Incidence and Risk Factors

Primary hepatic tumors are uncommon and account for less than 1.5% of all canine tumors and 1.0% to 2.9% of all feline tumors, but up to 6.9% of nonhematopoietic tumors in cats.^1-4 Metastasis to the liver from nonhepatic neoplasia is more common and occurs 2.5 times more frequently than primary liver tumors in dogs, particularly from primary cancer of the spleen, pancreas, and GI tract.^1,2 Primary hepatobiliary tumors are more common than metastatic disease in cats.⁴ The liver can also be involved in other malignant processes, such as lymphoma, malignant histiocytosis, and systemic mastocytosis.^2,3 Nodular hyperplasia is a relatively common diagnosis in older dogs but is benign and probably does not represent a preneoplastic lesion.⁴

There are four basic categories of primary malignant hepatobiliary tumors in cats and dogs: hepatocellular, bile duct, neuroendocrine (or carcinoid), and mesenchymal.⁴ Malignant tumors are more common in dogs, whereas benign tumors occur more frequently in cats.^2-8 There are three morphologic types of these primary hepatic tumors: massive, nodular, and diffuse (Table 22-7).⁵ Massive liver tumors are defined as a large, solitary mass confined to a single liver lobe (Figure 22-14); nodular tumors are multifocal and involve several liver lobes (Figure 22-15); and diffuse involvement may represent the final spectrum of neoplastic disease with multifocal or coalescing nodules in all liver lobes or diffuse effacement of the hepatic parenchyma (Figure 22-16).^4,5

The prognosis for cats and dogs with liver tumors is determined by histology and morphology. The prognosis is good for massive hepatocellular carcinoma (HCC) and benign tumors because complete surgical resection is possible and their biologic behavior is relatively nonaggressive.^7-11 In contrast, the prognosis is poor for cats with any type of malignant tumor, dogs with malignant tumors other than massive HCC, and cats and dogs with nodular and diffuse liver tumors because metastasis is more common.^2-14

Pathology and Natural Behavior

History and Clinical Signs

Hepatobiliary tumors are symptomatic in approximately 50% of cats and 75% of dogs, especially in animals with malignant tumors.^1-15 The most common presenting signs are nonspecific, such as inappetence, weight loss, lethargy, vomiting, polydipsia-polyuria, and ascites.^1-15 Weakness, ataxia, and seizures are uncommon and may be caused by hepatic encephalopathy, paraneoplastic hypoglycemia, or central nervous system metastasis.^5,9,32 Icterus is more common in dogs with extrahepatic bile duct carcinomas and diffuse neuroendocrine tumors.^2,5,12 Hemoperitoneum secondary to rupture of massive HCC has been reported in two dogs.³³ However, these symptoms rarely assist in differentiating primary and metastatic liver tumors from nonneoplastic hepatic diseases.³ Physical examination findings can be equally unrewarding. A cranial abdominal mass is palpable in up to three-quarters of cats and dogs with liver tumors, although palpation can be misleading because hepatic enlargement may be either absent in nodular and diffuse forms of liver tumors or missed due to the location of the liver in the cranial abdominal cavity deep to the costal arch.^1-15

Diagnostic Techniques and Work-Up

Therapy and Prognosis

Comparative Aspects

Hepatocellular carcinoma is one of the most common malignancies in humans as a result of viral infections with hepatitis viruses B and C and cirrhosis induced by alcohol consumption and other disease.¹⁶ A number of paraneoplastic syndromes have been described including hypoglycemia, erythrocytosis, and hypercalcemia.¹⁶ Ultrasonography is considered a good screening imaging modality, but advanced imaging with contrast-enhanced CT or MRI is preferred to determine the location, size, and extent of hepatic lesions.¹⁶ Other tests include serum α-fetoprotein, serologic tests for hepatitis B and C viruses, and histologic confirmation with core liver biopsies.¹⁶ Unlike HCC in dogs, the morphology of HCC in humans is often nodular or diffuse, which makes definitive treatment more problematic. Treatment options depend on the stage of disease and include surgery (e.g., liver lobectomy and liver transplantation), local ablative therapies (e.g., cryosurgery, ethanol or acetic acid injection, and microwave or radiofrequency ablation), regional therapies (e.g., transarterial chemotherapy, embolization, chemoembolization, or RT), and systemic treatment with chemotherapy or immunotherapy.¹⁶ Response rates to single- and multiple-agent chemotherapy protocols are less than 25%, and chemotherapy is no longer recommended for human patients with HCC.¹⁶

