A NEED FOR BIOPSIES AND AUTOPSIES

  • by Barbara Bouyet

    “Malignant histiocytosis,” (MH) was the diagnosis from the oncologist after receiving the results of the biopsy.  That information was not only vital to my peace of mind, but it was extremely important for the Leonberger because that type of cancer had never been recognized in the breed.

    Histiocytes are macrophages, cells produced in the bone marrow which play a vital part in the body’s immune system. They assist in recognizing invading bacteria and parasites, and are necessary for lymphocytes to produce antibodies.  Histiocytes are normally found in skin, connective tissue, liver, lung, gut, lymphatic glands, spleen, bones and parts of the brain. Any of these sites can be affected by the disease.

    With the exception of the Bernese Mountain Dog and the Flat-Coated Retriever, MH is uncommon in most other breeds, occurring only rarely. There are subtle differences between the types of MH in these two breeds, however it is a common cancer that takes a toll on both breeds. For this reason, it is believed to be inherited, probably with a polygenic mode of inheritance. 

    MH is believed to be rare in the Leonberger but one in every 5 Berners will die from the cancer. Because of the high incidence in the Bernese Mountain dog, their club has become active in researching this cancer.

    Pat Long of the Bernese Mountain Dog Club of America (BMDCA) writes: “Malignant histiocytosis (MH) is a very aggressive form of cancer that is usually already widespread before any symptoms are noted. Symptoms usually include loss of appetite (anorexia), weight loss, lethargy, weakness, and poor general condition. There could be difficulty breathing, coughing, shortness of breath, or abnormal lung sounds. Radiographs may show single or multiple tumors in the lungs, or enlargement of the spleen or liver (splenomegaly or hepatosplenomegaly). The lymph nodes may be enlarged. Blood chemistry may be normal; it may show anemia; it may show a decrease in the number of platelets (thrombocytopenia); or it may show high liver enzyme activity. This cancer affects the spleen, lymph nodes, lungs, and/or bone marrow, but can also affect the liver, central nervous system, kidneys, skeletal muscle, stomach, and adrenal glands.”

    “But malignant histiocytosis is a disease that attacks many organs simultaneously, or that metastasizes rapidly, so the dog eventually succumbs from the involvement of the other organs.”

    “MH is generally so far spread throughout the organs at the time of diagnosis as to preclude surgical excision as a viable treatment option. To date, no treatment has been found to be effective long-term. Survival from time of diagnosis may vary from hours, days, perhaps weeks, and very rarely months. The mean age at onset is 7 years. “

    We lost Magnum December 18, 2002—he was 8 years old.  About 3 years ago Magnum developed some hot spots and his blood tests indicated hypothyroid disease, another surprise in the Leo.  Damage to the thyroid gland can occur because of constant exposure to biocides, chemicals that block re-uptake of iodine.  Though we have never used any chemicals on our Leos, I know the area parks are polluted making exposure to these biocides unavoidable. Magnum was put on Soloxin.  In August, Magnum began suffering heat intolerance to such an extreme that we stopped taking him out during the daytime.  He was walked in the morning and in the evening.  (We learned how to compensate to keep him comfortable.)  At the same time, he began secreting clear fluid from his nose.  There were days when the amount of fluid under his face was alarming but his veterinarian felt it was “allergies,” and he was given benedryl which I used infrequently. 

    Because Soloxin can cause a slight intolerance to heat, I thought perhaps his thyroid levels were too high and we did a complete thyroid panel and blood chemistry.  His T4 was exactly where it should be.  One of his vets thought perhaps he had laryngeal paralysis and that his clear secretions were simply condensation from his breathing problem. We were not convinced because when he slept, he appeared to have little discomfort.  Another of his veterinarians said he lacked the labored breathing sounds typical of LP.

    In October 2002, during a routine examination, his veterinarian discovered that one testicle appeared to have atrophied.  Because Magnum had perfect Leo temperament and was a “Category I, Very Good,” we wanted to breed him to our female.  We could not delay neutering him—an atrophied testicle could signal a malignancy or an injury.  We believed it was an injury because 8-months earlier, Magnum had fallen on a slippery floor and sustained a groin injury.  Still, an injury could trigger a malignancy.  We decided to collect his sperm to bank and went ahead with our plan after an ultrasound showed the testicle was simply atrophied.  

    During the next month, Jazzie came into heat which always caused Magnum to stop eating.  (Usually, he lost about ten pounds during this time of forced celibacy.)  Magnum’s collections at the reproductive specialist were successful and his appetite picked up enough for him to gain back 4 pounds. 

