This neoplasm certainly appears to be on the rise. Practitioners and pathologists alike report an increased incidence of lymphosarcoma over the last few years - up to one to two cases weekly in some practices. While the increased incidence of lymphosarcoma and occasional clustering of cases has led to speculation of a viral cause, to date, a causative agent has not been isolated.
The "classic" form of lymphosarcoma, which causes marked enlargement of the peripheral nodes, is seen in older animals and has the more prolonged course of the two syndromes. In this disease, an infiltrate of small mature lymphocytes expands the peripheral and mesenteric nodes, eventually effacing nodal architecture. Late in the course of disease, neoplastic lymphocytes infiltrate visceral organs (including the liver, kidney, lungs, and spleen) resulting in organ failure and death. This disease is usually insidious, resulting in little clinical debility until extensive infiltration of visceral organs has occurred.
The lymphoblastic form [also called juvenile lymphosarcoma ], which affects ferrets from one to two years, is quite different. In this disease, large immature lymphocytes quickly infiltrate the viscera, including the thymus, spleen, liver, and many other organs. Little to no lymph node replacement is seen in these cases, a finding which results in a high rate of misdiagnosis by clinicians without extensive ferret experience. This form can take a myriad of clinical appearances depending on which organs are involved. One of the more common presentations results in dyspnea and is often diagnosed as cardiomyopathy or pneumonia. The lesion in this syndrome is actually a rapidly growing thymic mass which compresses the lungs. Less commonly, extensive hepatic infiltration by neoplastic lymphocytes may result in marked hepatic enzyme increases and icterus suggesting fulminant liver disease, and so on. Lymphoblastic lymphosarcoma should always be ruled out when dealing with any serious illness in young ferrets.
Finally, leukemic forms, in which neoplastic lymphocytes circulate within the peripheral blood, may be seen in the latter stages of either form, but are generally uncommon.
Over the last few years, a disturbing trend in diagnosis of this disease has been emerging - the interpretation of elevated lymphocyte counts as evidence of lymphosarcoma in the ferret. While many cases of lymphosarcoma may exhibit a lymphocytosis on the CBC, similar changes in the differential may be seen in any number of chronic smoldering infections, most notably gastric Helicobacter mustelae infection. The prudent practitioner requires a diagnosis by aspirate or surgical biopsy before any treatment is started.
References:
Signs vary, and as already stated, many animals have no outward signs for a long period. Disease in these animals may be detected by abnormalities in the complete blood cell count. Noticeable changes in other animals may include any of the following signs: swollen lymph nodes, enlarged spleen (there are many causes of enlarged spleens), wasting, lethargy, poor appetite, difficulty breathing, chronic diarrhea or hind leg weakness.
The diagnosis is from a combination of a complete blood cell count and either a biopsy of a lymph node or a bone marrow biopsy. [Which is done, and what kind of biopsy, is personal preference. A larger sample is harder to get, but also much more diagnostic -- according to Dr. Williams, diagnosing lymphosarcoma from a needle aspirate is very difficult.] X-rays may be helpful in cases where the cancer is in the chest. Treatment is achieved through chemotherapy, the details of which can be discussed with your veterinarian [see below]. We have had a 75% success rate with chemotherapy with life being prolonged for 6 months to 3 years post treatment. Most ferrets tolerate the therapy very well and have few side effects. Even those cases that are not good chemotherapy candidates, can be helped to continue a quality life with the use of steroids.
(Dr. Susan Erdman was kind enough to visit the June meeting of the GCFA [Greater Chicago Ferret Association] and she gave an excellent slide presentation on the work she and Dr. James Fox are doing on ferret lymphomas at M.I.T.)
Lymphoma is a very common cancer in ferrets, comprising about 20% of all reported neoplasms. It is probably the most common tumor in young ferrets. Lymphomas frequently occur in combination with pancreatic and adrenal tumors in older ferrets, and it is probably more common than we realize. Occasionally related or cohabitating ferrets will develop lymphoma, which is also observed in lymphomas in cats with Feline Leukemia Virus. Not surprisingly, viruses have also been suspected of causing lymphoma in ferrets [see below]. Although no causal virus has been identified, it is probably best to avoid introducing new ferrets into cohabitating groups of ferrets which have many lymphomas.
Manifestations of malignant lymphoma vary with the age of the ferret. Young ferrets usually become suddenly ill. Some owners report a ferret that seemed normal one day and was discovered very weak the next day. Ferrets may have difficulty breathing because of a large chest tumor. Some develop a very large spleen that fills the abdomen. Others get very large lymph nodes around the throat, armpits and knees.