Bile duct carcinomas are rare and, similar to cats and dogs, often associated with a poor prognosis.²⁶ Risk factors include primary sclerosing cholangitis, the liver flukes Opisthorchis viverrini and Clonorchis sinensis in endemic areas of Southeast Asia and China, and cholelithiasis.²⁶ Surgical resection is preferred but, because of the high rate of local or regional recurrence, adjuvant treatment with RT or chemotherapy is recommended.²⁶ However, because of the rarity of this tumor, studies supporting the efficacy of these adjuvant treatments are lacking. Papillary histology, extrahepatic location, and complete resection are favorable prognostic factors in humans with bile duct carcinomas.⁶⁷

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3. Hammer, AS, Sikkema, DA. Hepatic neoplasia in the dog and cat. Vet Clin North Am Small Anim Pract. 1995;25:419.

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5. Patnaik, AK, Hurvitz, AI, Lieberman, PH. Canine hepatic neoplasms: a clinicopathological study. Vet Pathol. 1980;17:553.

6. Patnaik, AK. A morphologic and immunohistochemical study of hepatic neoplasms in cats. Vet Pathol. 1992;29:405.

7. Post, G, Patnaik, AK. Nonhematopoietic hepatic neoplasms in cats: 21 cases (1983-1988). J Am Vet Med Assoc. 1992;201:1080.

8. Lawrence, HJ, Erb, HN, Harvey, HJ. Nonlymphomatous hepatobiliary masses in cats: 41 cases (1972 to 1991). Vet Surg. 1994;23:365.

9. Patnaik, AK, Hurvitz, AI, Lieberman, PH, et al. Canine hepatocellular carcinoma. Vet Pathol. 1981;18:427.

10. Kosovsky, JE, Manfra-Marretta, S, Matthiesen, DT, et al. Results of partial hepatectomy in 18 dogs with hepatocellular carcinoma. J Am Anim Hosp Assoc. 1989;25:203.

11. Liptak, JM, Dernell, WS, Monnet, E, et al. Massive hepatocellular carcinoma in dogs: 48 cases (1992-2002). J Am Vet Med Assoc. 2004;225:1225.

12. Patnaik, AK, Hurvitz, AI, Lieberman, PH, et al. Canine bile duct carcinoma. Vet Pathol. 1981;18:439.

13. Hayes, HM, Morin, MM, Rubenstein, DA. Canine biliary carcinoma: epidemiological comparisons with man. J Comp Pathol. 1983;93:99.

14. Patnaik, AK, Lieberman, PH, Hurvitz, AI, et al. Canine hepatic carcinoids. Vet Pathol. 1981;18:439.

15. Shiga, A, Shirota, K, Shida, T, et al. Hepatoblastoma in a dog. J Vet Med Sci. 1997;59:1167.

16. Bartlett, DL, Carr, BI, Marsh, JW. Cancer of the liver. In: DeVita VT, Hellman S, Rosenberg SA, eds. Cancer: principles and practice of oncology. Philadelphia: Lippincott Williams & Wilkins, 2005.

17. Evans, SM. The radiographic appearance of primary liver neoplasia in dogs. Vet Radiol. 1987;28:192.

18. Adler, R, Wilson, DW. Biliary cystadenomas of cats. Vet Pathol. 1995;32:415.

19. Trout, NJ, Berg, J, McMillan, MC, et al. Surgical treatment of hepatobiliary cystadenomas in cats: five cases (1988-1993). J Am Vet Med Assoc. 1995;206:505.

20. Nyland, TG, Koblik, PD, Tellyer, SE. Ultrasonographic evaluation of biliary cystadenomas in cats. Vet Radiol Ultrasound. 1999;40:300.

21. Willard, MD, Dunstan, RW, Faulkner, J. Neuroendocrine carcinoma of the gall bladder in a dog. J Am Vet Med Assoc. 1988;192:926.

22. Morrell, CN, Volk, MV, Mankowski, JL. A carcinoid tumor in the gallbladder of a dog. Vet Pathol. 2002;39:756.

23. Trigo, FJ, Thompson, H, Breeze, RG, et al. The pathology of liver tumors in the dog. J Comp Pathol. 1982;92:21.

24. Kapatkin, AS, Mullen, HS, Matthiesen, DT, et al. Leiomyosarcoma in dogs: 44 cases (1983-1988). J Am Vet Med Assoc. 1992;201:1077.

