Roxanne has Cancer[?*]

[So many people have expressed interest, concern and support since I first told them about Roxanne's diagnosis that the most efficient and effective way for me to keep them informed about her is by updating this web page. This is somewhat impersonal, but my energies are now very limited. I'm very grateful for all the support offered.]

By mid-July, nine month old Roxanne had one bump on either side of her face, over the maxillae; the one on her left was larger. I'd thought that the bumps were normal anatomical features because their precursors were present during January, Roxanne's first month with me, as apparently symmetrically placed, slightly elevated areas on either side of her face, and they grew very slowly as the rest of her grew very rapidly. Her health seemed otherwise excellent, she seemed to thrive on Innova and she took no apparent notice at all of these areas. (When bull stix appeared to alter her eliminative rhythms, I stopped giving them to her.) During the past month or so, these bumps have appeared to vary in size, but I'm not sure that this perception is accurate.

At our first Autumn Winds training session with Jan Santel in January, Jan directed me to massage every inch of Roxanne's body daily to encourage bonding, to get her used to being handled, and so that "if there's any bump or lump on your dog, you'll be the first to know." Since I always do what Jan tells me to do (when she's right), I followed these directions faithfully. Except for what's mentioned in the previous paragraph, I never found any other bumps, lumps or other anomalies.


In late July, Roxanne began sneezing several times daily and then developed some clear discharge from her eyes, with more from her right eye. I took her to the vet on 7/25, and she was found to have conjunctivitis in both eyes, with more irritation on the right. The vet, Dr. Long, then of Timberlyne Animal Clinic, conjectured that a seasonal allergy was probably the cause of the sneezing and eye irritation - a number of allergic dogs had been seen lately by the practice with similar symptoms - and prescribed Neomycin/Poly/Dex/Ophth Sup eye drops, which Roxanne received twice daily for nine days. (The directions were for seven days of drops, but there were probably more misses than hits during the first two days as Roxanne and I negotiated an acceptable method of administering them.) The discharge from her eyes diminished and then stopped. The discharge soon resumed but there was less of it. She occasionally pawed at her face (eyes?), but this was very infrequent. Since her sneezing had continued, she was put on hydroxyzine hydrochloride (50mg three times daily) on 7/30. She continued sneezing harder and more frequently, indoors and outdoors, at home and away. Twice on 8/15, barking while pulling on lead was immediately followed by what sounded like a small, hoarse cough.

During the 7/25 veterinary exam, I also asked about the bumps on the side of her face and a small, raised, slightly depigmented area that had just developed on the left of her nasal planum. The vet gave the usual, statistically-based reassurances about the two bumps, though she was not sure what to make of the raised area on Roxanne's nose. She recommended watching all three areas and bringing Roxanne back within two weeks for fine needle biopsies if there'd been no shrinking.

By 8/15, Roxanne had what seemed to be at least seven itchy insect bites in various areas of her body (tail, groin, back, shoulders, legs, face), with raised, sometimes bloody, appearances. (She'd received FRONTLINE TOP SPOT PLUS last on 8/6.)

On 8/17, there appeared what seemed to be many additional insect bites concentrated on her the mid-line of her upper and lower back, with raised, sometimes bloody, scaly appearances, and visible thinning of hair on her lower back. I couldn't tell where she was coming into contact with insects, and had already treated the yard with permethrin, but I re-treated it twice, washed all of her and Snickers's bedding in hot water, sprayed pyrethrin in strategic areas in the house, and vacuumed and vacuumed and vacuumed, changing the vacuum bag. I also misted Roxanne lightly with pyrethrin spray before walks off-property.

On 8/18, I gave Roxanne a MALASEB anti-fungal, anti-bacterial shampoo, letting her stand in it for 10 minutes and rinsing thoroughly, as directed, followed by application of RESICORT 1% hydrocortisone leave-in conditioner to her back and a small amount of Neosporin antibiotic ointment to the reddest spots. I continued giving her the hydroxizine in the hope it would help with these apparent bites. She had been sneezing far less. Several times, I put artificial tears (1% polyvinyl alcohol) in her eyes in the hope that she would find that soothing. By the time I gave Roxanne another such bath on 8/25, there'd already been considerable healing and hair re-growth, though some scaling remained. She continues to scratch at her neck below the ears.


On 8/11, I e-mailed the breeder two photos, one of Roxanne, that I'd marked to indicate the location of the larger facial bump. The photo of Roxanne was this one:

<-----The red arc marks the larger bump; the other bump is obscured here.

The reply:

I would have to see the bumps close up to determine a course of action. Bumps in this area are not normal, but unless they are becoming larger I would just continue to observe their progress. They may be small fatty or cholesterol deposits!

By 8/14, all three bumps appeared to be larger than in late July and the nasal bump was larger and pinker. These photos are from September 2 and 3:

On 8/16, the vet attempted to do fine needle biopsies of all three areas, but the fast-acting, quickly reversible sedative Roxanne was given did not sedate her; despite being muzzled, Roxanne nipped the vet. So I scheduled Roxanne for tissue biopsies under general anesthesia on August 20, when aspirate was also taken from the nose. The samples were sent to Antech Diagnostics [?] for pathology. These procedures and pathology cost $617.

While I waited for the pathology report, I downloaded about fifty arbitrarily selected adult Beauceron head photos from the web and examined them at various levels of magnification in ADOBE PHOTOSHOP. At least ten of those photos showed similarly placed, somewhat elevated ovoid areas. I guess that in some dogs, normal facial lymph nodes are slightly larger. I guess also that during Roxanne's several physical exams by vets and during close observation by trainers, they made similar, apparently very well-justified judgments. In many organisms, symmetry or near-symmetry is after all strongly associated with good health.

I wracked my brain trying to figure out whether Roxanne might have been exposed to any carcinogens during her months with me. Of course, modern life is full of carcinogens, but, so far as I can tell, she was not exposed to any unusual kind or quantity of such substances.

One very well-informed source suggested calcinosis as a reassuring, likely (and for Beaucerons not unprecedented) diagnosis. The vet conjectured that the nose bump was an infection, perhaps from an injury - Beaucerons are very actively nosy

- or insect bite and hoped that the facial bumps were lipomas or histiocytomas.


