...he always scrambled from the car and pranced through your door with a smile on his face. In his view every visit to you was a party with friends.
Update on Treatment of Canine Transitional Cell Carcinoma
Transitional cell carcinomas (TCCs) are the most common tumors of the urinary bladder. The Scottish Terrier, Sheltie and Beagle are breeds with a higher risk factor for developing this cancer. Other factors have been associated with a higher risk of development, including female gender, obesity and exposure to chemical lawn pesticides.1 Transitional cell carcinomas are typically very aggressive and invasive tumors associated with a moderate rate of metastasis. The incidence of metastasis to the locoregional lymph nodes in one study was reported to be 39% at initial diagnosis and 58% at necropsy. Thoracic radiographs have been noted to be positive for pulmonary metastasis in up to 16% of patients at the time of initial diagnosis.2
Because they are often located at the trigonal region of the bladder, complete surgical resection of the tumor is often not possible. There is, however, evidence to suggest that surgical debulking (if a large amount of the tumor can be debulked) followed by adjuvant chemotherapy will extend survival time.2 Intensity-modulated radiation therapy (IMRT) has been investigated in dogs with urogenital tumors in combination with other forms of either local or systemic treatment. This modality was shown to significantly improve both progression-free intervals and overall survival times. While it was found to be a well-tolerated form of locoregional therapy, the availability of treatment facilities with both IMRT and image-guided capabilities is limited.3
Chemotherapy in the face of gross disease has also been shown to be effective in treating TCCs. The combination of traditional cytotoxic chemotherapy with a non-steroidal anti-inflammatory drug results in a 30% overall response rate (with 75% feeling better at home) and a median survival of one year.4
Piroxicam (Feldene) is a non-steroidal anti-inflammatory agent (NSAID) that has been shown to improve clinical signs (hematuria, stranguria, pollakiuria), thus improving quality of life. In some patients, long term use may even result in partial decrease in tumor size.5 Other NSAIDs such as firocoxib and deracoxib have also been shown to be effective in the treatment of transitional cell carcinoma.2,6
There have been several chemotherapeutic agents utilized to treat transitional cell carcinomas. Prior studies suggest that injectable protocols utilizing mitoxantrone or vinblastine combined with piroxicam may increase both quality and quantity of life.7,8 Other injectable agents, such as doxorubicin, gemcitabine and carboplatin, have been investigated but have not been shown to be of significant benefit.9,10,11,12
Because of the locally aggressive nature of this disease, most dogs are ultimately euthanized due to poor quality of life secondary to significant discomfort or inability to urinate, with up to sixty percent of dogs being euthanized due to urinary obstruction. Urethral stenting under fluoroscopic guidance has been successfully utilized to manage urethral obstruction in many cases. As with any treatment modality, patient selection is paramount. While generally well-tolerated, complications may include urinary incontinence, stent migration and reobstruction.13
Recently, the use of metronomic chlorambucil has been shown to be well-tolerated and able to slow progression of disease for several months after dogs had failed other treatments.14 Newer prospective studies are currently underway to investigate this treatment as both a first-line therapy as well as in combination with traditional cytotoxic agents. Anecdotal reports of combination vinblastine, piroxicam and metronomic chlorambucil as first-line therapy suggest a promising increase in response rates. Hopefully, further clinical trials will continue to provide hope for improved outcomes for dogs with transitional cell carcinoma.
Ian Muldowney, DVM – 2015
- Knapp D (2013). Tumors of the urinary system. In: Withrow SJ, VailDM, eds. Withrow & MacEwen’s small animal clinical oncology. 5th ed. Philadelphia: WB Saunders Co;572–582.
- Knapp D, Glickman N, Widmer W, et al (2000). Cisplatin versus cisplatin combined with piroxicam in a canine model of human invasive urinary bladder cancer. Cancer ChemotherPharmacol,Vol 46:221–226
- Nolan M, et al (2012). Intensity-Modulated and Image-Guided Radiation Therapy for Treatment of Genitourinary Carcinomas in Dogs. JVIM, Volume 26, Issue 4: 987–995.