25. Patnaik, AK, Lieberman, PH, Erlandson, RA, et al. Hepatobiliary neuroendocrine carcinoma in cats: a clinicopathologic, immunohistochemical, and ultrastructural study of 17 cases. Vet Pathol. 2005;42:331.

26. Bartlett, DL, Ramanathan, RK, Deutsch, M. Cancer of the biliary tree. In DeVita VT, Hellman S, Rosenberg SA, eds.: Cancer: principles and practice of oncology, ed 7, Philadelphia: Lippincott Williams & Wilkins, 2005.

27. Scavelli, TD, Patnaik, AK, Mehlhaff, CJ, et al. Hemangiosarcoma in the cat: retrospective evaluation of 31 surgical cases. J Am Vet Med Assoc. 1985;187:817–819.

28. Brown, NO, Patnaik, AK, MacEwen, EG. Canine hemangiosarcoma: retrospective analysis of 104 cases. J Am Vet Med Assoc. 1985;186:56–58.

29. Srebernik, N, Appleby, EC. Breed prevalence and sites of haemangioma and haemangiosarcoma in dogs. Vet Rec. 1991;129:408–409.

30. Affolter, VK, Moore, PF. Canine cutaneous and systemic histiocytosis: reactive histiocytosis of dermal dendritic cells. Am J Dermatopathol. 2000;22:40.

31. Affolter, VK, Moore, PF. Localized and disseminated histiocytic sarcoma of dendritic cell origin in dogs. Vet Pathol. 2002;39:74.

32. Leifer, CE, Peterson, ME, Matus, RE, et al. Hypoglycemia associated with nonislet cell tumor in 13 dogs. J Am Vet Med Assoc. 1985;186:53.

33. Arohnson, MG, Dubiel, B, Roberts, B, et al. Prognosis for acute nontraumatic hemoperitoneum in the dog: a retrospective analysis of 60 cases (2003-2006). J Am Anim Hosp Assoc. 2009;45:72.

34. Rogers, KS. Anemia. In Ettinger SJ, Feldman EC, eds.: Textbook of veterinary internal medicine, ed 5, Philadelphia: WB Saunders, 2000.

35. Helfand, SC. Platelets and neoplasia. Vet Clin North Am Small Anim Pract. 1988;18:131.

36. Baatout, S. Interleukin-6 and megakaryocytopoiesis: an update. Ann Hematol. 1996;73:157.

37. Jelkmann, W. The role of the liver in the production of thrombopoietin compared with erythropoietin. Eur J Gastroenterol Hepatol. 2001;13:791.

38. Badylak, SF, Dodds, WJ, van Vleet, JF. Plasma coagulation factor abnormalities in dogs with naturally occurring hepatic disease. Am J Vet Res. 1983;44:2336.

39. McConnell, MF, Lumsden, JH. Biochemical evaluation of metastatic liver disease in the dog. J Am Anim Hosp Assoc. 1983;19:173.

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41. Center, SA, Slater, MR, Manwarren, T, et al. Diagnostic efficacy of serum alkaline phosphatase and γ-glutamyltransferase in dogs with histologically confirmed hepatobiliary disease: 270 cases (1980-1990). J Am Vet Med Assoc. 1992;201:1258.

42. Lowseth, LA, Gillett, NA, Chang, IY, et al. Detection of serum α-fetoprotein in dogs with hepatic tumors. J Am Vet Med Assoc. 1991;199:735.

43. Yamada, T, Fujita, M, Kitao, S, et al. Serum alpha-fetoprotein values in dogs with various hepatic diseases. J Vet Med Sci. 1999;61:657.

44. Hahn, KA, Richardson, RC. Detection of serum alpha-fetoprotein in dogs with naturally occurring malignant neoplasia. Vet Clin Pathol. 1995;24:18.

45. Friedrichs, KR, Thomas, C, Plier, M, et al. Evaluation of serum ferritin as a tumor marker for canine histiocytic sarcoma. J Vet Intern Med. 2010;24:904.

46. Feeney, DA, Johnston, GR, Hardy, RM. Two-dimensional, gray-scale ultrasonography for assessment of hepatic and splenic neoplasia in the dog and cat. J Am Vet Med Assoc. 1984;184:68.