Mid-day on August 24, I heard from Dr. Long about the pathology report, and the news could hardly have been worse: Mast Cell Disease in lymph nodes from the sides of her face and in the aspirate from her nose; that is, she has at least three malignant tumors on her head. (Mast cells produce histamine. Perhaps this connects with the apparent allergy history above.) During the rest of the day, I tried to deal with the tidal wave of psychological pain but I was unsuccessful; this is unusual since much of my personality developed to defend against chronic physical and psychological pain.

The fact that the tumors became evident first in lymph nodes strongly suggests that the malignancy spread there from somewhere else. The spread from the lymph glands to the nose (or did it go the other way?) indicates further metastasis. The current diagnosis is Stage III Mast Cell Tumors (MCT). Because of the location of these three tumors, they appear to be poor candidates for radiation treatment. [My understanding is that radiation would burn away Roxanne's nose and the sides of her face, with further damage to nearby tissue.] The standard treatment is instead palliative chemotherapy (typically prednisone plus medication - e.g., PEPCID AC and BENADRYL - to counteract its side effects), and only about 15% of dogs on such chemotherapy with grade III tumors survive beyond six months.

In many ways - age of dog, site of tumors, number of tumors - Roxanne's situation appears extremely unusual: 10-25% of all skin/subcutaneous tumors in dogs are MCT but only about 10% of those are young dogs. (Across breeds, the average age of dogs with MCT is 8-9 years.) Most MCT are solitary with multiple primary tumors in only 20% of patients. Only about 10% of MCT are located on the head and neck. Some long-time Beauceron breeders in France consulted by Roxanne's breeder said that they have never even heard of MCT in such a young Beauceron.


Dr. Long suggested further evaluation by Oncology Service at the NCSU College of Veterinary Medicine (NCSU-CVM). The initial work-up would cost $180 for the physical exam and $300-400 for tests; most treatments (surgery, chemotherapy, radiation) if feasible would of course be considerably more (many thousands of dollars, well beyond my rapidly diminishing means). She called the Oncology Service on 8/24 to arrange the referral. [Dr. Long remarked that it was very unusual that the pathology report from Antech did not grade the degree of malignancy of the two lymph node tumors; as is usual, no grade was given for the aspirate (from the nasal tumor). This might however be consistent with the difficulty that the NCSU-CVM pathologist had in grading the tumors using the Antech slides; see below.]

Dr. Long called me again on 8/27 to say she'd not yet gotten a response to her call to the Oncology Service and would call again 8/28 to press for an immediate response. She also FAXed a copy of the initial pathology report to Roxanne's breeder, whom I'd already alerted. She said that on 8/28, she would direct that Roxanne's tissue samples be sent from Antech to NCSU-CVM for re-examination. (CVM, she said, usually insists on examining samples themselves anyway, so this promised to speed up the usual process slightly. But there was no speed-up; see below.)

The NCSU-CVM Oncology service called me at 11:00AM, 8/29, and they managed to squeeze Roxanne into their busy schedule. I took her to the Vet School at 10:30AM on Tuesday, September 4, for a day of examination and testing. Ms. Gail Miller, the Oncology Veterinary Technician to whom I described Roxanne's situation on the phone called her case "complex" and seemed to express some qualified pessimism based on Roxanne's youth and the metastasis that had already occurred. I appreciated her forthrightness.

Roxanne might turn out to be a candidate for the Vet School's on-going vinblastine chemotherapy study, if such therapy seems appropriate. (Vinblastine can have many side effects in humans, here listed in order of decreasing likelihood: cough or hoarseness accompanied by fever or chills; fever or chills; lower back or side pain accompanied by fever or chills; painful or difficult urination accompanied by fever or chills; blood in urine or stools; pain or redness at place of injection; pinpoint red spots on skin; unusual bleeding or bruising; black, tarry stools; joint pain; sores in mouth and on lips; swelling of paws or legs; difficulty in walking; dizziness; double vision; drooping eyelids; headache; jaw pain; depression; numbness or tingling in hands; pain in hands; weakness. Dogs are allegedly less likely than humans to suffer these effects.) There are of course other chemotherapeutic agents available (e.g. lomustine=CCNU, vincristine), with their own unpleasant side-effects.

For further expert advice, Roxanne's breeder is contacting Professeur Didier Fau, Ecole Nationale Vétérinaire de Lyon, a veterinarian who is highly knowledgeable about Beauceron health problems.

A Beauceron owner whose own dog, Ned, is battling osteosarcoma told me about the list CanineCancer. When I posted an inquiry to CanineCancer, Victoria from The Perseus Foundation replied suggesting that I contact Professor Cheryl A. London, an oncologist at UC/Davis-SVM who studies MCTs.

I e-mailed Dr. London and she replied immediately:

... We can test your dog for a mutation in a gene that we think influences the prognosis of mast cell cancer. Sometimes, mast cell disease in very young dogs regresses over time (a similar syndrome exists in people), so your dog's disease may not be actually be "cancer" but may represent a form of dysregulated mast cell proliferation.

I then asked, "If dysregulated mast cell proliferation were at issue, what kind of treatment options if any would there be?"

Dr. London replied, again immediately:

Often the disease in young animals will spontaneously regress on its own. Evidence of mutation in the gene we are looking at would indicate a malignant rather than a benign process.

This isn't enough to make me hopeful, and I know nothing yet about the cost of such testing or how long one must wait for results.


Roxanne was seen September 4th by Dr. David Proulx of the Oncology Service at NCSU-CVM-Veterinary Teaching Hospital. MCTs are among the top five problems the Oncology Service sees. He described her clinical presentation as "bizarre" and said that neither surgery nor radiation were likely treatment options given the tumor locations. While the already evident metastasis and lymph node invovlement are not good signs, the fact that the disease has apparently been in place so long suggests that it may not be of the most aggressive sort.

Roxanne was well-behaved while we waited to be seen and during my conversation with Dr. Proulx. She protested, however, when time came for me to leave and for her to go for the tests and lab work.

I drove to my office on the main campus to find that my office thermostat was broken and the temperature was fifty-five degrees. The thermostat was replaced (with unprecedented speed, by 3PM) but the refrigeration did not make it any easier for me to wait calmly. A very good friend kindly brought me some liquid (non-alcoholic) lunch so that I could remain by the phone. I picked Roxanne up around 6:30PM.