- Fulkerson C, Knapp D (2015). Management of transitional cell carcinoma of the urinary bladder in dogs: A review.The Veterinary Journal,Volume 205, Issue 2: 217–225.
- Knapp D, Richardson R, Chan T, et al (1994). Piroxicam therapy in 34 dogs with transitional cell carcinoma of the urinary bladder. J Vet Intern Med, Vol8:273–278.
- McMillan S, et al (2011). Antitumor effects of deracoxib treatment in 26 dogs with transitional cell carcinoma of the urinary bladder. JAVMA,Vol. 239, No. 8: Pages 1084-1089.
- Henry C, et al (2003). Clinical evaluation of mitoxantrone and piroxicam in a canine model of human invasive urinary bladder carcinoma. Clinical Cancer Research, Vol 9: 906-911.
- Arnold E, et al (2011). Clinical trial of vinblastine in dogs with transitional cell carcinoma of the urinary bladder. JVIM, Vol 25:1385-1390.
- Robat C, et al (2013). Retrospective evaluation of doxorubicin-piroxicam combination for the treatment of transitional cell carcinoma in dogs. Journal of Small Animal Practice,Vol 54: 67-74.
- Marconato L, et al (2011). Toxic effects and antitumor response of gemcitabine in combination with piroxicam treatment in dogs with transitional cell carcinoma of the urinary bladder. JAVMA, Vol 238, No. 8: 1004-1010.
- Boria P, et al (2005). Carboplatin and piroxicam therapy in 31 dogs with transitional cell carcinoma of the urinary bladder. Veterinary and Comparative Oncology, Volume 3, Issue 2: 73–80.
- Chun R, et al (1997). Phase II Clinical Trial of Carboplatin in Canine Transitional Cell Carcinoma of the Urinary Bladder. JVIM,Volume 11, Issue 5: 279–283.
- McMillan S, et al (2012). Outcome of urethral stent placement for management of urethral obstruction secondary to transitional cell carcinoma in dogs: 19 cases (2007-2010). JAVMA, Vol 241, No 12: 1628-1632.
- Schrempp D, et al (2013). Metronomic administration of chlorambucil for treatment of dogs with urinary bladder transitional cell carcinoma. JAVMA,Vol. 242, No. 11: 1534-1538.
Mast cell tumors (MCT) are commonly identified tumors in dogs, comprising close to 25% of all diagnosed skin tumors. These tumors may be seen in any age dog, but are more typically found in middle aged to older patients. Breeds at an increased risk for developing these tumors include boxers, Boston terriers, Labrador retrievers, beagles and schnauzers. The etiology of MCTs is largely unknown, although genetic factors and molecular alterations may play prominent roles. Recently, there has been an increased focus on understanding these genetic and molecular alterations, including the identification of activating mutations in the growth pathway involving c-kit, the receptor for stem cell factor, which promotes the malignant process within mast cell tumors when mutated. Since this mutation is not present in all dogs, it is likely only a contributing mechanism to a more complex process of neoplastic transformation.
Controversies with MCTs
The pathology and behavior of a MCT depends substantially on the histologic pattern of the tumor, which is associated with the tumor grade. However, there is variation within the grading scheme used among pathologists that lends itself to subjectivity in assigning a tumor to a particular category. Traditionally, these categories are grade I (well-differentiated or low grade), grade II (intermediate grade), and grade III (poorly-differentiated or high grade). Subsequently, guiding the appropriate therapy and providing prognostic information based on the traditional grading scheme has become complicated and unpredictable. The introduction of a two tier system (Kiupel) of low and high grade designed to minimize the subjectivity was introduced several years ago and has since been further validated. In a study of 137 surgically resected cutaneous MCTs, the relationship between grade and survival was evaluated. All grade I MCTs were low grade in the Kiupel system, and all grade III were deemed high grade. Among grade II, 71 (85.6%) were low grade, and 12 (14.4%) were high grade, with a 1-year survival probability of 94% and 46%. Per this study, the 2-tier system had a high prognostic value and was able to correctly predict the negative outcomes of some grade II MCTs. Currently pathologists are reporting both grading schemes.