47. Vörös, K, Vrabély, T, Papp, L, et al. Correlation of ultrasonographic and pathomorphological findings in canine hepatic diseases. J Small Anim Pract. 1991;32:627.

48. Newell, SM, Selcer, BA, Girard, E, et al. Correlations between ultrasonographic findings and specific hepatic disease in cats: 72 cases (1985-1997). J Am Vet Med Assoc. 1998;213:94.

49. Leveille, R, Partington, BP, Biller, DS, et al. Complications after ultrasound-guided biopsy of abdominal structures in dogs and cats: 246 cases (1984-1991). J Am Vet Med Assoc. 1993;203:413.

50. Barr, F. Percutaneous biopsy of abdominal organs under ultrasound guidance. J Small Anim Pract. 1995;36:105.

51. O’Brien, RT, Iani, M, Matheson, J, et al. Contrast harmonic ultrasound of spontaneous liver nodules in 32 dogs. Vet Radiol Ultrasound. 2004;45:547.

52. Kutara, K, Asano, K, Kito, A, et al. Contrast harmonic imaging of canine hepatic tumors. J Vet Med Sci. 2006;68:433.

53. Nakamura, K, Takagi, S, Sasaki, N, et al. Contrast-enhanced ultrasonography for characterization of canine focal liver lesions. Vet Radiol Ultrasound. 2010;51:79.

54. Roth, L. Comparison of liver cytology and biopsy diagnoses in dogs and cats: 56 cases. Vet Clin Pathol. 2001;30:35.

55. D’Angelica, M, Fong, Y, Weber, S, et al. The role of staging laparoscopy in hepatobiliary malignancy: prospective analysis of 401 cases. Ann Surg Oncol. 2003;10:183.

56. Cuccovillo, A, Lamb, CR. Cellular features of sonographic target lesions of the liver and spleen in 21 dogs and a cat. Vet Radiol Ultrasound. 2002;43:275.

57. Stowater, JL, Lamb, CR, Schelling, SH. Ultrasonographic features of canine hepatic nodular hyperplasia. Vet Radiol. 1990;31:268.

58. Martin, RA, Lanz, OI, Tobias, KM. Liver and biliary system. In Slatter DH, ed.: Textbook of small animal surgery, ed 3, Philadelphia: WB Saunders, 2003.

59. Covey, JL, Degner, DA, Jackson, AH, et al. Hilar liver resection in dogs. Vet Surg. 2009;38:104.

60. Seki, M, Asano, K, Ishigaki, K, et al. En block resection of a large hepatocellular carcinoma involving the caudal vena cava in a dog. J Vet Med Sci. 2011;73(5):693–696.

61. Weisse, C, Clifford, CA, Holt, D, et al. Percutaneous arterial embolization and chemoembolization for treatment of benign and malignant tumors in three dogs and a goat. J Am Vet Med Assoc. 2002;221:1430.

62. Cave, TA, Johnson, V, Beths, T, et al. Treatment of unresectable hepatocellular adenoma in dogs with transarterial iodized oil and chemotherapy with and without an embolic agent: a report of two cases. Vet Comp Oncol. 2003;1:191.

63. Elpiner, A, Brodsky, E, Hazzah, T, et al. Single agent gemcitabine chemotherapy in dogs with hepatocellular carcinoma. Vet Comp Oncol. 2011;9(4):260–268.

64. Fry, PD, Rest, JR. Partial hepatectomy in two dogs. J Small Anim Pract. 1993;34:192.

65. Ogilvie, GK, Powers, BE, Mallinckrodt, CH, et al. Surgery and doxorubicin in dogs with hemangiosarcoma. J Vet Intern Med. 1996;10:379.

66. Rassnick, KM, Frimberger, AE, Wood, CA, et al. Evaluation of ifosfamide for treatment of various canine neoplasms. J Vet Intern Med. 2000;14:271.