From Dr. Proulx's September 4 written discharge report, which he reviewed with me orally, and his follow-up telephone call on September 5, here is a summary of the exam and test results:

Roxanne looks good on examination. The abdominal ultrasound to check for liver and spleen area anomalies and the bloodwork did not show any evidence of mast cell tumor. (The adrenal glands are thin bilaterally, and this is sometimes associated with Addison's disease, but in the complete absence of other signs, the latter diagnostic possibility is not even worth pursuing.) Buffy coat evaluation: no mast cells observed. The bone marrow aspirate was clean - no mast cells. Submandibular lymph nodes are of normal size. They would be the next likely location for any metastasis, and the left submandibular lymph node is abnormal, containing a significant number of mast cells. (The right submandibular lymph node is somewhat puzzlingly classified as normal, despite containing a few mast cells.) The abnormal lymph node finding is disappointing and makes it more likely that chemotherapy will be the recommended treatment.The original biopsy slides from Antech will be sent out 9/6 (not 8/28) to the Oncology Service and the results of the slide review by NCSU-CVM Pathology should be available by Tuesday, 9/11. Once we have this review, we can further discuss Roxanne's treatment plan. If we believe Roxanne truly has a mast cell tumor then we should consider placing her on a chemotherapy protocol consisting of prednisone and either vinblastine or CCNU. ....

[I omit e-mail contact information for Oncology because one of the supervising oncologists said, in response to e-mail from me:

... contact the oncology service via phone and not e-mail. There are many times during busy days in the clinic where we do not check e-mail, or members of our service are off-clinics, and therefore the reliable way to ensure we are communicating in a timely fashion is via phone. You may reach the oncology service at (919) 513-6690.

So I once again called the latter number. The voice mail message explains that because of the very heavy load the Oncology service is experiencing, calls from referring veterinarians will be returned in 2-4 business days and calls from clients will be returned in 1-3 business days. Another number to call at the Veterinary Teaching Hospital is also given for emergencies. It's difficult to resist the conclusion that the service is understaffed. When Dr. Ruslander of Oncology called between 5:30PM and 6:30PM on September 12, I was walking Roxanne and missed his call about the Pathology review of Roxanne's slides. I very much hoped to learn more on September 13, but was not re-contacted; with Dr. Proulx out of town, the load on the remaining oncologists has increased. I did learn that Dr. Ruslander practiced in Switzerland and may have some familiarity with Beaucerons.]

Dr. Ruslander did get hold of me by phone around 5:15PM September 14, and confirmed the earlier diagnosis of Stage III Mast Cell Tumors. In its review of the slides, Pathology found it difficult to grade the lymph node tumors but assigned them a grade of I or II, describing them as well-defined with obvious granules; but the metastasis still reaffirmed the earlier diagnosis. The pathology report remarked that although the slide review was consistent with mastocytosis in young dogs - the non-"cancer" diagnosis mentioned by Dr. London - in such cases the tumors typically recede and that has not happened in Roxanne's case. And it is the staging, rather than the grading, that is, according to Dr. Ruslander the key to prognosis. While emphasizing how the very unusual nature of Roxanne's case and the highly variable course of MCT itself makes a definite prognosis infeasible, he estimated that she would survive for one year or less.

The treatment options are, as expected, the three chemotherapeutic ones mentioned above: prednisone alone, prednisone plus CCNU, or prednisone plus vinblastine. The first option is relatively inexpensive even for a dog of Roxanne's weight. The others would involve treating Roxanne every three weeks for six months, at a cost of about $250 per cycle (including monitoring for untoward side effects), for a total cost of over $2000. According to Drs. Proulx and Ruslander, most dogs tolerate a course of prednisone well and suffer far fewer side effects from other sorts of chemotherapy than do human beings, with mild, transient loss of appetite perhaps with an episode of vomiting most common, and transiently decreased white blood cell count and reduced platelet counts also common and liver malfunction a risk. The latter are usually compensated for by reducing the dose of chemotherapeutic agent and providing antibiotics to protect against infections. Emphasizing again how the very unusual nature of Roxanne's case and the highly variable course of MCT itself makes a definite prognosis infeasible, he said that rough estimates would be six months survival on prednisone alone and one year on prednisone plus a more toxic agent.

So far, the additional CVM evaluation has cost $556, and I assume that Pathology review will add to the cost. [Both the supervising oncologist at NCSU, Dr. Laurel Williams, and Dr. Cheryl London (UC/Davis) trained at Tufts (as did Dr. Proulx) and have co-authored papers on MCT treatment. It may be feasible for Dr. London to do the test she suggested using the biopsy slides, but the result would effect prognosis and not treatment plan. I will certainly seek Dr. London's advice about whether it is worth checking Roxanne for the c-KIT mutation apparently associated with the malignant form of MCT, especially in light of the oddity of Roxanne's case. But I have no good reason to be hopeful.] Given my severely limited and shrinking resources and the real chance that adding CCNU or vinblastine to prednisone could well diminsh the quality of extra time, if any, gained, I chose prednisone therapy alone. So at 10:55 PM, September 16, I left the following message on the NCSU-VTH Oncology Service voice mail:

David Austin/Roxanne Austin-Ward Patient #NNNNNN

Please start her on prednisone as soon as possible. Let me know when I can pick up a prescription for prednisone along with instructions about supplementary antacid and antihistamine dosing as recommended. Her weight is approximately 34 kg.

I do not request treatment with vinblastine or CCNU.

I have asked Dr. Cheryl London of UC/Davis to contact the Oncology service about testing Roxanne for a possibly prognostically relevant c-kit mutation.

My contact information is as before. I welcome e-mail.

(Dr. Ruslander tried to contact me at my office by phone early on September 18, but I was working at home that morning and missed his call.) By September 21, a prescription for prednisone was ready for pick-up at the NCSU-VTH Pharmacy; it will be given along with PEPCID AC and BENADRYL in the standard way during the following six months (if Roxanne survives that long).

[Clicking the link in the previous sentence initiates a download of a .pdf file of: Gigi Davidson, BS, RPh, FSVHP, DICVP, "Providing Positive Outcomes through Compounding for Animal Cancer Patients," International Journal of Pharmaceutical Compounding Vol. 4 No. 4 (July/August 2000) 264-272. The free Adobe Acrobat Reader is required to read .pdf files.]