To assist in more objectively categorizing a grade II MCT, which account for 70% of all MCTs, various immunohistochemical and molecular tests of tumor cell proliferation are now recommended in addition to routine histopathology. These markers of proliferation are now clinically available and are readily performed on tissue biopsy samples in the form of MCT panels (www.dcpah.msu.edu/Sections/Immunohistochemistry/FAQ.php#08). These assays provide clinicians with the ability to make more sound recommendations regarding the appropriate adjuvant therapy. This particular panel evaluates argyrophilic staining nucleolar organizing regions (AgNOR), proliferation cell nuclear antigen (PCNA), Ki-67, c-kit pattern assessment, and PCR for c-kit gene mutation. AgNOR frequency is an indirect measure of tumor cell proliferation and may be equally or even more important as the tumor grade in terms of predicting the biologic behavior of the MCT. PCNA and Ki-67 are also indirect measures of tumor cell proliferation and are most useful when interpreted in conjunction with one another. c-kit is the protein receptor for stem cell factor found in many cells including mast cells. A genetic mutation of the c-kit gene, which encodes for the c-kit receptor itself, has been identified in some MCTs. When mutated, the receptor is constitutively active and promotes the malignant process within the cells. Mutations within the c-kit gene are associated with a more aggressive phenotype. With the new two tier system, ideally this should decrease the need for further panels, as low grade tumors for the most part are associated with longterm survival.
When should one use a MCT panel?
If one goes on the assumption that the new grading scheme will soon become standard of care, then the data suggest 5% of “low grade” tumors will behave more aggressively. Ideally, a MCT panel, may help differentiate these patients and thereby guide the clinician to either a more aggressive surgery or adjuvant therapy that could benefit that patient. Although more recent data suggest 15% may metastasize, to run MCTs panels on all “low grade” tumors seems overkill. It also takes away the validity of grading scheme if it is being suggested to be run in conjunction with grading.
Ideally, the MCT panel should be reserved for cases in which the biopsy results do not fit the clinical picture; ie a more aggressive site (muzzle), fast growing tumor, severely ulcerated, large tumor, lymph node involvement, etc. Another application may be in patients with incompletely excised Grade II tumors. A recent study, evaluated whether the extent of surgical excision affects recurrence rate in dogs with grade II MCTs that had a low proliferation activity, determined by Ki67 and AgNOR. Eighty-six dogs with cutaneous MCT were evaluated. All dogs had surgical excision of their MCT with a low Ki67 index and combined AgNORxKi67 (Ag67) values. Twenty-three (27%) dogs developed local or distant recurrence during the median follow-up time. Of these dogs, six had local recurrence,,of which one had complete excision and five had incomplete excisions. This difference in recurrence rates between dogs with complete and incomplete histologic margins was not significant. The authors hypothesized that ancillary therapy may not be necessary for patients with incompletely excised grade II MCT with low proliferation activity, thus, in these select cases, a MCT panel may provide additional information regarding treatment.
For high grade tumors, performing portions of the panel may be useful for treatment decision. Knowing a kit mutation status in a high grade tumor may change the treatment choice from purely chemotherapy to a combination of chemotherapy and a TKI, whereby a higher response rate is noted in kit mutation positive patients. Currently studies are underway utilizing mutation status to help logically guide treatment decision for a more personalized medicine approach, albeit on a very basic level.
