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Ilona and Bill
An 8-year-old female spayed Golden Retriever initially presented to her primary veterinarian for surgical resection of a subcutaneous mass suspected to be associated with the left 2nd mammary gland. It was unknown how long the mass had been present and the rate of growth. The mass was bilobed on palpation and reported to be freely moveable. The mass was removed using a CO2 laser and a Penrose drain was placed. Rimadyl was prescribed and all resected tissue was submitted for histopathology, which revealed adenocarcinoma with vascular invasion and extension to the margins. There were on average 2 mitotic figures/HPF. Anisocytosis and anisokaryosis were moderate to marked and there was individual cell necrosis and focal necrosis noted. The tumor was poorly differentiated but it was suspected that it might be mammary in origin. Referral to an oncologist was recommended for further evaluation and treatment.
The patient presented to the oncology service at Hope Veterinary Specialists approximately 2 weeks post surgery. Blood work performed at that time was unremarkable. Three view thoracic radiographs were performed which did not reveal any evidence of metastatic disease. Four treatment options were discussed including a revision surgery followed by chemotherapy vs. chemotherapy alone vs. no further therapy or only low dose therapy. Due to the incomplete margins and the aggressive appearance on histopathology (high growth rate and vascular invasion) surgical reexcision to remove the scar and residual neoplasia followed by chemotherapy was the recommended treatment of chose. The chemotherapy protocol discussed was Adriamycin IV q 3 weeks x 4-5 cycles with a CBC postop 1-week Adriamycin administration.
The owner scheduled an appointment with the surgery service a week later. On physical examination an 8 cm scar coursing from cranial to caudal centered over the left 2nd mammary gland was noted with the previous drain exit site noted ventral and caudal to the scar. Scar resection with margins laterally and deep including margins around the drain exit site were discussed, as were possible complications and postoperative care. Surgery was performed the same day and the patient was discharged to the owner the following day. Postoperatively the patient did well. The histopathology revealed residual mammary adenocarcinoma with complete excision. There was greater than 5 mm lateral margins and greater than 5 mm deep margins with the sections examined having a layer of skeletal muscle deep to the site.
Postoperatively the patient did well. The incision was healed at the 2 week postoperative examination and the skin sutures were removed. She has completed her Adriamycin based protocol and is currently receiving an NSAID as a maintenance therapy for putative anticancer effects. All restaging visits have been clear and she is currently 9 months from diagnosis.
Mammary tumors occur in both dogs and cats, however, the incidence is higher in dogs than any other species. They are the most third most common tumor in cats and account for 17% of all tumors in female cats. In dogs, half of the mammary tumors are considered malignant, and half of these have metastasized at the time of diagnosis. In contrast, nearly 90% of mammary tumors in cats are malignant.
In dogs, intact females have a seven-fold increased risk of developing mammary cancer compared to neutered females and the age at which ovariohysterectomy is performed is proportional to the risk of developing mammary cancer. The greatest reduction in risk occurs when an OVH is performed prior to the first heat cycle, however a protective exists still exists if performed prior to 2.5 years of age.
Obesity may be a factor in mammary neoplasia in dogs. In cats, exogenous progestins and the combination of estrogen-progestins are associated with a 3-fold risk of developing either benign or malignant mammary tumors. Benign fibroepithelial hyperplasia may also be caused by administration of sex steroids.
It has been shown that roughly half of canine mammary tumors are malignant and half are benign. A FNA is not always diagnostic and therefore histopathology needs to be submitted to reveal if it is benign or malignant. Benign mammary tumors include adenoma, benign mixed tumor and papilloma with the simple/complex fibroadenoma being the most common. Malignant tumors include carcinoma, adenocarcinoma, sarcoma, carcinosarcoma and inflammatory carcinoma with carcinomas being the most common.
Typical clinical presentation involves a lump or mass being reported on or near the mammary gland or the nipple itself . Approximately 2/3rds to 3/4ths of the tumors occur along the 4th and 5th glands. Signs that are often associated with malignancy include rapid growth, ill-defined borders of the tumor, fixation to the underlying tissue and ulceration of the tumor.
Staging for mammary tumors involves blood work (CBC, serum chemistry), thoracic radiographs, abdominal ultrasound (if caudal glands), and aspiration of nearby lymph nodes if possible. Pending staging results, surgery is normally the first recommended treatment of choice. Surgery can be performed to remove the mass, the gland itself or the entire chain. Studies have shown no difference in overall survival when comparing removal of the gland itself vs. the entire chain. At the time of surgery, if possible, removal of the draining lymph node is recommended to look for metastasis.