As of November 21, I know of no pertinent contact between Dr. London and Roxanne's oncologists, though Dr. London did contact me on September 22 and again on October 2; on the latter date, I left a phone message for Dr. Ruslander asking him to e-mail Dr. London directly. I again left very similar messages for Dr. Ruslander on October 11 and October 15. Within an hour of leaving the latter message, an Oncology veterinary technician called back to tell me that Dr. Ruslander had received all three phone messages and was interested in getting in touch with Dr. London. Dr. Ruslander did respond on November 20 to a request for a refill of Roxanne's prednisone prescription.

Dr. Ruslander also confirmed my impression that no one knows what causes MCT, and while I will try to make the environment here as hypoallergenic and carcinogen-free as I can, there's no good reason to think that the environment played a significant role in the development of Roxanne's MCT. I also realized that her MCT's initial visibility in a pair of lymph glands means that, very likely, metastasis had already occurred and hence that earlier action on those bumps would probably not have changed the outcome - though I will always wonder.

Some Relevant Articles
Authors: Rassnick, KM Moore, AS Williams, LE London, CA Kintzer, PP Engler, SJ Cotter, SM
Title: Treatment of canine mast cell tumors with CCNU (Lomustine) JOURNAL OF VETERINARY INTERNAL MEDICINE
Authors’ addresses: Tufts Univ, Sch Vet Med, Harrington Oncol Program, 200 Westboro Rd, N Grafton, MA 01536 USA Tufts Univ, Sch Vet Med, Harrington Oncol Program, N Grafton, MA 01536 USA Tufts Univ, Sch Vet Med, Dept Pathol, N Grafton, MA 01536 USA Boston Rd Anim Hosp, Springfield, MA USA
Abstract: The efficacy and toxicity of CCNU (1-[2-chloroethyl]3- cyclohexyl-1-nitrosurea) were evaluated in 23 dogs with measurable mast cell tumors (MCT). Twenty-two dogs had cutaneous MCT and 1 dog had an intranasal MCT Nineteen (83%) dogs had biopsy of their original mass performed and 4 (17%) had aspiration cytology of masses. Of the 19 tumors histologically graded, 1 (5%) neoplasm was classified as grade I, 10 (53%) were grade II, and the remaining 8 (42%) were grade III. Dogs were treated with CCNU at a dosage of 90 mg/m(2) body surface area every 3 weeks. Response could be evaluated in 19 dogs. Eight of the 19 dogs (42%) had a measurable response to CCNU. One dog had a durable complete response for 440 days. Seven dogs (37%) had a partial response for a median and mean duration of 77 days and 109 days, respectively (range, 21-254 days). Treatment with CCNU resulted in stable disease in 6 dogs (32%) for a median and mean duration of 78 days and 122 days, respectively (range, 42-347 days). The acute dose-limiting toxicity was neutropenia 7 days after administration of CCNU. The median and mean neutrophil counts 7 days after CCNU were 1,452 cells/mu L and 1,683 cells/mu L, respectively (n = 17). Other toxicoses were uncommon. CCNU should be considered an active agent in the treatment of MCT in dogs.
Times Cited 2
Beginning Page 601
End Page 605
Periodical Year 1999
Periodical Date NOV-DEC
VoLume Number 13
IsSue Number 6
Authors: Thamm, DH Mauldin, EA Vail, DM
Title: Prednisone and vinblastine chemotherapy for canine mast cell tumor - 41 cases (1992-1997) JOURNAL OF VETERINARY INTERNAL MEDICINE
Authors’ addresses: Univ Wisconsin, Sch Vet Med, Dept Med Sci & Pathobiol Sci, 2015 Linden Dr W, Madison, WI 53706 USA Univ Wisconsin, Ctr Comprehens Canc, Madison, WI 53706 USA Univ Wisconsin, Sch Vet Med, Dept Med Sci & Pathobiol Sci, Madison, WI 53706 USA
Abstract: Forty-one dogs with mast cell tumors (MCTs) were treated with oral prednisone and injectable vinblastine (VBL), both in the adjuvant setting (23 dogs) and in dogs with gross disease (18 dogs). Adverse effects were noted in 20% (8/41) of the patients, usually after the Ist dose of VBL. Adverse effects were considered mild in 6, and severe, necessitating treatment discontinuation, in 2 (5%). Overall response rate in the evaluable dogs with gross disease was 47% (7/15), consisting of 5 complete responses and 2 partial responses. Median response duration was 154 days (24 to >645 days). As adjuvant therapy to incomplete surgical resection, prednisone and VBL conferred a 57% 1- and 2-year disease-free rate. Median survival time (MST) for the entire patient population was not reached with a median follow-up of 573 days; however, the MST for dogs with grade III MCT was 331 days, with 45% of dogs alive at 1 and 2 years. This is an apparent improvement over historical survival data employing surgery alone. Upon univariate analysis, significant prognostic factors (P < .05) for survival included presence of a locally recurrent tumor, presence of gross disease, argyrophilic nucleolar organizer region frequency, lymph node status, histologic grade, previous chemotherapy, and ulceration of the tumor. Similar criteria were significant when analyzed for time to treatment failure. Response to therapy was also predictive of survival in the gross disease group. Upon multivariate analysis, histologic grade (P = .012) and presence of a locally recurrent tumor (P < .001) were significant factors for survival.
TC 1
BP 491
EP 497
PY 1999
VL 13
IS 5
Authors: London, CA Galli, SJ Yuuki, T Hu, ZQ Helfand, SC Geissler, EN
Title: Spontaneous canine mast cell tumors express tandem duplications in the proto-oncogene c-kit EXPERIMENTAL HEMATOLOGY
Authors’ addresses: Stanford Univ, Med Ctr, Dept Pathol, L-235,300 Pasteur Dr, Stanford, CA 94305 USA Brigham & Womens Hosp, Dept Pathol, Div Immunol Res, Boston, MA 02115 USA Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA USA Harvard Univ, Sch Med, Boston, MA USA Univ Wisconsin, Sch Vet Med, Dept Med Sci, Madison, WI 53706 USA
Abstract: Spontaneous mast cell tumors (MCT) are the most common malignant neoplasm in the dog, representing between 7% and 21% of all canine tumors, an incidence much higher than that found in humans. These tumors often behave in an aggressive manner, metastasizing to local lymph nodes, liver, spleen, and bone marrow. The proto-oncogene c-kit is known to play a critical role in the development and function of mast cells, Point mutations in the kinase domain of c-kit leading to tyrosine phosphorylation in the absence of ligand binding have been identified in three mastocytoma lines, (P815, RBL, and HMC-1), and some human patients with various forms of mastocytosis. We now demonstrate that although c-kit derived from canine MCT did not contain the previously described activating point mutations, 5 of the 11 tumors analyzed possessed novel mutations consisting of tandem duplications involving exons II and 12, We also show that one such duplication, detected in a canine mastocytoma cell line, was associated with constitutive phosphorylation of c-kit protein (KIT), suggesting that these mutations may contribute to the development or progression of canine MCT. (C) 1999 International Society for Experimental Hematology. Published by Elsevier Science Inc.
TC 6
BP 689
EP 697
PY 1999
VL 27
IS 4
Authors: Bensignor, E Fontaine, JJ Delisle, F Devauchelle, P
Title: Mast cell tumors in dogs: An anotomoclinical and therapeutical study of 85 cases RECUEIL DE MEDECINE VETERINAIRE
Abstract: The results of an experimental study about 85 cases of mast cell tumors are presented. A great number of young Boxer dogs suffering from tumors of low grade of malignancy is observed. Epidemiological data are compatible with the previous studies. The interest of the Patnaik's grading for this tumor is confirmed, with average survival times about 2 years fur the grade II, and 6 months only for the grade III. Corticotherapy appears as the treatment of choice compared with others chemotherapy protocols, allowing higher survival times and survival rate over 50% at 30 months. The authors believe that this treatment should be proposed in every case of mast cell tumor in the dog.
TC 0
BP 351
EP 358
PY 1996
VL 172
IS 7-8
Authors: London, CA Kisseberth, WC Galli, SJ Geissler, EN Helfand, SC
Title: Expression of stem cell factor receptor (c-kit) by the malignant mast cells from spontaneous canine mast cell tumours JOURNAL OF COMPARATIVE PATHOLOGY
Abstract: Stem cell factor receptor (SCFR, c-kit), normally expressed on haematopoietic and mast cells, plays a regulatory role in cellular growth and differentiation. Dysregulated expression of SCFR may contribute to neoplastic transformation. We investigated expression of SCFR on malignant canine mast cells obtained directly from spontaneous canine mast cell neoplasms, in an attempt to determine whether these undifferentiated cells maintained expression of this growth-promoting cytokine receptor. Malignant mast cells (histological grade 2) from skin tumours or lymph node metastases were collected from canine patients, and SCFRs were detected by flow cytometric analysis of these cells. All of the tumours bound mouse and canine recombinant stem cell factor (SCF), indicating that the cells not only expressed SCFRs, but that the receptors possessed the functional property of ligand binding. Immunoglobulin Fc receptors for canine IgE were identified on these cells by flow cytometry, a further indication that the cells analysed were mast cells and retained some differentiated features. Immunohistochemical analysis of formalin-fixed, paraffin wax- embedded mast cell tumour biopsies confirmed expression of SCFRs by malignant cells from each tumour. The relative binding of SCF to suspensions of tumour cells, as assessed by flow cytometry, correlated with the intensity of immunolabelling for SCFR in sections of the same tumours, suggesting variability in SCFR expression between tumours. Agarose gel electrophoresis of the products of SCFR reverse transcription-polymerase chain reaction derived from each tumour had the molecular weight predicted for canine SCFR cDNA on the basis of the mouse and human counterparts. This further confirmed SCFR expression by malignant canine mast cells. Taken together, these results show that a membrane receptor capable of triggering cell growth is expressed by malignant canine mast cells, suggesting a role for this receptor in the aetiology of canine mast cell cancer. This relatively common malignancy of the dog would seem to present an opportunity for the investigation of the potential role of the SCF/ SCFR pathway in the development of spontaneous malignancies of mast cells. (C) 1996 W.B. Saunders Company Limited
TC 8
BP 399
EP 414
PY 1996
VL 115
IS 4
Genes, Dogs, and Cancer: Emerging Concepts in Molecular Diagnosis and Therapy J. F. Modiano (Ed.) Publisher:  International Veterinary Information Service (Ithaca, New York, USA).