Tissue aspirates and biopsies are needed to confirm lymphoma because sometimes a node that appears to be enlarged is actually a fat pad in a ferret with a healthy appetite. Ferrets with internal involvement may have diarrhea or difficulty urinating or defecating. Radiographs usually reveal the characteristic soft tissue swellings of in the chest and abdomen.
Although a few young ferrets respond well to chemotherapy, the prognosis for long term survival and well-being is poor, especially in ferrets which are less that one year of age upon diagnosis. Getting an early diagnosis may increase life expectancy slightly with much supportive care and chemotherapy. A young ferret should be playful and have a good appetite, so if your ferret has a change of appetite or attitude, contact your veterinarian for a thorough exam. Older ferrets have more variable disease. Some develop sudden disease like that of younger ferrets. Others have a prolonged illness that begins with periods of weakness, poor appetite and weight loss that may go on for several years.
The earliest changes appear to occur in the spleen and blood, and may be detectable by your veterinarian using palpation of an enlarged spleen or interpretation of changes in the blood counts. A sample of the affected tissue is necessary to confirm the disease. You veterinarian and pathologist can evaluate the tissue cell distribution and cell division that help predict whether the tumor will be rapidly progressive.
Many of these older ferrets do very well for many years following the diagnosis of lymphoma with minimal chemotherapy. Some drugs such as steroids, which are used therapeutically for beta cell tumors of the pancreas may provide some chemotherapeutic benefit for lymphoma as well. Older ferrets should be examined regularly by a veterinarian, and any ferret demonstrating recurrent poor appetite or lethargy should be examined more frequently. Early diagnosis of disease gives a much better prognosis and allows you to make informed decisions about the health management decisions of all of your ferrets.
One final point: an enlarged spleen is common with lymphoma in ferrets, but has been associated with many other conditions in ferrets as well. Even certain anesthetics can cause a big spleen. Because ferret spleens can fluctuate in size over days or weeks, an enlarged spleen should only be removed if it poses an immediate threat to health such as splenic rupture, or confirmed splenic lymphoma or other cancer.
1. This is another commonly seen neoplasia in ferrets. It occurs at all ages. Research is currently being done on this disease to try to isolate a viral agent [see below].
2. Signs of disease are variable depending on the system affected.
a. Splenomegaly
b. Peripheral and localized lymphadenopathy
c. Wasting and lethargy, despite normal eating habits
d. Mediastinal and/or sternal lymph node enlargement with associated
dyspnea, tacchypnea and exercise intolerance
e. Pyrexia and collapse
f. Masses or lumps on the skin
g. Persistent absolute lymphocytosis (over 3500)
h. Persistent leukocytosis (10,000 or higher) with 45% or higher
lymphocyte count
3. Diagnosis by a variety of methods
a. CBC may be helpful - may see leukocytosis with abnormal circulating
lymphocytes, persistent absolute lymphocytosis, anemia, leukopenia,
and/or thrombocytopenia. However, many CBC's appear normal.
b. Lymph node removal (biopsy is difficult due to the large amount of
fat around lymph nodes); popliteal nodes are the easiest to remove.
c. Thoracic fluid aspirate and cytology
d. Bone marrow aspirate (femur is the easiest)
e. Biopsy of mass
f. Splenic aspirate, which can be accomplished with a 25 ga needle and
a 3 cc syringe through the body wall (We find this to be only of
occasional value)
4. Treatment
a. Prognosis is guarded. Young animals are poor treatment cases. Older
animals with more subtle disease are better candidates.
b. Do a complete pretreatment workup, CBC, chemistries, and
radiographs.
c. Start chemotherapy with prednisolone at 2 mg/kg p.o. on the same
day as the vincristine is started i.v. The pred is continued daily
throughout vincristine therapy. The vincristine dose of 0.05 mg (0.05
cc) for ferrets up to 1 kg and 0.10 mg (0.10 cc) for ferrets over 1
kg. Use a butterfly catheter and a saline flush before and after
administration of vincristine. A light sedation with ketamine or
isoflurane is recommended.
d. Vincristine therapy is continued weekly for 4 weeks total. CBC's
should be checked weekly and if the WBC drops below 2,000 or if severe
thrombocytopenia or anemia occurs, then vincristine is discontinued
for one or more weeks until the blood picture improves.
e. Cytoxin* is given once every three weeks p.o. for 3 doses at 1/4 of
a 25 mg tablet per ferret. DO NOT GIVE CYTOTOXIN ON THE SAME DAY
AS VINCRISTINE - HAVE A THREE DAY INTERVAL.
f. After vincristine therapy is completed continue pred for 4 to 5
more weeks, gradually weaning down the dosage and doing exams and
CBC's weekly.
g. Complications of chemotherapy have been similar to those seen in
other animals including depression, weakness, anorexia, whisker loss,
generalized hair loss, bone morrow suppression. GI signs are uncommon.
h. We have about a 70% success rate with over 2 years remission in
some cases.