Based upon histopathology and staging results, there are several factor that are prognostic. These include:
Based on these factors, it has been found that if dogs have mostly good prognostic indicator they may have a very good quality of life and an overall median survival of >2 years depending upon the case.
In dogs, the extent of surgery does not influence either survival or disease-free interval . The histologic completeness of surgical margins is prognostic for survival so the most aggressive surgery needed to achieve complete margins is recommended.
Chemotherapy is recommended for dogs and cats with malignant and metastatic mammary tumors. The role of chemotherapy is still unknown, despite understanding the poor outcome associated with this disease and the high incidence of metastatic disease. Drugs commonly used in protocols include 5-fluorouracil+cyclophosphamide, doxorubicin alone or with cyclophosphamide, carboplatin, mitoxantrone, paclitaxel and docetaxel. The parent compound Paclitaxel is from the Taxane group of chemotherapy agents with efficacy against breast, lung and ovarian cancer in human oncology. Use in veterinary medicine is limited as a result side effects associated with its excipient Cremophor® EL. Oasmia Pharmaceutical AB has managed to produce a water soluble formulation of Paclitaxel (Paccal® Vet), that does not require premedication and abolish Cremophor® EL related side effects. A Phase I/II study on multiple types of cancers and showed an overall response rate of 74 % with responses noted in patients with mammary carcinoma, squamous cell carcinoma and mast cell tumor. The FDA has given Conditional Approval (CA) for use in patients with nonresectable stage III, IV, or V mammary carcinoma in dogs that have not received previous chemotherapy or radiotherapy; and resectable and nonresectable squamous cell carcinoma in dogs that have not received previous chemotherapy or radiotherapy. Two trials are ongoing further evaluating Paccal Vet-CA1 in a larger number of dogs with mammary and squamous cell carcinoma.
Responses of nonresectable mammary tumors to metronomic therapy and tyrosine kinase inhibitors has been reported, however, data is lacking.
Nonsteroidal medications such as Feldene, Deramaxx or Metacam, have been shown to have anticancer effects against mammary tumors and Omega-III fatty acids have been shown to also have anticancer effects and can decrease the risk of these tumors (in people).
Submitted by Lauren May VMD, DACVS
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Sorenmo, K. U., Shofer, F. S., and Goldschmidt, M. H. Effect of spaying and timing of spaying on survival of dogs with mammary carcinoma. J. Vet Intern Med 14, 266-270. 2000.
Yamagami T, Kobayashi T, Takahashi K, Sugiyama M. Influence of ovariectomy at the time of mastectomy on the prognosis for canine malignant mammary tumors. J Small Anim Pract 1996; 37:462-464.
Sonnenschein EG, Glickman LT, Goldschmidt MH, McKee LJ. Body conformation, diet, and risk of breast cancer in pet dogs: A case-control study. Am J Epidemiol 1991; 133:694-703.
Philibert JC, Snyder PW, Glickman N, Glickman LT, Knapp DW, Waters DJ. Influence of host factors on survival in dogs with malignant mammary gland tumors. J Vet Intern Med 2003; 17:102-106.
Yamagami T, Kobayashi T, Takahashi K, Sugiyama M. Prognosis for canine malignant mammary tumors based on TNM and histologic classification. J Vet Med Sci 1996; 58:1079-1083.
Figures 1,2. Histopathological images showing residual carcinoma surrounded by a fibroblastic response and adjacent cross section through suture material. Images and description courtesy of Dr. Danielle Reel, DVM, Diplomate ACVP, KDL VetPath.
An 8 year old female spayed domestic short hair cat was referred for abdominal ultrasound due to a 7 month history of chronic intermittent vomiting, diarrhea and inappetence.
Sonographic exam of the abdomen revealed mild to moderate thickening of the muscularis layer throughout the entire length of the small intestinal tract. Additionally there was a pair of markedly enlarged, rounded hypoechoic lymph nodes at the ileocolic junction. Ultrasound guided fine needle aspiration of the lymph nodes was attempted with the patient sedated however the lymph nodes were extremely firm, difficult to penetrate with the needle and yielded relatively acellular samples. Surgical biopsies of the intestines and lymph nodes were recommended as the next diagnostic step.
Exploratory laparotomy was performed and incisional biopsies obtained from the stomach, duodenum, jejunum, and ileocolic lymph node.
Histopathology of the stomach demonstrated infiltration of the lamina propria with low numbers of lymphocytes, eosinophils and plasma cells as well as superficial mucosal fibrosis and edema. Lamina propria of the duodenum was moderately infiltrated with plasma cells. The lamina propria of the jejunum was moderately infiltrated with increased plasma cells, low numbers of lymphocytes and eosinophils and multifocal clusters of atypical round cells presumed to be mast cells. Submucosa was also infiltrated with lymphocytes, plasma cells and eosinophils.