c-kit Mutations and Mast Cell Cancer (Last Updated: 21-May-2001 )

C. A. London, M. B. ChienJ. Pfieff, S. Downing and R. A. Grahn - School of Veterinary Medicine, University of California Davis, Davis, CA, USA.

Mast cell tumors (MCT) are the most frequently diagnosed malignant tumor of the dog. Their natural history is difficult to predict as they can behave in an extremely aggressive or benign manner. The proto-oncogene c-kit is known to play a critical role in the development and function of mast cells. Mutations in c-kit leading to constitutive activation of Kit have been identified in several malignant mast cell lines, as well as from some human patients with various forms of mastocytosis. We have demonstrated the presence of novel mutations consisting of tandem duplications in c-kit in spontaneous canine MCTs. These mutations, all located in exons 11 and 12 (encoding the negative regulatory juxtamembrane domain), lead to tyrosine phosphorylation in the absence of ligand binding. Moreover, these tandem duplications result in constitutive association of PI 3-kinase with mutant Kit. Extensive analysis of archived MCT specimens from the pathology data base at the VMTH of UC Davis revealed that tandem duplications in c-kit were present in those tumors more likely to behave in a malignant manner, with an incidence of over 40% in Grade III MCTs. We used the canine C2 MCT line (possessing a tandem duplication in c-kit) to evaluate Kit signaling and found that PI 3-kinase was constitutively associated with the mutant Kit. Moreover, the tandem duplication did not disrupt binding of the tyrosine phosphatases SHP-1 or SHP-2. These results indicate that constitutive phosphorylation of mutant Kit is most likely due to continuous dimerization of the receptor, rather than disruption of phosphatase regulation of receptor function. In summary, preliminary results suggest that c-kit mutations are associated with more aggressive MCT. We are currently in the process of developing mouse models of Kit dysfunction in which the expression of various forms of constitutively active Kit is controlled by a tightly regulated inducible promoter. The integration of detailed investigations of Kit dysregulation in the mouse, and comprehensive studies of a spontaneous model of c-kit mutation in the dog will clarify the biological and biochemical consequences of c-kit mutations and likely result in significant new information with broad applicability to human cancers as well as to the development and implementation of novel therapeutic strategies.