    Another blood panel was done before surgery as part of his pre-surgical work-up.  This time it showed an elevated ALT.  ALT is an enzyme involved in the metabolism of the amino acid alanine. ALT is found in a number of tissues but it is in highest concentrations in the liver. Injury to the liver results in release of the enzyme into the blood.  An elevated value is not clinically significant when all other liver enzymes appear normal, we were assured.

    Shortly after his surgery, he stopped eating and began to lose weight.  We began taking him in for vitamin shots and began testing him for every tick disease, blood borne parasite--anything and everything we could imagine, including the Coombs test for autoimmunity.  His daily walks were very short, and he appeared exhausted after a short walk, another alarming symptom; Magnum loved going for walks more than anything on earth. 

    His blood tests indicated a low-grade anemia. Thinking perhaps his thyroid levels were dropping his medication (Soloxin) was increased, and we began to give him herbal iron supplements.  Within a week his chest began to fill with fluid.  My perfect friend was dying, it was obvious to my husband and me, but we did not know what to do.  After phone calls to a dear friend, Dr. Jean Dodds, she arranged for Magnum to see an internist that evening. An ultrasound showed a diffused mass in his chest next to his heart.  We brought him home and nursed him until his appointment with an oncologist a few days later. He was on lasix to keep fluid build-up down, but we had him to the pet emergency hospital the next night for an emergency aspiration. That was one more nightmare to haunt us—that Magnum had to suffer through these awful aspirations to allow his lungs to fill with oxygen by removing the fluid that was crushing him.

    The oncologist explained that only surgery could tell us what was in his chest and so we decided to do the surgery. I always believed we could remove the tumor and have Magnum back home—even for a month it would have been worth everything. They asked to keep him that night to put him on a morphine drip, and drain fluid to make him comfortable.  We agreed, and I will regret that for the rest of my life because his last hours were spent without us.  On the operating table, they opened his chest and saw he had cancer throughout his chest, into his spleen, liver and stomach.  They phoned us to say it was hopeless and we allowed him to go--again I regret bitterly that I was not there to see his soul enter the light. I pray constantly that he passed over knowing how much we loved him.  I had the presence of mind to ask that they take some tumor for a biopsy--I had to know what the cancer was because Magnum was raised homeopathically.  We used minimal vaccines, organic food, supplements to support immune function and detoxify against pollution; we never sprayed chemicals, we never applied chemicals to his body, and yet my Leonberger was dead at the age of 8, his body filled with malignancy. The cancer took on a life of its own and I had to have a name for it. It was an enemy.

    When the biopsy came back, “malignant histiocytosis,” I began to research this cancer and posted the information to the LeoList.  I learned that Magnum’s littermate, Gage, another boy with the same wonderful temperament and a laundry-list of obedience titles, died of the same cancer.  Thanks to his owner, Beth O’Conner, Gage’s tumor was also biopsied and confirmed as MH.  Two confirmed cases of MH in the same litter pointed to more than coincidence.  Magnum’s breeder had also lost another littermate to cancer 3 months earlier—squamous cell carcinoma—and she encouraged me to go forward with this article in hopes of saving lives in the future. Another littermate, a female, had been found dead 6 months earlier when her owner returned from work.  Her death was attributed to “unknown causes.”  She could have died from MH; as the oncologist explained, dogs can be found dead by owners and no one would know they died from MH a cancer that can rupture the spleen causing death by blood loss.  If her remains had been autopsied, we would have another piece to the puzzle.  Many other Leos may have died from this cancer but without a confirmation from a biopsy, their deaths remain a mystery.

    The wonderful honesty apparent in Leonberger owners and breeders led to the discovery that another case of confirmed MH had occurred in a 7 year old male a few years ago.  That male was a cousin to Magnum and Gage.  More recently, I learned that a 5 year old female related to Magnum (a niece) died from MH, also confirmed through a biopsy.  Two Leonbergers in the Mid-West died from confirmed MH years ago but we have not located their owners, which means we cannot confirm their familial link to Magnum’s line.

    Research and MH

    For years, the Bernese Mountain Dog Club and the Flat-Coated Retriever Club have been funding research into the genetics of MH in their breeds.  In the FCR, research is focused on the p53 tumor-suppressor gene; a tumor registry has been set-up at The Ohio State University. 

    The BMDCA has a study ongoing at UC Davis to “evaluate MH tumor specimens for mutations in genes that may contribute to the development of this devastating cancer.  The genes of interest are those that code for proteins known as growth factor receptors.”  The BMDCA study underway at the Fred Hutchinson Cancer Research Center in Washington is a broader study with more ambitious goals. 