Submitted by Craig A. Clifford DVM, MS, DACVIM (Oncology)
Hope Veterinary Specialists, Malvern, PA
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History: An 8-year-old male castrated Labrador Retriever was presumptively diagnosed with osteosarcoma of the left distal radius. His presenting clinical signs included acute grade 3 lameness and a bony mass associated with the distal radius. Radiographs taken at that time revealed an aggressive lesion of the distal radial metaphysis with moth-eaten lysis and a mixed periosteal reaction, which varied from smooth to palisading to more amorphous. There was a short zone of transition and mild overlying soft tissue swelling. (see figure 1). Initial staging tests were performed: CBC and serum chemistry were within normal limits and thoracic radiographs (three-view) did not reveal evidence of pulmonary metastasis. His owners were given curative-intent (amputation and chemotherapy) and palliative intent (radiation therapy) options. They elected to pursue a palliative approach consisting of radiation therapy in the form of CyberKnife stereotactic radiosurgery (SRS) with the goal of improving comfort and quality of life. CyberKnife stereotactic radiosurgery/ radiation therapy entails precise administration of radiation therapy via a robotic delivery system with submillimeter accuracy, resulting in the ability to deliver a definitive-intent radiation therapy protocol in 1-3 treatments. Adjuvant treatment in the form of pamidronate, a bisphosphonate drug used to decrease bone resorption by inhibiting osteoclast activity was administered prior to radiation therapy (Protocol: 1mg.kg IV over 2 hours q 4 weeks)1. The patient received a single fraction of 25 Gy delivered to the distal radius, which was preceded by a dose of pamidronate the day before.
Following discharge, the patient received 4 additional more treatments of pamidronate and experienced a complete remission of his discomfort, however, the bony deformity remained at his distal radius based upon repeat imaging. Thoracic and limb radiographs of the left front limb 8 months after CyberKnife treatment and then again 12 months after treatment (see figures 2 and 3). At the time this case report was being written, the patient is 13 months post-CyberKnife treatment with some minimal bony changes/ remodeling of the distal radius and no evidence of distant metastatic disease based upon serial radiographs.
Comparison of the radiographs by a board-certified radiologist yielded the following report: Monostic aggressive lesion of the distal radius consistent with a primary bone tumor-osteosarcoma most likely. Between the Aug 2014 and Aug 2015 there is mild to moderate progression of the periosteal reaction without a significant progression of lysis.
Reduction in bone pain as a result of irradiation is theorized to result from multiple mechanisms: by direct killing of tumor cells and inflammatory cells and by reducing bone destruction by osteoclasts. Prostaglandins produced by neoplastic cells as well as tumor-associated macrophages may also stimulate nociceptors and increase the pain response23. Radiation may mitigate this response thereby improving patient comfort.
Two published studies on SRS treatment of osteosarcomas have been published in dogs. The first reported published in 2004 on 11 dogs that received 20-30 Gy of radiation in a single treatment. The overall medial survival time in this study was 363 days with a 36% pathologic fracture rate5. The second study was published in 2014 and evaluated dogs that received a single SRS treatment but either had a fracture prior to SRS or developed one on the months following radiation treatment. Fractures were addressed either with internal fixation, external fixation or plating. All dogs also received chemotherapy with a protocol containing doxorubicin (30 mg/m2) and carboplatin (300 mg/m2) or single agent doxorubicin. Distant metastatic spread was documented in 5 dogs (lungs n=4; rib n=1). Survival time ranged from 364-897 days with one dog lost to follow up at 8 months. In this study, histopathology of their lesions was performed after SRS, and demonstrated extensive necrosis and proliferation of fibrous connective tissue. Interestingly, no evidence of neoplastic cells was found6.
Alternatives to stereotactic radiosurgery include the previously mentioned standard of care, amputation + chemotherapy, or treatment with conventional fractionated radiation therapy. Amputation followed by chemotherapy typically yields survival times of 235-540 days. Several chemotherapy protocols have been evaluated with none demonstrating superiority8-22.
Using conventional hypofractionated radiation therapy, or “palliative radiation therapy”, typically 2-4 fractions (treatments) of radiation are given once a week for 2-4 weeks. It has been documented that, on average, 76-96% of dogs will experience pain relief after 11-15 days from the start of a radiation protocol. The typical duration of pain relief is 60-120 days and average survival time is 120-180 days2-4.
This case demonstrates that treatment with stereotactic radiosurgery with CyberKnife yielded similar results to amputation + chemotherapy. This modality of treatment may be preferred by owners of dogs that are not good candidates for amputation due to concurrent orthopedic disease or because of owners’ wishes. One potential drawback of SRS treatment of osteosarcoma lesions, however, is the ongoing risk of pathologic fracture, which likely peaks approximately 6 months after irradiation but then decreases as new bone is formed7.