Roxanne's appetite was slightly diminished and she seems a bit less energetic than usual, but Dr. Long felt confident that this was caused by the cephalexin she is being given to make sure her incisions heal well. She completed a 14 day, two grams per day, course of this antibiotic on September 3 and the incisions did heal well.

On the morning of September 1, I gave her the usual 1 gram dose of cephalexin and offered her breakfast. She ate about a quarter of it. We then went for our usual long morning walk during which she seemed less enthusiastic than usual. Towards the end of the walk, Roxanne vomited what she had eaten and wanted to sit for several minutes before finishing our walk at a slower pace than usual. When we returned home, I gave her some PEPCID AC with a small biscuit. She played some, but was more subdued than usual. That evening, I offered her about sixty percent of her usual supper topped with crumbled baked lamb lung (BAA-BECUE), her favorite treat, and she ate it with enthusiasm and no apparent ill effects.

On the morning of of September 2, when I uncrated her to walk and feed her, I found that she had chewed off her flat collar - this must have taken some effort as it was not too loose at bedtime - and was scratching at her neck more than she had been. After giving her 500mg of cephalexin with PEPCID AC, I offered her breakfast in which she took no interest. I then brushed her with the slicker, which she seemed to enjoy. On our walk, she was extraordinarily hyper, her behavior resembling her January 18 allergic reaction to some component of her DHLPP vaccination (-probably L, which was omitted next round). Since the remedy then was BENADRYL (about 1mg per pound), I gave her some with a large biscuit which she demolished despite showing continued disinterest in her breakfast.

Roxanne's abdomen and right shoulder had to be shaved for the ultrasound and bone marrow aspirate. And she came home still somewhat sedated, though she gave me an enthusiastic greeting at pick up, and rested quietly in her crate at home during the evening of September 4.

She ate very little September 5, and was somewhat hyper. This may be because of the testing and her diminished physical activity the previous day. On September 6 her appetite was somewhat better, but she sought less activity than usual. By September 7, her food consumption was, with the help of some added cottage cheese or parmesan cheese, back to normal as was her energy level. Thanks to Kay, one of her favorite humans, and Cyrus, Kay's 165 lb. Great Dane, Roxanne had a wonderful time that morning, and her appetite and energy remain normal, though she continues to scratch at her neck and has (as of September 11) developed some dandruff on her back. The latter could be a result of another Malaseb bath on September 8, though it too was followed by application of Resicort. On September 13 she behaved and ate normally, though she went to the back yard to vomit at 9:45PM. After I gave her some PEPCID AC and cleaned up, she dashed back out to retrieve what she'd given up and seemed in no particular distress. September 14 was also a day of normal behavior and food consumption.

On Saturday, September 15, in addition to her usual activities, Roxanne got to play with Kay on an agility course at Autumn Winds and with Peppermint, a good friend of hers who is a 100lb.+ female Great Dane puppy. On September 16, she was a bit more difficult than usual during the day, but still within normal limits, and she'd calmed by evening. On September 17, she seemed a bit more subdued than usual but ate well. September 19th she seemed to tire sooner than usual and the next morning, her appetite was down a bit, her stools were a bit looser than usual and they ended with a very small quantity of blood-tinged mucus, but she seemed playful later in the day and ate all of the half-supper I offered her. I suppose that now I will worry every time her behavior varies.

Roxanne begin palliative treatment on September 22, when she also got to play again with Cyrus. She seems to be doing okay on 40mg prednisone, 15mg PEPCID AC and 150mg of BENADRYL daily; after 7 days at 40mg, the prednisone dose drops to 20mg daily for 14 days, and then to 20mg every other day for up to five months. Because of the prednisone, she does drink and urinate more. She also seems calmer overall. That could be mild sedation from the BENADRYL, but I wonder for how long she may have been irritated and irritable because of the disease itself and thus if the prednisone is reducing the irritation.

She behaved extremely well during our long September 25 evening post-prandial, despite encountering seven dogs, two morbidly obese men (who moved quite oddly, by her lights) and assorted other humans, including a bicycle-helmeted little girl who startled both of us by emerging from behind some dense vegetation, running across our path and running away screaming when Roxanne gave a couple of desultory barks.

Beginning September 27, she was less energetic than usual, though still playful, and has had somewhat looser stools. For example, after puppy class on September 29, she napped a good deal of the afternoon and has not wanted to go as far on walks as we usually do. Prednisone can slow dogs down and cause GI problems. So can MCTs. She began her halved dose of prednisone on September 29. The bump on her nose is smaller and more nearly normal in color. But MCTs can vary in size.

Her appetite seemed suddenly to increase on October 3. That evening, for the first time, she 'stole' some briefly unattended food that she'd previously have considered out of reach. On October 4, she ate her breakfast far more rapidly than usual. At the same time her naps and reluctance to take longer walks have both increased. Her first two weeks on prednisone ended October 5; her dose is scheduled to be halved again, to 20mg every other day, beginning October 13. October 6 and 7 Roxanne was playful but her stamina seemed down; she did not want to take long walks on October 7, despite it's being clear and cool. She was enthusiastic about a long walk the morning of October 9, and behaved very well even when we encountered one of Snickers's cousins, but she resisted long walks on Oct 10. On October 11, she again resisted long walks and was hyper during the evening until I gave her her nightly BENADRYL and PEPCID AC. Her appetite continues to be greater than usual and she is spending more time on walks and at other times looking for things to ingest. During October 11-15 she refused long walks and was less energetic than was typical. On October 13, she began receiving prednisone every other day. The evening of October 16 and the morning of October 17, she was glad to take long walks but refused to do so the evening of October 17.

During the week of October 8, I found an odd area of irritation on her left hock (back ankle) with a thick white, peeling covering akin to (but not) partially dried caulk. The covering came off with whatever hair was embedded in it and I applied some topical antibiotic; the area is hairless but is not red.

