glutamic acid for valine ad amino acid number 600 the v600e mutation in the serine threonine protein kinase b raf what does all of this mean well the evidence of research since the 1970s shows that cancer starts as a genetic disease mutations acquired in cells can fit one of two qualities in normal activity tumor suppressor genes regulate cell activity they prevent the cell from doing anything that would cause it to uncontrollably replicate typically if one copy of the tumor suppressor gene mutates a second normal copy can still work to do that regulation but if that second copy gets mutated too then cells may not stop replicating if the body doesn't catch this in time then masses can form from these cells on the other hand there's also something called proto oncogenes these are genes that gain function and by gain it means that they obtain the ability to promote the cell to replicate uncontrollably this means that they can bypass any regulatory signals inside the cell to say hey stop reproducing uncontrollably when cells need to send signals they do that signaling through all steps involving multiple chemicals one prominent chemical is phosphate you hear this name in many things like adenosine triphosphate which is ATP which is what cells use for energy the phosphate bond holds lots of energy and breaking it off gives off energy in the context of b-raf notice that we called it a serine threonine protein kinase the ACE suffix in kinase indicates that we're talking about an enzyme here a kinase is a type of enzyme that phosphorylates so it puts a phosphate onto something serine and threonine are both amino acids proteins are made of amino acids meaning that b-raf phosphorylates serine and threonine on proteins in the cell there's something called the mitogen-activated protein kinase pathway map K this is a major signal pathway that leads to cell replication and this is where b-raf sits on the surface of cells there's a protein called wrasse when the map case signal needs to be activated a linker protein is sent to a factor to bind to wrasse the factor gets an additional phosphate for wrasse and this new complex can activate lots of different proteins this is still a relatively higher and upstream process so one of the proteins that's activated by wrasse is raf keep in mind b raf is just one kind of raf there's multiple kinds of raf in normal function b raf changes shape when bound to wrasse it's in this shape that b ref can phosphorylate other proteins because remember kinase puts phosphate on in this pathway the protein that b raf phosphorylates is called mek phosphates on mek activates other protein called Kirk this sends a giant cascade of signals to other factors that go into the nucleus and activate genes that promote cell growth proliferation and survival and this is where problems can come from if there's a mutation in B ref that causes it to activate neck without needing to be bound to wrasse and binding to wrasse is one part of that process that regulates how b raf works then it means that a mutant can cause b-raf to continuously activate MEC and promote cells to keep dividing and reproducing leading to what we know as cancer in 2002 a landmark study in nature identified that a large proportion of melanoma tumors appeared to have in common a single point mutation at nucleotide number 1799 where a T was present instead of an A this correspond to a single change in one amino acid which causes the protein to fold just a little bit differently and allowing it to function independent of upstream regulatory signals this B ref v600e mutation which in the nature paper was called the beer FV 599 e mutation because they didn't count for the methionine initiator doesn't just happen in skin cancer it also happens to be found in thyroid cancers as well as colorectal cancers the latter indicating poor prognosis acquisition of a b-raf mutation is thought to be an early event in melanoma development over 80% of neva harbor a b-raf mutation as a single hit driver mutation oncogenic b raf drives melanocytes into senescence that is malfunction and additional genetic insults are required for melanoma Genesis among the hits identified so far that contribute to melanoma development are alterations in other regulatory pathways for things like p53 and the cell cycle the interesting thing about this map k pathway is that even though the 2002 nature paper outlines some cancers have this beer at v6 under a mutation we had known about the map k pathway for at least 20 years prior to that there trying to understand the action of insulin and we know that insulin is an anabolic hormone signaling for cells to store nutrients thus shifting glucose from the blood into the cells and promoting the synthesis of cellular materials and energy storage the original name for map K was mapped to instead of mitogen-activated protein kinase it stood for microtubule associated protein to notice that at first they thought it was just the single protein that was activated by insulin they later found out that it was families of hundreds of different proteins living inside an intricate signaling cascade and it was through the understanding of the action of insulin that humanity was able to discover its impact on human cancers notice sometimes people will say the action of insulin can help mitigate cancer disease while that could be true the reality is is that even if you're not eating carbs you can still trigger an insulin response by eating anything and that that can activate this pathway all of this brings us back to KC as he awaits the testing results as an admitted patient KC starts seizing again it doesn't spontaneously resolve and it keeps going on for minutes nurses have determinated with medicines the medical team sentiment for a brain MRI the scan with contrast finds multiple enhancing mass lesions developing in the patient's left frontal right frontal and left temporal regions these were surrounded by a t2-weighted hyper-intense signal a finding that's consistent with melanoma brain metastasis