    The Dog Genome Project is a collaborative study involving many scientists and universities  including Fred Hutchinson Cancer Research Center in Washington. When completed, the canine genome will show a map of all the chromosomes in dogs which can be used to locate the genes causing disease and those controlling morphology and behavior.

    Colleen Hacker of the BMDCA explains the importance of the research by Dr. Heidi Parker, working in Dr. Elaine Ostrander’s laboratory at the Fred Hutchinson Cancer Research Center.  Dr. Parker’s goal is to find DNA markers associated with this disease in the Berner and the actual gene mutations that cause MH. “Heidi and colleagues in the Ostrander lab are taking the genome-wide scanning approach to identify the DNA variants that cause MH. This approach makes no assumptions up front about what genes contribute to the disease. The whole genome scan will be conducted using a subset of markers from the 3,400 marker map that are evenly distributed across the dog genome. DNA isolated from blood samples of dogs affected with MH and unaffected normal controls will be tested for these markers to determine which marker alleles or combination of alleles is associated with MH. Once an association is found, the team will perform a deeper screen of the surrounding region using a more dense set of markers in order to more precisely define the region of the dog genome that is associated with MH. Once the region is defined, they will look for nearby genes either from the 10,000 genes currently being mapped or from comparisons with human DNA sequence,” said Colleen.

    A list of genes in the associated region will be compiled, “and the genes ranked in order of which ones are most likely to cause MH based on what is known about each gene function. (For instance, an oncogene, such as p53, would be ranked high on the list). Starting with the most likely gene candidate, they will then begin searching each affected and control dog for mutations in the gene. Meanwhile, the genome scan will continue, searching for other associated markers and mutations that contribute to developing the disease.”

    The Leonberger and MH

    To give meaning to such a hollow death, I often think that Magnum died so other Leonbergers could live. I carefully packaged up a swab of his DNA taken when the sperm collection started last October.  I had frozen sperm if necessary, though it would never be used for breeding, only as a source of more DNA to fight this disease. 

    Through Pat Long of BMDCA, I had arranged for the Leonberger to participate with the Berner in Dr. Parker’s study.  An appeal for unrelated blood samples to be sent to Dr. Parker was met with an overwhelming response from Leo folks and I am relieved to report that the Leonberger is minimally included in this study, though we have not contributed funds, only DNA. Dr. Parker believes she will be able to determine if the genetic sequencing is the same in the Leonberger as it is in the Berners.  With that knowledge, we will have to decide on the next step—hopefully, funding research to find a genetic test to screen for carriers.  Imagine a world with healthy Leonbergers who live long, satisfying lives!

    Different dog breeds suffer from different types of cancers.  For example, some giant breeds, including the Bernese Mountain dog, Irish Wolfhound, Great Dane and the Leonberger suffer a high incidence of osteosarcoma. German shepherds appear to be predisposed to hemangiosarcoma; Bull mastiffs to lymphosarcoma, Golden Retrievers are prone to fibrosarcoma, familial lymphoma occurs in Saint Bernards, and Boxers are predisposed to mast cell tumors.  Veterinary geneticists and researchers believe these breed susceptibilities are important and are related to the high incidence of autosomal recessive diseases in dogs arising from selective breeding for desired traits.

    The complexity of canine cancer is tremendous.  For example, a growing body of evidence links exposure to common lawn pesticides with non-Hodgkins lymphoma, childhood cancers, multiple myeloma, leukemias, breast, prostate, ovarian, pancreatic cancers, and birth defects.  A case-control study of canine malignant lymphoma reports a positive association with an owner’s use of the popular crabgrass killer 2,4-D and their dog’s chances of getting cancer.

    There are four forms of lymphoma that may develop in the dog and the primary symptoms are fatigue, weight loss, anorexia, fluid build-up, and difficulty breathing. With subtle differences, these are the same symptoms as malignant histiocytosis, hemangiosarcoma, leukemia, and many other canine cancers. Knowing who the enemy is allows you to prepare a battle plan.  We cannot avoid breeding dogs with possible genetic cancers unless you know the causes of death of the dogs in that breed.  How many Leonbergers have died of cancer?  The LCA Health Committee tells us it is the number one killer of all Leonbergers, a statistic that applies to all breeds of dog. 

    The only way to compile statistics on the incidence of a particular canine cancer is by biopsies when tissue is available, and by a necropsy or postmortem on a dog that dies of unknown causes. Yes, it does cost money but we spent $6,000 trying to learn why Magnum was dying and we have nothing to show for that expense except the cause of his death, which gives us all an opportunity to work toward prevention. 