Further studies are needed to evaluate the rate of metastatic disease development after treatment of OSA with SRS or CyberKnife. Currently most palliative RT protocols do not include chemotherapy as most dogs succumb to intractable pain prior to the development of metastatic disease, however, with the ability of stereotactic radiosurgery to control pain for a significantly longer period of time, the addition of chemotherapy to control metastatic disease may be warranted. Limitations of the current case report include a lack of a definitive histopathologic diagnosis.
Figure 1. The left front limb in August 2014
Figure 2. The left front limb in April 2015
Figure 3. The left front limb in August 2015
- Milner RJ, Farese J, Henry CJ, Selting K, Fan TM, de Lorimier LP. Bisphosphonates and cancer. J Vet Intern Med 2004;18:597–604. http://www.researchgate.net/profile/Louis_Philippe_De_Lorimier/publication/8203927_Bisphosphonates_and_
- McEntee MC, Page RL, Novotney CA, Thrall DE. Palliative radio- therapy for canine appendicular osteosarcoma. Vet Radiol Ultrasound 1993;34:367–370. http://onlinelibrary.wiley.com/doi/10.1111/j.1740-8261.1993.tb02022.x/pdf
- Ramirez O, III, Dodge RK, Page RL, et al. Palliative radiotherapy of appendicular osteosarcoma in 95 dogs. Vet Radiol Ultrasound 1999;40:517–522. http://onlinelibrary.wiley.com/doi/10.1111/j.1740-8261.1999.tb00385.x/pdf
- Green EM, Adams WM, Forrest LJ. Four fraction palliative radiotherapy for osteosarcoma in 24 dogs. J Am Anim Hosp Assoc 2002;38:445–451. 12. Mueller F, Poirier V, Melzer K, Nitzl D, Roos M, Kaser-Hotz B. Palliative radiotherapy with electrons of appendicular osteosarcoma in 54 dogs. In Vivo 2005;19:713–716. http://jaaha.org/doi/abs/10.5326/0380445
- Farese JP, Milner R, Thompson MS, Lester N, Cooke K, Flx L, Hester J, Bova FJ. Stereotactic radiosurgery for treatment of osteosarcomas involving the distal portions of limbs in dogs. Journal of the American Veterinary Medical Association 2004;225;1567-1572;1548 http://avmajournals.avma.org/doi/abs/10.2460/javma.2004.225.1567
- Covey J, Farese J, Bacon N, Schallberger S, Smsellem P, Vavanaush R, Milner R. Stereotactic radiosurgery and fracture fixation in 6 dogs with appendicular osteosarcoma. Vet Surg. February 2014;43(2):174-81. http://onlinelibrary.wiley.com/doi/10.1111/j.1532-950X.2014.12082.x/full
- Sugimoto M, Takahashi S, Toguchida J et al.,: Changes in bone after high-dose irradiation: biomechanics and histo-morphology. J Bone Joist Surg 1991;73-B:492-497 http://www.bjj.boneandjoint.org.uk/content/73-B/3/492.short
- Berg J, Gebhardt MC, Rand WM. Effect of timing of postoperative chemotherapy on survival of dogs with osteosarcoma.Cancer 1997;79:1343–1350
- Straw RC, Withrow SJ, Richter SL, et al. Amputation and cisplatin for treatment of canine osteosarcoma. J Vet Intern Med. 1991;5:205–210. http://onlinelibrary.wiley.com/doi/10.1111/j.1939-1676.1991.tb00950.x/pdf
- Thompson JP, Fugent MJ. Evaluation of survival times after limb amputation, with and without subsequent administration of cisplatin, for treatment of appendicular osteosarcoma in dogs: 30cases (1979-1990). J Am Vet Med Assoc 1992;200:531–533. http://europepmc.org/abstract/med/1559895
- Mauldin GN, Matus RE, Withrow SJ, et al. Canine osteosarcoma.Treatment by amputation versus amputation and adjuvant chemotherapy using doxorubicin and cisplatin. J Vet Intern Med 1988;2:177–180. http://onlinelibrary.wiley.com/doi/10.1111/j.1939-1676.1988.tb00313.x/abstract