67. Chung, C, Bautista, N, O’Connell, TX. Prognosis and treatment of bile duct carcinoma. Am Surg. 1998;64:921.

Incidence and Risk Factors

Reports vary, but overall intestinal tumors are rare in dogs and cats.^1-3 In a survey of insured dogs in the United Kingdom, a standardized incidence rate of 210/100,000 dogs was reported for alimentary tumors. This accounted for 8% of all tumor submissions.⁴ Incidence of feline digestive neoplasia in a South African survey comprised 13.5% of all tumors, which likely included oral tumors.⁵ In the United States, a query of over 300,000 cat submissions to the Veterinary Medical Database (VMDB) found 8% to relate to cancer and less than 1% (13% of the cancer cases) to be intestinal neoplasia.⁶ Less than 1% of over 10,000 dogs submitted for necropsy at one institution were diagnosed with intestinal adenocarcinoma, which agrees with other reports.^2,7,8 Regarding specific tumor types, lymphoma comprises nearly 30% of all feline tumors and 6% of all canine tumors and is the most common intestinal tumor in most reports.^2,9-11 Adenocarcinoma is the second most frequent tumor in both species, with mast cell tumors in cats and leiomyosarcomas or GISTs in dogs next.

As with many cancers, incidence of intestinal neoplasia increases in older dogs and cats. Mean ages of affected cats for small and large intestinal neoplasia generally range between 10 and 12 years, and increasing risk after age 7 has been reported.^2,6,12-20 Dogs are also usually middle aged or older, with mean ages most often between 6 and 9 years, possibly older (12 years) for dogs with leiomyosarcoma.^11,21-24 Some earlier studies of feline lymphoma report younger median ages, most likely a result of a larger percentage of FeLV-positive cats in the study population.^25,26

There is a slight sex predilection for males to develop intestinal tumors in some studies for both dogs and cats. Many studies report a near equal incidence among male and female dogs,^24,27-29 although one study did find 76% of dogs with intestinal adenocarcinoma to be male.³⁰ Males also appear overrepresented in smooth muscle tumors, comprising 82% of GI leiomyomas³¹ and 76% of dogs with leiomyosarcoma.²³ Additionally, 90% of dogs with GI lymphoma were male.²² Furthermore, there is a slight male predominance in nonlymphomatous small intestinal tumors in dogs.^11,32,33

In cats, there also is a predominance of males in some studies,^17,34 with males equaling or only slightly exceeding females in others,* although three of four cats with large granular lymphoma were female.¹⁴

Siamese cats are 1.8 times more likely to develop intestinal neoplasia.⁶ Siamese cats are overrepresented in studies of intestinal adenocarcinoma, up to eight times greater than other breeds, suggesting a predisposition for this disease.^2,6,15,32,38 Although small numbers of Siamese cats are included in many series of feline intestinal lymphoma, one study did show a significant overrepresentation.¹³ Otherwise, there is no breed predilection for intestinal lymphoma in cats.

In dogs, few studies of intestinal neoplasia report an overrepresentation of specific breeds. Large breed dogs in general constituted most cases in a series of smooth muscle tumors.²⁸ Collies and German shepherd dogs are overrepresented in some reports for intestinal tumors, especially adenocarcinoma and rectal carcinoma and polyps.^21,39 It is interesting to note, however, that in 104 benign and malignant tumors diagnosed in a cohort of military working dogs (German shepherd dogs and Belgian Malinois), only one (a leiomyosarcoma) was intestinal.⁴⁰ Mast cell tumors have been reported primarily in Maltese, among other miniature breeds. Although these reports came from Japan where small breeds are popular, over 50% of reported cases in two series were in Maltese dogs, with a male predominance.^41,42

With the exception of retroviral influence on the development of feline lymphoma, there are no known etiologic organisms or chemical agents that reliably contribute to the development of spontaneously occurring intestinal neoplasia in dogs and cats. There is a known association of FeLV and feline immunodeficiency virus (FIV) with feline lymphoma. Older cats with intestinal lymphoma are usually negative for FeLV on serology, although evaluation of feline intestinal lymphoma by polymerase chain reaction (PCR) for the long terminal repeat region and immunohistochemistry (IHC) for gp70 antigen has shown some tumors to be positive for viral DNA, even when seronegative for FeLV p27 antigen. For intestinal lymphoma, PCR was more often positive than IHC.^43,44 These results suggest FeLV exposure in the development of lymphoma in some cats serologically negative for FeLV, and they support PCR as the most useful of these tests for identifying possible occult, latent, replication-deficient, or partial genome virus infection in tissue. With younger cats more often IHC positive and IHC correlating well with seropositivity, PCR may identify cats with lymphoma that have been exposed to FeLV but are seronegative.⁴³ There is no association between retroviral infection and nonlymphomatous intestinal neoplasia in cats, with most cats testing negative for FeLV and/or FIV serologically.^15,32