In cases of persistent lymphocytosis, that were unable to be confirmed as lymphoma by diagnostics, but that histopathology calls lymphoid hyperplasia, we recommend treating these with Alkeran* (melphalan) There is great suspicion that these may be preneoplastic lymphoma cases.
The following protocol was suggested by Dr.Thomas Kawasaki of Woodbridge, Va.
a. Use in cases of persistent absolute lymphocytosis (3500 or
higher)
b. Perform CBC's weekly throughout therapy
c. Have pharmacist make up Alkeran in small capsules in 0.10 mg
and 0.05 mg amounts.
d. Start therapy with one 0.10 mg Alkeran capsule per ferret SID
for two weeks.
e. Then go to one 0.05 mg Alkeran capsule per ferret SID for two weeks.
f. Finally wean off using 0.05 mg Alkeran capsule per ferret every 2
days for 2 doses, then every 3 days for 2 doses, then every 4 days for
2 doses.
g. Discontinue therapy if CBC shows changes as described under
chemotherapy section (above).
Thought the list folks would be interested in the treatment protocol, which follows below. Bandit is being treated by Dr. K. Ann Jeglum of West Chester, PA. Her phone is 215-696-1585. She told Jeff that she has treated a number of ferrets with this protocol and apparently most have gone into remission. She says we should see no side effects from this first treatment, and so far we have not.
I talked with Dr. Karen Rosenthal at the Animal Medical Center, who oversaw Bandit's surgical treatment there, and she says this is the same treatment they use for ferret lympho at AMC, although she says they do blood testing (CBC) every 1-2 weeks. She says their best case went 8 months on this treatment.
The language is mostly Greek to me, but you can pass it on to your vets. I know our vet student-in-residence, Jenny Au, will be interested (If she hasn't already seen this). Anyway, here it is (I know it says Feline but this is what they are using):
This protocol has been shown to be effective in the multicentric, alimentary and renal forms of feline lymphoma (Jeglum, JAVMA, 1987). Several modifications have been made since publication to improve efficacy and ease of administration. The LA-COP protocol should be used in the mediastinal form.
WEEK 1 L-aspariginase 400 iu/kg IM, SC or IP
WEEK 2 Vincristine 0.03 mg/kg IV (Do not extravascate)
WEEK 3 Cytoxan 12.5 mg (1/2 of 25 mg tablet) once daily for 4 days
WEEK 4 Vincristine 0.03 mg/kg IV
WEEK 5 Methotrexate 2.5 mg tablet one dose
Blood counts do not need to be evaluated unless the cat is showing
clinical signs of toxicity such as anorexia, lethargy, vomiting and/or
diarrhea. It is recommended to continue weekly cycles for the first 6
months after which treatment intervals may be extended if in
remission.
END OF PROTOCOL
Dr. Rosenthal says AMC does CBC's every 1-2 weeks to monitor whether the progress of the cancer, but would defer to Dr. Jeglum in this case since she is treating Bandit.
Addendum from Katie as of July 1994:
Bandit started that protocol in March 1992, went into remission in July 1993, and in July 1994 is still disease-free!!Update from Valerie Williams <104603.3221@compuserve.com>, July 1996:
Important changes to the protocol: because of toxicity problems Dr. Jeglum is no longer using methotrexate. Also, Cytoxan MUST be given at least 2 weeks after vincristine. Cytoxan dosage is still undergoing revision because of ferrets getting ill from treatment (106 degree fevers, cystitis, pneumonia, abdominal pain). Please feel free to contact me or use me as a reference.
Susan E. Erdman, Phyllis J. Kanki, Frances M. Moore, Susan A. Brown, Thomas A. Kawasaki, Keith W. Mikule, Karin U. Travers, Steven F. Badylak, and James G. Fox. "Clusters of lymphoma in ferrets." 1996 _Cancer Investigation_ Volume 14, Number 3, pages 225-230.