- Bergman PJ, MacEwen EG, Kurzman ID, et al. Amputationand carboplatin for treatment of dogs with osteosarcoma: 48cases (1991 to 1993). J Vet Intern Med 1996;10:76–81. http://onlinelibrary.wiley.com/doi/10.1111/j.1939-1676.1996.tb02031.x/abstract
- Bacon NJ, Ehrhart NP, Dernell WS, et al. Use of alternating administration of carboplatin and doxorubicin in dogs with microscopic metastases after amputation for appendicular osteosarcoma: 50 cases (1999-2006). J Am Vet Med Assoc 2008;232:1504–1510. http://avmajournals.avma.org/doi/abs/10.2460/javma.232.10.1504
- Bailey D, Erb H, Williams L, et al. Carboplatin and doxorubicin combination chemotherapy for the treatment of appendicular osteosarcoma in the dog. J Vet Intern Med 2003;17:199– 205.http://onlinelibrary.wiley.com/doi/10.1111/j.1939-1676.2003.tb02434.x/pdf
- Berg J, Weinstein MJ, Springfield DS, et al. Results of surgery and doxorubicin chemotherapy in dogs with osteosarcoma. J Am Vet Med Assoc 1995;206:1555–1560. http://europepmc.org/abstract/med/777523
- Chun R, Kurzman ID, Couto CG, et al. Cisplatin and doxorubicin combination chemotherapy for the treatment of canine osteosarcoma: A pilot study. J Vet Intern Med 2000;14:495–498. http://onlinelibrary.wiley.com/doi/10.1111/j.1939-1676.2000.tb02265.x/pdf
- Chun R, Garrett LD, Henry C, et al. Toxicity and efficacy of cisplatin and doxorubicin combination chemotherapy for the treatment of canine osteosarcoma. J Am Anim Hosp Assoc. 2005;41:382–387. http://jaaha.org/doi/abs/10.5326/0410382
- Liptak JM, Dernell WS, Straw RC, et al. Proximal radial and distal humeral osteosarcoma in 12 dogs. J Am Anim Hosp Assoc 2004;40:461–467. http://www.jaaha.org/doi/abs/10.5326/0400461
- McMahon M, Mathie T, Stingle N, et al. Adjuvant carboplatin and gemcitabine combination chemotherapy postamputation in canine appendicular osteosarcoma. J Vet Intern Med2011;25:511–517. http://onlinelibrary.wiley.com/doi/10.1111/j.1939-1676.2011.0697.x/full
- Moore AS, Dernell WS, Ogilvie GK, et al. Doxorubicin and BAY 12-9566 for the treatment of osteosarcoma in dogs: A randomized, double-blind, placebo-controlled study. J Vet InternMed 2007;21:783–790. http://www.researchgate.net/profile/Barbara_Kitchell2/publication/6132345_Doxorubicin_and_BAY_12-9566_for_the_treatment_of_osteosarcoma_in_dogs_a_randomized_double-blind_placebo-controlled_study/links/53f65ada0cf2888a749424b1.pdf
- Shapiro W, Fossum TW, Kitchell BE, et al. Use of cisplatin for treatment of appendicular osteosarcoma in dogs. J Am Vet Med Assoc 1988;192:507–511 http://europepmc.org/abstract/med/3163684
- Kraegel SA, Madewell BR, Simonson E, et al. Osteogenic sarcoma and cisplatin chemotherapy in dogs: 16 cases (1986-1989). J Am Vet Med Assoc 1991;199:1057–1059. http://europepmc.org/abstract/med/1748612
- Mayer M, Grier C. Palliative Radiation Therapy for Canine Osteosarcoma. Canadian Vet Journal 2006. Vol 47; 707-710 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1482437/
A 6-year-old spayed female Great Dane presented to a medical oncologist with a 2-week history of inappetance, intermittent vomiting, fever, and a non-productive cough. Thoracic radiographs by the rDVM showed an area of consolidation in her right caudal lung lobe so she was initially treated on an out-patient basis with subcutaneous fluids and antibiotics. The patient failed to improve, remained febrile, and became almost completely inappetant. Subsequent radiographs show persistence of the consolidated right caudal lung. Abdominal ultrasound and general lab work were unremarkable except for mild hyperglobulinemia and hypoalbuminemia. The consolidated area of lung can be seen peripherally on ultrasound so was aspirated to obtain a diagnosis.