The ileocolic lymph node contained multifocal islands formed by sheets of neoplastic round cells having irregular round to oval nuclei with inconspicuous nucleoli and moderate to abundant amounts of foamy cytoplasm with distinct cell borders. Moderate anisokaryosis was present with low mitotic activity (1 per 10 high power fields). Numerous eosinophils and few macrophages were also present. The final histopathologic diagnosis was mast cell tumor of the jejunum and ileocolic lymph node as well as mild lymphoplasmacytic and eosinophilic enterits.
Chronic intermittent vomiting, diarrhea, inappetence or weight loss are common clinical signs prompting abdominal sonography in cats. Diffuse small intestinal thickening, particularly of the muscularis layer along with mesenteric lymphadenopathy can be common sonographic findings in these patients and has been associated with inflammatory diseases and infiltrative neoplasias of intestinal tract. It can also occasionally be noted in cats with no clinical signs referable to the gastrointestinal tract. While lymphocytic-plasmacytic enteritis is the most common histopatholgic form of inflammatory bowel disease, eosinophilic enteritis is also occasionally diagnosed (1). Cats with eosinophilic enteritis tended to have a slightly greater intestinal wall thickness with a thicker muscularis layer. Peripheral eosinophilia can also be documented in some but not all cats.
Lymphoma is the most common gastrointestinal neoplasia in cats. The classic sonographic description of lymphoma has been that of hypoechoic mural masses and symmetric or asymmetric circumferential thickening with a loss of normal wall layering detail (2,3). Enlarged, hypoechoic and rounded mesenteric lymph nodes may or may not be present. This form of lymphoma tends to be a B-cell lymphoma and can be associated with hepatic or renal lesions as well. More recently a sonographic appearance of muscularis layer thickening with preserved intestinal layering detail and the absence of mass lesions has been described in cats with gastrointestinal lymphoma. These cases tended to be a small cell T-cell variety of lymphoma (4,5). Mesenteric lymphadenopathy may or may not be present in these cases.
Mast cell tumor can be seen in both the cutaneous and visceral form in cats. The visceral form can occur as both intestinal and splenic infiltration with mast cell tumor being the third most common intestinal neoplasia of cats, comprising approximately 4% of intestinal neoplasias (6,7). Mast cell infiltration can occur in the small intestine or colon. The sonographic appearance of feline intestinal mast cell tumor can be that of either single or multifocal mural mass lesions or more diffuse small intestinal thickening, particularly of the muscularis layer. Metastasis to the mesenteric lymph nodes, liver or spleen may be noted. In contrast to the cutaneous form of MCT in cats the prognosis with the intestinal form is very poor (8).
In conclusion muscularis layer thickening and mesenteric lymphadenopathy are common sonographic findings in cats present for chronic intermittent vomiting, diarrhea, inappetence or weight loss. While these serve as important imaging biomarkers for intestinal disease they are not specific enough to differentiate between inflammatory or neoplastic conditions. Also, in addition to the commonly discussed and diagnosed lymphocytic-plasmacytic enteritis and lymphoma, other inflammatory and neoplastic diseases must be considered including eosinophilic enteritis and visceral mast cell tumor. These imaging findings should prompt intestinal biopsies as the next diagnostic step to obtain a histopathologic diagnosis and allow for formulation of an appropriate treatment plan as well as more accurate prognosis.