I then discovered a smaller, similar area on her left loin and one on each of her wrists. No pain seems associated with any of these areas. On October 18, I brought her to Dr. Long to have these areas checked. Dr. Long seemed to rule out a parasite infection (e.g., Malasezzia, demodedtic mange) made possible by Roxanne's immunosuppression. Aspirate from her left hock was sent to the lab for pathology since a few mast cells were seen it it; the report should be available on October 22, the day before Roxanne's first birthday. Dr. Long found no signs of lymph node swelling anywhere and suggested that the white patches were pressure callouses. On October 19, Roxanne enjoyed puppy class, and was very cooperative during a Malaseb and Resicort bath, but seemed unusually tired during the rest of the day. The next morning, I was dismayed to find that she'd vomited a small amount in her crate during the night, and she ate very little of her breakfast. Her appetite and energy returned during the day, she was willing to take an extra long walk during the afternoon of October 21, and she ate all of the half-supper I offered her, as well as several Innova Health Bars during the evening. In the following week, her energy level seemed consistently higher than during her initial weeks on prednisone.

On October 22, Dr. Long called to report that the serology report on the left hock aspirate said that although it wasn't possible to be confident that the small mass on the left hock was a mast cell tumor (MCT), a very few mast cells were observed so it might be an MCT. Dr. Long is contacting the Oncology Service at the NCSU Veterinary Hospital to get advice about whether to remove the mass. Unless the mass is causing her significant discomfort - no evidence of that at all - which can be relieved only through surgery, or removal would affect the prognosis, neither I nor, I believe, Dr. Long would see any point in subjecting her to a painful, stressful surgical procedure. Dr. Long's eventually got in touch with Dr. Proulx, who agreed with the latter strategy.

Roxanne shows no signs of discomfort, and I have seen much more than broad hints of the very steady, confident, sweet, playful, smart (and beautiful) adult she might have become. While I'm not sure what it means to say that a dog or breed of dog is (for a dog) unusually stoical, people with far more experience than I have with Beaucerons do describe them in this way. So I worry that my (or anyone else's) being unable to see signs of discomfort in her is a reliable indicator that she isn't suffering. I am grateful, however, that she passed her first birthday, October 23, 2001.

During early November, Roxanne's energy increased, with more long walks welcomed, and her appetite diminished somewhat. I have no idea what the significance of any of this is. For all I know, Roxanne has benign mastocytosis presenting atypically, or malignant mast cell disease with atypical ("bizarre") presentation.

In mid-November, her appetite, thirst and energy seemed to resume normal levels. Her occasional loose stools are attributable to the stuff she snarfs down on walks, despite my assiduous efforts. On November 21, I found a small bump on the right side of her face, behind the location of the mast cell tumor that was removed from that side. Perhaps this could provide one of the tissue samples Dr. London would need, though I don't know that it is a mast cell tumor. Her appetite and energy levels were down on November 22.

The five red dots in the photo below (not of Roxanne) indicate areas on her left side where anomalies had been found before November 21, with the three on her head confirmed MCTs. In addition, the right maxillary lymph node was found to be a MCT.

Although she's shown no signs of being very ill, Dr. Proulx said that her seeming good health has very limited longer-term prognostic significance.


Whatever the final diagnosis - and I believed it was in place - I would want to do for Roxanne what I'd want done for myself in comparable circumstances. It is wonderful when resources are available to prolong the person's life. But I have also seen prolonged dying imposed on both human and canine persons, even after their identities have been destroyed by illness, and I would not allow Roxanne to suffer in that way. There should be time for almost all of her favorite human friends - Alex, Eric, Jan, Kay and others - to say goodbye to her, though I worried that she'd not reach her first (and probably last) birthday, on October 23.

Having Roxanne has spoiled me for almost any other breed, and, as a Parisian veterinary dermatologist familiar with Beaucerons remarked to me, Roxanne's problem is so unusual that it's no reason to shy away from the breed. So I hope that I can adopt another black Beauceron female at an appropriate time.

During a difficult twelve years, Snickers was the only sentient being I could rely on always to be glad to see me. I did research for the latter ten of those twelve years before choosing to get a Beauceron, with the last three of the ten years focused on the Beauceron and its breeders. Since adopting Roxanne on December 28, 2000, I have taken her everywhere I could with me (occasionally bending rules to do so) and, with the exception of two days she spent at the vet's, have spent about fifteen hours each day at her side (without slighting Snickers's needs). According to very recent medical exams, my health has improved significantly and measurably as a result.

Given Roxanne's probable prognosis and Snickers's advanced age, it is likely that, to put it selfishly, I will lose them both around the same time. And I'll have nowhere to go where they'll not be missing.


It's been over a month since I last updated this page. Roxanne continues on her medication. I've found no new growths and her appearance and behavior are that of a very healthy young dog. Her appetite is not what it once was, but then she's no longer growing as rapidly. She's still enjoying long walks, agility and Great Dane-flattening. It was great fun to watch her romping in the snow left by a recent storm.

She'd finish six months of medication on March 22, at which point she'd be gradually taken off the prednisone.

It may still be that Roxanne has (or had) benign mastocytosis presenting atypically, or malignant mast cell disease with atypical ("bizarre") presentation. I still have to wait and watch.


February 19, 2002 -- Today, Roxanne saw Dr. Long for vaccinations and a check-up.

Aside from minor problems that are all probably explicable as side effects of the prednisone she's taking [dry skin, thirst, slow hair re-growth on her flanks (shaved for August ultrasound scan), some weight gain - 90 lbs now, a bit high - and slightly increased fear/aggressiveness] Dr. Long found Roxanne to be in excellent health: no new growths detectable, no lymph node swelling, strong heart, clear eyes and ears, glossy coat, etc.

And I reported that no one who knows her well sees any signs of illness: Roxanne looks and acts as if she is very healthy.

Though the vet's office is far from her favorite place, she behaved well there (and was thrilled to leave).

Dr. Long thought it reasonable to wonder if benign mastocytosis atypically presented mightn't be the correct diagnosis instead of malignant mast cell disease. Nor did she dismiss my suggestion that some sort of allergic reaction inadequately compensated for because of 'sub-clinical' Addison's Disease might have led to mastocytosis.

After hearing from Dr. Long about Roxanne's current status, Dr. Proulx advised tapering her off the prednisone immediately.

March 7, 2002 -- Roxanne began two weeks of 10mg every other day of prednisone, half the dose she's been on for the past several months. Then she'll be on 5mg every other day for two weeks, after which the prednisone will be stopped.

I don't know how long it will take before any side effects will wear off. (In human beings, it can take weeks, but dogs live faster.)

I will continue watch and wait.