The slides from the consolidated lung were moderately to highly cellular and consisted of few to many red blood cells and a nucleated cell population predominated by individual round to irregularly- shaped cells with an abundant amount of lightly to moderately basophilic cytoplasm that commonly contains many small clear punctate vacuoles. The nuclei are round to irregularly-shaped with a coarsely- to finely-stippled chromatin pattern and 2-4 prominent nucleoli of variable size and shape. Bi- and multinucleation are commonly noted, including many very large multinucleate giant cells. Anisokaryosis and anisocytosis are marked. Mitotic figures are commonly noted. Leukophagocytosis is occasionally noted. The definitive cytologic diagnosis was histiocytic sarcoma. Representative photos are below.
Canine histiocytic tumors are a very complex group of neoplasms that range from the benign cutaneous histiocytoma to the malignant histiocytic sarcoma complex, with several other histiocytic diseases in between. Within the histiocytic sarcoma complex, there is the solitary histiocytic sarcoma which is typically locally or regionally aggressive, and malignant histiocytosis or disseminated histiocytic sarcoma, which metastasizes beyond regional lymph nodes and commonly infiltrates visceral organs such as liver, spleen, and/or bone marrow. Like the cells in this case, the cytomorphology of neoplastic cells from histiocytic sarcomas are distinctive. In comparison to the more common immature large lymphocytes of high-grade lymphoma, malignant histiocytes from histiocytic sarcomas typically exhibit more extreme pleomorphism with more irregularly-shaped nuclei, more extreme anisokaryosis and anisocytosis, and abundant binucleate and multinucleated cells. The cells also typically have more abundant light gray cytoplasm that can contain vacuoles and may also contain phagocytized erythrocytes or leukocytes. In some cases, differentiating between high-grade lymphoma and histiocytic sarcoma can be more challenging, in which cases immunocytochemical (ICC) or immunohistochemical (IHC) markers must be used to obtain a definitive diagnosis.
At this time, the tumor in this patient is localized to the right caudal lung lobe, but the oncologist is worried other sites of disease may be present. The patient has new onset stridor, therefore there is a concern for metastasis to cervical lymph nodes. The patient also has unexplainable GI signs, inappetance and vomiting, which have improved with her treatment; thus concern exists for other sites of metastasis that were not detected via ultrasound. A few days after receiving doxorubicin, Zometa™ (zoledronic acid), and supportive care, the patient is feeling much better and her hypoalbuminemia is improving.
Submitted by Casey J. LeBlanc, DVM, PhD, DACVP of KDL VetPath – June 201
See image legends below.
Lymphoma is one of the most common cancers in both dogs and cats and one of the most commonly treated cancers in veterinary medicine. As a veterinary oncologist, I cannot remember a more exciting time in this field, as there are now some wonderful new therapeutic options available, including monoclonal antibody therapy for both T and B cell lymphoma in dogs.
Antibodies are proteins produced by plasma cells (mature B cells) used by the immune system to identify and neutralize foreign antigens like bacteria, viruses, parasites, and cancer cells. Each antibody recognizes a specific antigen and monoclonal antibodies are identical antibodies that each recognize a single, specific antigen. The scientist who discovered monoclonal antibodies shared the Nobel Prize in Medicine in 1984, signifying how important this discovery was to the world.