Jeff Johnston, an epidemiologist, gave this report in October 1996:
Bob Church writes:I don't want to panic anyone. So as not to be alarmist, there does not appear to be a raging epidemic of adult lymphosarcoma. It's more common than it should be, but it is by no means the #1 cause of ferret deaths. Also, ferret owners have had ferrets with lympho housed with other ferrets who never got the disease. So, it can't be very contagious, whatever it is.
So, there's the latest. The studies will continue, but in the meantime, none of this really gives ferret owners a way yet to keep ferrets from getting lympho. But, perhaps knowing that this is a transmissible disease, ferret owners can rely on their experience to come up with some theories. If you've had the unfortunate experience to have suffered through more than one ferret with lymphosarcoma, maybe you can provide the clue that leads to a way to prevent other ferrets from getting this cancer. Think back about what was different between the ferrets that got sick and those that didn't get sick.
As for treatment, perhaps knowing that this may be a retrovirus- associated cancer may point to a therapy, but I wouldn't be too encouraging. Retroviruses are very difficult to treat because the virus inserts itself into the host's own chromosomes. Unlike viruses or bacteria that are on the outside of the host cells, it's very difficult to fight an invader that hides out in the host's own genome. If this is a retrovirus, prevention, rather than treatment will be where the emphasis should go.
This paper goes into depth on various factors, and indeed, investigated a number of possible reasons for the clustering. The end conclusion of the study was that the clustering of lymphomas in ferrets follows the same pattern as seen in diseases caused by a virus. This has medical precedent, in cats and mink for example. To say it again, these highly esteemed scientists seriously think a virus may be behind the clustering of lymphoma, and while they haven't found the virus yet (think how hard it has been to isolate the HIV virus, much less the ECE virus), they are sure the outbreaks are not associated with specific breeders or familial lines. (Pandas may be the exception, and the authors note correlations between coat and illness in other animals.)
JL [juvenile lymphoma] is one of three types of lymphosarcoma which affect ferrets. Other people may classify them differently, but I don't believe in splitting them down any further, as these artificial classifications add nothing to the treatment or outcome of this disease. Of the three classifications that I discern, juvenile lymphosarcoma is one.
JL affects ferrets less than 14 months of age. I generally refer to this as the "lymphoblastic" type based on the appearance of the very immature lymphocytes which characterize this neoplasm. (Lymphocytes are a type of white blood cell which are the backbone f th immune response in humans and animals.) It differs from most cases of lymphosarcoma, which we see in animals over 4.5 years of age, not only in the maturity of the cells, but in many other features. In JL, the lymph nodes rarely get enlarged; the neoplastic cells accumulate in the organs of the body. In LL (lymphocytic leukemia), the neoplasm generally starts in the lymph nodes, causing enlarged lymph nodes all over the body.
JL often causes neoplasms in many organs of the body at once. The most common sites are the thymus, spleen and liver. The accumulation of massive numbers of neoplastic lymphocytes cause equally massive enlargement of these organs from 2-10X their normal size.
However, as the thymus resides in the thoracic cavity, while the spleen and liver reside in the abdomen, most animals with JL die as a result of thymic enlargement. As the thymus enlarges with the addition of the neoplastic lymphocytes, it compresses the lungs, resulting in fluid accumulation in the chest, difficulty breathing, and eventual death. I can certainly understand why many of these cases are misdiagnosed as cardiomyopathy - the signs of both are quite similar and both result in a profound accumulation of fluid in the chest. If the chest is full of fluid, then all of the normal structures of the thorax - the thymus, lungs, and heart, will all be hidden by the fluid on chest X-rays.
My advice to vets and ferret breeders - don't automatically assume that the difficulty that your less-than-2-year-old ferret is showing is due to heart trouble. ALWAYS keep lymphosarcoma in your differential diagnosis for any severe disease of young ferrets.
BTW - JL is not the province of ferrets alone. We see forms of JL in a number of species, with cattle being the most renowned for deaths due to lymphosarcoma in animals less than a year of age.
Bruce Williams, DVM, DACVP
Dr. Williams is available to help with diagnoses and answer questions.
Sukie Crandall comments:
Juvenile lympho, which differs from adult lympho, shows up suddenly with extreme symptoms and rages through a kit very, very rapidly, and we still have not heard of a case of it being successfully treated even though there are some (proven by biopsy) survivors of adult lympho due to long-term chemo treatment (such as the Jeglum Protocol). Juvenile lymphoma is a heart breaker; you have to see your loved one suffer but it progresses so fast that you can't have time to adjust to what is happening. Our Helix had it about 9 years ago.
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