    Many people have an aversion to doing these invasive tests and I can understand because I loved Magnum with all of my heart. Learning from the death of a beloved dog is more important than our aversions.  Colleen Hacker writes:  “When Pat Long’s dog, Maggie, got sick, Pat “knew” that Maggie had MH based on diminished appetite, swollen liver, and abdominal fluid. The vet who examined Maggie suspected that cause as well. Pat insisted on necropsy, and they were both shocked to learn that the diagnosis was hepatocellular carcinoma, a liver cancer that affects many older dogs. Had Pat not insisted on confirmation, writes Colleen, the use of a sample from Maggie could have complicated the painstaking research into the cause of MH.”

    How many Leonbergers died from true lymphoma and how many have died from malignant histiocytosis, the least treatable most fatal canine cancer?  How many Leonbergers were confirmed by biopsy with hemangiosarcoma?  We really need to know.  We need to know how often a cancer occurs so that research efforts and eventually, funding can be put to use in the right order—starting with the most prevalent cancer.  The LCA Health, Education and Research Committee does not see malignant histiocytosis as a significant cancer in Leonbergers, therefore, they have not pursued the research started at Fred Hutchinson Cancer Center and will not go forward with any research into this cancer.  For that reason, your help is vital--if we are to count the cases of malignant histiocytosis in the Leonberger, we will have to do that as individuals joined together.  PLEASE, do a necropsy and have your vet send tissue samples in for pathology.  We know too many Leonbergers die from cancer, but we need to know if this always fatal cancer can be avoided by breeding away from carriers, was it a fluke in one line of Leos, is it rare, is it common????

    I had to ask myself—would Magnum have wanted me to treat his disease ravaged body as sacrosanct?  Would he have wanted me to ignore my responsibility to determine the cause of his death, why his life was cut off in its prime?  If he could have understood those concepts, he would have wanted me to use that empty vessel to better understand what destroyed him. 

    After Magnum’s cremated remains came home, my husband and I heard the distinct sound of his big feet pushing off the wall by the front door to roll over.  We heard the sound on three occasions and now we hear only silence.

    PLEASE fill out the Cause of Death Registry form to participate in understanding and some day preventing diseases that kill our Leonbergers.  Click here:


    (c) 2003 Barbara Bouyet

     

    Last updated 08/01/2017 .
    © 2004  All Rights Reserved.

     

    LINKS

    What it is
    DVM Magazine
    Cornell
    Polygenic Mode of Inheritance

    Learn as much as you can
    The Bernese Mountain Dog
    Fred Hutchinson Cancer
    Research Center

    More Questions and Answers
    Research Involves Berners--
        not Leos
    And Other Breeds
    What is a Necropsy?
    It Can Yield Important
        Information
    What is a Biopsy

                     

     

    IF YOU SUSPECT MH

    If you suspect your Leo died
    from MH, please send the
    information to us.  We need as
    much information as possible
    to motivate the Health Committee
    to investigate research projects 
    for MH in the Leonberger.  We
    believe it is a bigger problem than
    previously recognized; the LCA
    Health Committee does not agree.

         


                     
     

    BERGIE


     

    "Bergdorf Gutman vom Haus Gutfreund

    Sire: Hause v. Lowen’s Gabriel
    Dam: Agatha Christi vom
    der Haus Gutfreund
    DOB: November 8, 1997
    Owner: Tom and Karin Gutman
    DOD:  June 12, 2003
    Cause of death: 
    Hystiocytosis
    Adult weight: 134 lbs

    Bergie was a lover.  Gave
    and wanted love as a
    main staple. She always
    pushed her nose under
    your arm for a pet on the
    head that ultimately led
    to a super hug.  She was
    very strong and enduring. 
    A smile that produced smiles
    on others.  She had blond
    fur that contrasted well
    with her black face.  She
    ate well but with a feminine touch.  Her tail was a plume
    of fur and when walking she
    waved it like a “look-at-me”
    flag.  Her best friend was
    her half brother Moose. 
    They never were apart.  

    As a Therapy Dog, Bergie’s
    visits to the children’s hospital included a crawl up on the patient’s bed to give and get
    a big hug.  She put many
    smiles on the faces of young
    and old.  Bergie was so tall
    and long, she would put her
    front paws on my shoulders
    and meet me face to face. 
    I’m 6’ 2”.  We had a nickname
    for Bergie, “boogie.”  I don’t
    know why, but we did.