The immune system attacks foreign proteins (parasites, viruses, bacteria) in your body, but it doesn’t always recognize cancer cells as foreign. Therapeutic monoclonal antibodies can be directed to attach to certain parts of a cancer cell, and therefore allow the immune system to more easily detect and eliminate the cell. Monoclonal antibodies do this through a variety of mechanisms: activating Antibody Dependent Cellular Cytotoxicity (ADCC); blocking growth factor signaling; stopping new blood vessels from forming; delivering radiation to cancer cells; and delivering chemotherapy to cancer cells
As canine lymphoma is incredibly similar to non-Hodgkin’s lymphoma (NHL) in people, it is helpful to look at the “human” experience with monoclonal antibodies. In the late 1990’s a large group of oncologists tested the various chemotherapy regimens for NHL and found that the standard CHOP regimen was just as good as the other more intense chemotherapy regimens. (see chart #1)
Chart 1. Comparison of a Standard Regimen (CHOP) with Three Intensive Chemotherapy Regimens for Advanced Non-Hodgkin’s Lymphoma:
Fisher RI et al. N Engl J Med 1993;328:1002-1006.
It wasn’t until the development of Rituximab that there was any significant advancement in the treatment of NHL in people (see chart #2). The monoclonal antibody drug rituximab (Rituxan) attaches to a specific protein (CD20) found only on B cells, one type of white blood cell. Certain types of lymphomas arise from these same B cells. When rituximab attaches to this protein on the B cells, it makes the cells more visible to the immune system, which can then attack. Rituximab lowers the number of B cells, including your healthy B cells, but your body produces new healthy B cells to replace these. The cancerous B cells are less likely to recur.
“The most substantial advancement in the treatment of B-cell malignancies, since the advent of combination chemotherapy, has been the addition of the monoclonal anti-CD20 antibody rituximab (Rituxan).” -Pharmacy and Therapeutics 2010 Mar; 35(3): 148–157.
Impact of Rituximab (Rituxan) on the Treatment of B-Cell Non-Hodgkin’s Lymphoma
Chart 2. JCO, Feugier, et al, 2005
The veterinary oncology community has also been testing an anti-CD20 monoclonal antibody, also from Aratana. In the first trial, dogs were treated with either 1 cycle of CHOP along with the anti-CD20 MAb or 1 cycle of CHOP alone. The results are quite impressive (see chart #3) in that the median progression free survival times and the median overall survival times of the dogs treated with MAbs were 167 and 325 days, respectively, compared to 93.5 and 177 days for the placebo arm. In the second trial dogs were treated with either single agent doxorubicin and the anti-CD20 MAb or single agent doxorubicin alone. The number of dogs achieving a complete remission was greater in the group receiving the MAb than in the group receiving doxorubicin alone.
Monoclonal antibody therapy for T cell lymphomas in dogs is also available. T cell lymphomas are typically more aggressive than the B cell lymphomas in both dogs and people. There are however, indolent forms of T cell lymphoma that dogs can survive with for years. Not all T cell lymphoma are “terrible”. For those T cell lymphomas that are not indolent, the response to chemotherapy alone is not robust. In people, the addition of monoclonal antibodies to chemotherapy for T cell lymphomas has increased survival times and response rates. Clinical responses to the anti-CD52 antibody, alemtuzamab, were observed in over 33% of people with chemotherapy-refractory or relapsed peripheral T cell lymphoma. The canine (“caninized”) monoclonal anti-CD52 antibody developed by Aratana was granted a conditional license in Jan 2014. Since that time there have been 3 clinical programs involving the antibody—T-CHOMP, T-LAB and T-CEP.
T-CHOMP was a clinical study evaluating the anti-CD52 antibody in conjunction with a multi-agent chemotherapy protocol. T-LAB is the clinical trial in which the monoclonal therapy is used in addition to a short protocol involving single agent CCNU. Final results regarding the efficacy of the drug has not been published, but in our experience, the drug was well tolerated and safe. The T-CEP or Clinical Experience Program is the third piece in this program. This program is designed to determine in what scenario or scenarios this therapy is most effective—at the start of chemotherapy, after chemotherapy, when the pet has achieved minimal residual disease status, as maintenance therapy or as induction therapy.
The fact that monoclonal antibody therapy for canine lymphoma is now available is hugely important to veterinarians and pet owners alike.
Gerald Post, DVM, MEM, DACVIM (Oncology)
For more information about monoclonal antibody clinical trials and treatment options at Hope VS, please visit HERE