the density of these masses shown in the scan are either from the melanin which is the pigment from the melanocytes or they're from hemorrhaging and bleeding whatever the case is the melanoma team confirms now that Casey has distant melanoma metastases to his central nervous system under the 2018 8th edition staging guidelines Casey has m1 disease and the 5-year survival in this group is less than 10% this brings us back to the idea of tumor thickness in reality we don't know what Casey's primary tumor thickness was because he cut it out himself it's possible that the cancer was already spreading by the time that he cut it out as the medical team never got to evaluate him for this but it's also possible that some of the cells that came off as he cut it off himself had spread into the bloodstream and stuck itself in his lymph nodes the general idea is that we don't know what staging of disease Casey had at the time when he excites his tumor but what we do know is that after being able to classify melanomas for at least the last four to five years some of the cells from that tumor got into his right axillary lymph nodes where they were able to start to spread all throughout his body melanomas are the third most common cancer spread to the brain breast and lung cancers have a higher incidence of brain metastasis but data shows that 40 to 50 percent of patients who have a melanoma that spreads somewhere in the body will eventually have it spread to the brain the brain is a specialized micro environment with specialized cells and its unique vasculature gives way to the so called blood-brain barrier we know this barrier as a functional entity that has tight junctions and the ability to preferentially select molecules for entry through an active process at the molecular level the tight junctions in the cerebral vascular endothelium are made of ik luden 0 1 and cloud n' as well as a functional basement membrane in the barrier the way that cancer metastasizes is through a process that we understand today as a cycle the circular nature of the pathway is critical and understanding that metastasis can occur from other metastasis a small fraction of primary tumour cells are known to in Travis 8 into the circulation that's why tumor thickness on skin is so important in understanding the staging of melanoma disease on a biologic basis we know that fluid with any viscosity and any velocity that is speed not equal to zero that comes into contact with an interface will produce a shear stress onset interface and in result a very small fraction of the cells from that interface can enter the bulk flow of the fluid it's possible that this is the mechanism whereby melanoma cells enter the systemic circulation as we know a tiny fraction can survive there extravasation an arrest in a distant organ are the two steps in where the biology of the brain demonstrate melanomas metastatic propensity to the brain we know that there's a series of proteins over expressed on the surface of melanoma cells which allow for preferential adherence to the cerebral endothelium the most well-documented currently in the late 2010's are the chemokine receptors CCR for tetris bannon's and integrins these have been demonstrated in experimental models with modest translation to clinical correlates and they make up the extravasation step of the metastatic process the arrest in a distant organ step to be the result of serine protease secretion by melanoma cells which would affect those tight junctions on the endothelium side and on the basement membrane side proteinase and heparin ace secreted by the melanoma cells appear to disrupt the integrity of the blood-brain barrier and enable their entry into the brain astrocytes secrete neurogenic growth factors as part of their normal biology which will promote the growth and survival of the invading melanoma cells as neovascularization neo angiogenesis occur and a brain metastasis begins to develop repeating the cycle melanoma brain Mets commonly grow into the cerebral cortex therefore neurologic signs and symptoms such as headache seizure and intracranial bleeding are more common in melanoma brain Mets than compared to lung and breast brain Mets bringing us back to Casey Casey isn't offered surgery for his brain Mets because there's just too many of them typically we won't want to operate on the brain in cases like this because there's a big risk that something is going to go wrong what was offered to him was radiation therapy radiation uses ionized radiation which is not the same thing as 4 g + 5 g cellular networks this radiation damages the DNA of cancerous tissue leading to cell death it was Marie Curie and her husband who discovered the elements polonium and radium and she was the one who coined the term radioactivity but humans at the time didn't realise the full extent to how radiation affects cells in the 1910s just some time after the Curie's made their discovery a New Jersey corporation called u.s. radium started to mix radium with paint it looked cool there was a glow-in-the-dark paint and they used it on things like watches back in the early 1900's this paint was applied to products by people to paint watches you needed people who had steady hands since there was a precision necessary to create an aesthetic women were encouraged to do this painting without any precautions or personal protective equipment I would like to think that they didn't know how harmful this could be at the time but it seems like that may not have been the case Emil Grubb at least to today's account seems to be one of the first people to use in medicine in cancers in his observations it looked like double and quadruple doses of radiation did not translate into more cures for cancer but that not controlling where the radiation went caused patients to suffer side effects like going blind u.s. radium had its young women workers lick the paintbrushes with their tongues to produce the lettering on the watches in some time after these workers started to complain of jaw pain fatigue skin