March 16, 2002 -- Because she was concerned about Roxanne's increased aggressiveness, Jan talked with Fred Caristo on March 8. He reportedly said that the prednisone was very likely responsible for almost all of the increased aggressiveness, that he'd doubted she had cancer, and that her underlying sweetness and calmness - characteristics of both of her parents - would re-emerge after the effects of the prednisone diminshed or wore off. (A very similar hypothesis about prednisone and aggressiveness was suggested to me by Anne Sharpe.)

Since cutting her prednisone dose to 10mg every other day, the change in Roxanne's behavior has been dramatic. She is far calmer, attentive and hence more obedient, and her skin no longer appears dry. Her appetite remains good.


April 4, 2002 -- Roxanne continues to do well and will get her last 5 mg dose of prednisone on April 6th. On March 21, she stepped on a partially buried sharp stick on the way home from a long walk in Duke Forest and lacerated a pad on her right rear foot. Thanks to Dr. Vora's excellent care, she is healing very well, but her activity has had to be restricted since March 21, and she misses her exercise, as do I.


April 30, 2002 -- Roxanne's foot has healed well. However, her appetite and stamina seem somewhat reduced and last week I discovered a bump just forward of her right hip, where there is apparently a cluster of lymph nodes in dogs.

She now averages less than one long walk daily, and will sit or lay down to rest several times on longer walks. Some of this might be explained by the increased heat here, and she's certainly not inactive. But even at Autumn Winds she does not seem able to go as long without resting. During the healing of her foot, she began more nipping and I thought it was just the result of her restricted activity, but it has persisted and it is reminiscent (though far less severe than) her nipping behavior as a younger puppy, behavior I attributed to mast cell overgrowth. So another biopsy is very likely in her near future.

May 3, 2002 -- Roxanne's appetite continues to be variable. Despite near 90 degree F heat yesterday she virtually insisted on a long walk and remained active afterwards. Today, it was overcast and around 70 degrees F, and she took two long walks happily - but she's eaten very little, has been doing more nipping, and has also been dashing around in the back yard in the way she did as a puppy. It now seems to me that a bump's begun to appear on the left side of face, where the larger of the original MCT's grew. She sometimes coughs after running around, but this may be caused by grass eating.

May 23, 2002 -- During the past week or so, Roxanne's stamina and appetite have been very good and her behavior around people has been excellent. Over the last four days, since the weather's been unseasonably cool, we've taken three six mile walks on the Duke Forest trails. She had plenty of energy left after each walk. On the walks, we came close to many runners, walkers, bicyclists, walking-stick bearers, and children in or out of strollers. She watched them all, of course, but showed not a trace of hostility. Today on campus we (figuratively speaking) ran into someone she's met a few times before only briefly and she was very friendly, immediately sitting and wagging her tail energetically and then nuzzling him and letting him pat and scratch her all over. And it was clear by last night that the two bumps near Roxanne's right hip had shrunk. But I took her to the vet appointment at 5:30PM today anyway.

Dr. Long said that the palpable bump near Roxanne's right hip was muscle tissue, and the asymmetry with the left was attributable to her having been thrown off balance by her lacerated pad and two weeks of having her right rear foot bandaged (March 22-April 6). Neither of us could find the second bump further back and the vet guessed that given how quickly it appeared (developing in less than 24 hours) and how relatively quickly it diminished, it was the result of an insect bite. (I use pyrethrin in the back yard, Frontline Topspot Plus on Roxanne and I go over her with a fine tooth comb daily, as well as doing additional checks, but the ticks are exceptionally plentiful this year.)

Dr. Long said that Roxanne's face looked normal though there is a very slight asymmetry near the areas where her mast cell tumors had been. She also assured me that all of each lymph node had been removed and so no re-growth was possible in that area.

So, she said, there was no need for a biopsy, especially in light of Roxanne's stamina, appetite and good behavior lately.

(Roxanne's weight is down from a prednisone-high of 93 lbs to 89 lbs, which is good too.)

I've never been so glad to be wrong.

July 5, 2002 -- Roxanne still seems to be in excellent health. Weather permitting, we take 1-2 five mile walks daily, in addition to agility and play. On our walks, people often remark about her, "What a well-behaved dog!" - sometimes as they are attempting to get their own dogs to behave. While Roxanne is not always well-behaved, the behavior that she exhibited while on the higher (20 mg/day) dose of prednisone is long gone.

July 9, 2002 -- Over the past few days, I've noticed some discoloration on Roxanne's nose in the same area as before. She's gotten some bites on walks and sticks her nose in a lot of places where it may not belong. Of course, this worries me.

I hope to have some new photos of her up by mid-August, after we return from our summer travels northward.

September 5, 2002 -- A small raised area grew very slowly on Roxanne's nose during the summer. According to an NCSU Vet School pathology report on a tissue biopsy of the bump, it is a grade II mast cell tumor, as before. In light of her history, her vet, Dr. Vora, suggested that Roxanne receive 4 weeks of prednisone, 2 weeks at 10 mg every other day and 2 weeks at 5 mg every other day, with Pepcid AC to protect against stomach irritation. This dosage of prednisone did not result in behavior problems during her prior treatment.

Roxanne appears otherwise to be in excellent health.

Dr. Vora remarked that she has seen a few dogs who regularly develop grade 2 mast cell tumors but do not appear sick otherwise and who seem fine after tumor removal (though where a tumor grows will determine what effects it has; dogs with mast cell growths in kidneys, liver, spleen or bone marrow will present with the relevant organ problems).

While I wish that the pathology report had come back differently, Roxanne's history is cause for some optimism.

June 27, 2003 -- Roxanne still shows no signs of any recurrence of mast cell disease, and seems to be in excellent health.

On June 13, she was suddenly attacked by an eighteen month old male Akita who'd previously played very well with her; the reasons for the attack will never be known. In 20 seconds, she sustained seven bites which took an hour under general anesthesia to repair. But she recovered very quickly, figured out how to use an e-collar as a battering ram, and has energy to spare.

December 29, 2001, August 3, 2002and November 2005 photos of Roxanne

August 26, 2006 -- Roxanne remains healthy. She is almost six years old and has calmed considerably - a result of her maturation and mine. A few months ago, she grew her first white whisker - at the very same time as did her sister, Reka. I grew white whiskers years ago. Given that we are both middle-aged now, we're doing pretty well though.

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Last updated on August 26, 2006