- Tucker S, Penninck DG, Keating JH, Webser CRL. Clinicopathological and ultrasonographic features of cats with eosinophilic enteritis. J Fel Med and Surgery 2014;16: 950-956 http://jfm.sagepub.com/content/early/2014/02/27/1098612X14525385.abstract
- Penninck DG, Moore AS, Tidwell AS, et al. Ultrasonography of alimentary lymphosarcoma in the cat. Vet Radiol Ultrasound 1994;35:299–304. http://onlinelibrary.wiley.com/doi/10.1111/j.1740-8261.1994.tb02045.x/abstract
- Grooters AM, Biller DS, Ward H, et al. Ultrasonographic appearance of feline alimentary lymphoma. Vet Radiol Ultrasound 1994;35:468–472. http://onlinelibrary.wiley.com/doi/10.1111/j.1740-8261.1994.tb02073.x/abstract
- Zwingenberger AL, Marks SL, Baker TW, Moore PF. Ultrasonographic evaluation of the muscularis propria in cats with diffuse small intestinal lymphoma or inflammatory bowel disease. J Vet Intern Med 2010:24:289-292 http://onlinelibrary.wiley.com/doi/10.1111/j.1939-1676.2009.0457.x/full
- Daniaux LA, Laurenson MP, Marks SL, Moore PF, Taylor SL, Chen RX, Zwingenberger AL. Ultrasonographic thickening of the muscularis propria in feline small intestinal small cell T-cell lymphoma and inflammatory bowel disease. J Fel Med and Surgery 2014;16: 89-98 http://jfm.sagepub.com/content/16/2/89.short
- Head KW, Else RWand Dubielzig RR. Tumors of the alimentary tract. In: Tumors in Domestic Animals, 4th, DJ Meuten, ed., Ames, IA, Blackwell Publishing Co, 2002: 401–482. http://onlinelibrary.wiley.com/doi/10.1002/9780470376928.ch8/summary
- Rissetto K, Villamil JA, Selting KA, Tyler J, Henry CJ. Recent trends in feline intestinal neoplasia: an epidemiologic study of 1,129 cases in the veterinary medical database from 1964 to 2004. J Am Anim Hosp Assoc 2011;47: 28-36 http://www.jaaha.org/doi/abs/10.5326/JAAHA-MS-5554
- Vail DM and Thamm DH. Mast cell tumors. In: Small Animal Clinical Oncology, 4th edn., SJ Withrow and EG MacEwen, eds., Philadelphia, WB Saunders Co, 1997: 402–424.
Figure 1: Sonographic appearance of feline visceral (intestinal) mast cell tumor. No the markedly enlarged, hypoechoic rounded mesenteric lymph node as well as the thickened muscularis layer of the jejunum demonstrated with yellow arrows.
Owners of pets with cancer frequently ask if there are orally administered alternatives to injectable chemotherapy drugs. Often this is out of misconception that oral drugs afford fewer side effects. Unfortunately, any cytotoxic medication has the potential to cause adverse effects, regardless of route of administration.
Many owners also feel treating their pet with an oral chemotherapy drug will be a less stressful option for their pet. Whether actual or perceived, if an owner feels their animal will experience distress or anxiety from an injection of a drug, they will seek another form of treatment, or potentially decide to not pursue treatment at all. The idea of their pet taking their chemotherapy as a “treat” is often a far more appealing and viable option.
Owners also may be familiar with oral chemotherapy because they, or a friend or family member, have been prescribed such drugs themselves. As is the case for much of veterinary oncology, there are far more of such options available for people with cancer than for animals.
One such relatively unexplored option for veterinary patients with cancer is a drug called temozolamide (TMZ). TMZ is an oral alkylating chemotherapy agent of the imidazotetrazine family.
In people, TMZ is used to treat primary and metastatic brain tumors, melanoma, and cutaneous lymphoma. Its use in veterinary oncology has generally been restricted to treating relapsed or refractory lymphoma in dogs, however other tumor types could be responsive as well.
The metabolism and mechanism of action of TMZ are similar to those of dacarbazine (DTIC), which is a chemotherapeutic frequently prescribed in veterinary medicine. Unlike DTIC, which requires activation by the hepatic cytochrome p-450 system, TMZ is activated non-enzymatically via hydrolysis in the bloodstream. Another advantage of TMZ is that it is administered orally, whereas DTIC is given over a prolonged intravenous infusion (5-8 hours) or as a daily bolus for 5 consecutive days.
One study examined treating dogs with relapsed or refractory lymphoma with TMZ combined with either doxorubicin or dactinomycin. The response rates, remission duration, and frequency of gastrointestinal side effects were comparable to dogs treated with combinations of either DTIC and doxorubicin or DTIC and dactinomycin. However, the frequency of hematological toxicity was greatly reduced. The ease of administration of TMZ and less chance of causing leukopenia or thrombocytopenia (as compared to DTIC) makes it an attractive option for treating dogs with relapsed or refractory lymphoma.
TMZ has been evaluated for use in cats with a variety of tumor types. Responses to treatment were detected in feline patients with refractory lymphomas, however unacceptable and unanticipated toxicities occurred, therefore the study was terminated prior to target enrollment. Further investigation into the use of TMZ in cats is therefore carefully warranted.
Having options is important to owners of pets with cancer. It’s important to listen to their goals and expectations and devise a treatment plan that provides the best chance of success, but also empowers owners in the decision making process. If you have a patient you believe could be a candidate for treatment with oral TMZ treatment, please do not hesitate to contact the Hope VS Oncology Department at 610-296-2099 or email: firstname.lastname@example.org.