and tooth problems about ten years later medical examination of these women found that the bones in their jaws had necrosis their tongues had been scarred by radiation and many of them had anemia and meaning without an Meo meaning presence of blood this indicated that there was damage to their bone marrow over the next couple decades these women started developing tumors soft tissue sarcomas leukemia that is leukocyte presence in blood and other head and neck tumors these radium girls as the media at the time called them sued us radium corporation and a settlement was made out of court but a lot of the money wasn't collected because many of these women were too weak to even raise their arms now the point of this story is to say that radiation does in fact kill cells it kills any kind of cell by interfering and damaging its DNA if cancer is a disease where the DNA has caused alterations in the cell to proliferate non-stop then radiation should be able to kill these cancer cells people like a meal grub established that more than a hundred years ago radiation can penetrate human tissue and go directly to the site where the cancer is but the problem with all of this is that in killing the cancer cells we end up killing our own cells too Casey was offered two options for his radiation therapy the first was stereotactic radiosurgery this means that the radiation would be concentrated to specific parts of his brain where the melanoma Mets are this would ensure targeted delivery to the lesions to minimize any damage that would happen if the whole brain were irradiated but on the other hand melanoma cells wouldn't just be where the lesions are on MRI small groups of melanoma cells may exist in the brain and may not yet have formed large enough tumor to be detected on MRI this means that while stereotactic radiosurgery may kill the detectable tumors it wouldn't prevent the growth of another tumor that has origins too small to detect at this point in time so he was given another option whole brain radiation this would ensure that the whole brain gets radiation so that those small undetectable cells would get hit it would deliver the radiation to the brain Mets as well but it would also kill normal brain cells this would cause fatigue alopecia which is baldness and neurocognitive deficits the latter can be permanent as healthy brain cells are killed off in the irradiation studies have also shown that whole brain radiation does improve intracranial control of the cancer but that it doesn't prolong overall survival which means for Casey despite the radiation or medicine that could be given options are limited as all of this cancer has spread around his body and his brain in the english-speaking world melanoma first makes an appearance described as a cancerous fungus extra sense by John Hunter in 1787 dr. hunter had just excised the tumor from a jaw of a young man that he just saw and detailed that the tumor had recurred on the patient's chin several years later thought to have men may be caused by trauma because he had just been caught up in a bar fight at that time the specimen that was excised by John Hunter was preserved for 200 years in the Han terian Museum of the Royal College of Surgeons in London and is now specimen number 219 in 1968 specimen 219 was examined and using contemporary techniques it was identified as melanoma the first fall description of melanoma as a disease was in 1806 by Rene Laennec who was still a medical student at the time by 1820 William Norris had published a post-mortem description of a patient with an atypical Nev eye who ended up dying of metastatic melanoma it took another 24 years by dr. Samuel Cooper to document that advanced melanoma that is once it has started spreading all throughout the body is untreatable and a death sentence in his textbook first lines of theory and practice of surgery he said that the only chance for survival was early removal of the disease all of this comes from the english-speaking world though my guess is that there were earlier documentation 'he's not just in Europe but all around the world because archaeological evidence from mummified skeletal remains of Peruvian Incas dating back to 2400 BC that is at least 1500 years before the early Romans give examples of melanoma present with the discovery of the BRF v600e mutation scientists were able to determine the exact shape of the protein binding site they were able to design a molecule that would bind into the site and stop b-raf from doing that phosphorylating this would stop its action and it could cause it to stop forcing the cell to replicate without any regulatory feedback but the thing is casey is presenting to the emergency room in 2011 this was as that molecule was being tried in humans but this wasn't the only therapy that was being investigated by 2011 immunotherapy that is allowing the body's immune system to target the cancer was also being looked at as well a girl caught her hand behind a train seat this is what happened to her bones Edie is a 17 year old girl presenting to the emergency room with a swollen and discolored right hand she tells the surgeon that she had caught it behind the seat level of a Pullman railcar and her hand had become painful swollen and discolored she couldn't sleep with the pain on examination a slight swelling of her hand half the size of an olive like an extra knuckle where the metacarpal met the pinkie was observed the mass was tender but it didn't move examination of her head and neck and axilla found no palpable at an OP of these meaning there was no lymph node involvement this probably wasn't an infection she was diagnosed with pareo situs an inflammation of bone connective tissue and sent home as the doctors were confident that she would get better but she didn't get any better in the emergency room again weeks later Edie saw the same doctor again she wasn't able to feel anything in her right hand anymore he performed an exploratory surgery to find out what was happening to her hand the lesion had become larger now and he took samples of it to send him for biopsy the pathologists report returned what was growing on her hand was cancer the doctor thought he would only need to amputate her right hand to prevent it from spreading but further examination finds that it had already started spreading all around her body buckshot like nodes were present in her chest just above her womb was a growing mass that the doctor described as the size of a child's head diffuse infiltrates were in her liver over the next few months Edie became physically unrecognizable as she lost about half of her body weight as her skin turned gray with lumps growing all over her skin she presented to the emergency room in August and by late January that next year Edie passed away the year was 1891 William Coley was the surgeon in this case and the patient was Elizabeth Bessie deshield Coley was in the New York Hospital surgical service yeah just finished medical school two years prior at Harvard and Bessie was one of his first patients Bessie was good friends with someone named john d rockefeller Jr who was just of high school age like Bessie was at that time the death of a 17 year old patient shook dr. Coley any new doctor in any era of practice is going to be shocked by death but especially so in a patient who one did not expect to decline the way that Bessie did her cancer was called a sarcoma which is an aggressive type of bone cancer that can spread all around the body back in the late 1800s medical records were decently documented Koli went through the entire hospitals written records looking for cases of soft tissue sarcoma and after seeing seven years worth of records he found a certain mr. Fred Stein a 31 year old German immigrant mr. Stein presented to the emergency room with a large egg sized mass in his left cheek by his neck line in the winter of 1885 this turned out to be sarcoma the surgeon dr. William T bull was able to resect the tumor from the neck only to have it come back a few months later dr. bull operated again on mr. Stein and then it came back again and they removed it again and it came back again and again until it was removed a total of five times an open wound was left on mr. Stein's surgical site where he started to develop an infection called Erie simple in the late 1800s without any antibiotics available this infection was basically a death sentence it was known in the Middle Ages as st. Anthony's fire a red rash would start at the face and neck spreading rapidly followed by raging fever chills and inflammation this would eventually lead to the patient dying as did many surgical patients and amputees did during this time not much had changed since the American Civil War and it wouldn't for many more decades until the advent of penicillin is one of the first widely manufactured antibiotics Fred Stein was thought to be on his deathbed a recurring tumor that was huge along with an open wound infection and fever would wipe out anyone in the late 1800s but Fred Stein didn't die he stayed a life and even more interesting the tumor on his neck started to shrink the fever would wax and wane some days he'd be conscious and okay during those times the tumor didn't budge but then the fever would come back and Fred Stein's tumor would start to shrink again and again four and a half months later Fred Stein walked out of the New York Hospital with no cancer and no infection no residential records were written in this hospital record so Coley was only able to speculate on what could have happened and it was here that he developed the idea that fever and the body's immune system may have been responsible for treating this patient of cancer Coley had gotten the idea of injecting bacteria into cancer patients to try to trigger an immune system reaction however without antibiotics at this time and without any way of potentially rescuing the patients should something go wrong this would have been really risky at the time so he settled for using killed bacteria and using those to trigger an immune response over time he did have some success in treating patients this way but as the decades passed with some mixed results this method was eventually shelved and even forgotten by the 1970s in the 1990s there was some renewed interest in looking at this mechanism of immunotherapy but at the time it wasn't reliable and the treatment paradigms thought all of this was not going to actually amount to anything because at that time most cancer treatments didn't really amount to there was some survival but it wasn't great now the only thing that I can say is that the treatments that started seeing the light of day in those experiments from the 1990s have been available now since 2014 in the form of an immunotherapy and in some cancer types they have changed the landscape of how we treat patients for example in metastatic melanoma in the 80s and 90s chemotherapy was used by the late 90s an immunotherapy was approved with some benefit in early stage melanomas but it was only approved in the United States and not in Europe and by 2011 multiple kinds of treatments hadn't just emerged they were becoming adequately available but Cayce presented before those therapies were available although given his advanced disease I'm not sure how much he would have benefited if at all despite everything that has happened since because just a few days after he presented to the emergency room and just before he could choose a radiation treatment modality Cayce passed away I hope in another 10 or 20 years when another person like Casey's situation presents to the emergency room will have something for him at that time thank you so much for listening take care of yourself and be well

Channel: Heme Review

Views: 276,428

Keywords: melanoma, skin cancer, oncology, brain metastases, stage iv, melanoam, malanoma, cancer biology, genetic mutation, gene, cancer physiology, metastatic, history of melanoma, farmer, sunscreen, sun, uv, national cancer institute

Id: bxGS07U-B98

Length: 29min 56sec (1796 seconds)

Published: Mon Apr 13 2020