In other species, type-A retrovirus particles have been found in a metastatic intestinal adenocarcinoma in a boa, and cytomegalovirus has been associated with GI epithelial masses in macaque monkeys infected with simian immunodeficiency virus.^45,46

Helicobacter pylori infection is associated with increased risk of gastric cancer in humans, although no such association has been confirmed in domestic animals. Concurrent lymphoma and Helicobacter infection has been reported in a cat, but causal association was not proved.⁴⁷ Multiple gastroduodenal adenocarcinomas and a rectal adenoma were found in a cougar with concurrent Helicobacter-like organisms and spirochetes.⁴⁸ Some cats shed Helicobacter species in the feces and thus may represent normal flora rather than pathogens.⁴⁹

Finally, lymphoma (although not specifically intestinal) has been reported in a dog 4 weeks after initiation of cyclosporine and ketoconazole therapy for anal furunculosis.⁵⁰ There is an association between cyclosporine use in human transplant patients and the development of lymphoma.

Pathology and Natural Behavior

Epithelial, mesenchymal, neuroendocrine, and discrete/round cell neoplasias can all be found in the intestinal tract. In both cats and dogs, lymphoma is the most common type of small intestinal neoplasia, followed by adenocarcinoma. Subtypes of feline intestinal lymphoma include lymphocytic, lymphoblastic, epitheliotropic, and large granular lymphocyte (LGL) types. Because of advances in novel targeted receptor tyrosine kinase inhibitors (TKIs) in human medicine, characteristics of GISTs have also been reported in dogs. Other tumors include leiomyosarcoma in both dogs and cats, carcinoids in dogs, and mast cell tumors in cats. There are scattered case reports of uncommon tumors, such as extramedullary plasmacytoma, extraskeletal osteosarcoma, and hemangiosarcoma. Although most small intestinal neoplasia is malignant in dogs, most rectal tumors are benign polyps, adenomas, or carcinoma in situ^29,51 (Figure 22-22).

Most alimentary adenocarcinoma in cats is found in the small intestine.^1,30,37 However, the colon and rectum are a more common site in dogs.^7,8 Of colorectal adenocarcinomas, the rectum is a more common site than the colon.⁵² The cecum is more likely to develop leiomyosarcoma or GIST than adenocarcinoma.^8,23 Histologic descriptors for carcinoma of the intestine include adeno- (forming glands), mucinous (>50% mucin), signet ring (>50% of cells have intracellular mucin), and undifferentiated or solid (no evidence of gland formation).⁷ Grossly, colorectal adenocarcinomas may demonstrate a pedunculated (especially in the distal rectum), cobblestone (middle rectum), or annular (middle rectum) appearance, which may relate to behavior and prognosis^8,52,53 (Figure 22-23).

Adenomatous polyps are found in the rectum of dogs, and carcinoma in situ is found in both the colon and rectum. Most lesions are solitary, although multiple and diffuse lesions can be seen and are associated with increased recurrence rates.²⁹ In cats, polyps are more common in the duodenum.

The term carcinoid refers to tumors that arise from the diffuse endocrine system rather than the intestinal epithelium, despite histologic similarity to carcinomas. Carcinoid cells arise from enterochromaffin cells of the intestinal mucosa and contain secretory granules that may contain substances such as 5-hydroxytryptamine (serotonin), secretin, somatostatin, and gastrin, among others.⁷ IHC for cytokeratin and for secretory substances such as serotonin may be positive, and serum concentration of serotonin has been documented at 10 times the normal range in one dog with a carcinoid.⁵⁴ Described in many species, carcinoids may occur in both the large and the small intestines and frequently metastasize to the liver.^2,8,54 Carcinoids may follow an aggressive and debilitating clinical course.⁵⁴

GISTs are well documented in humans and have been reported in dogs.⁵⁵ These nonlymphoid tumors of mesenchymal origin were originally diagnosed as leiomyosarcomas and some but not all were leiomyomas. Histologically, GISTs are highly cellular mesenchymal tumors that do not show ultrastructural characteristics consistent with smooth muscle differentiation. GISTs are thought to arise from multipotential stem cells phenotypically similar to interstitial cells of Cajal, driven by activating mutations of Kit. These cells regulate intestinal motility via an autonomic pacemaker effect. Although these cells can differentiate into smooth muscle cells if deprived of Kit, GISTs are a discrete clinical entity from leiomyosarcoma.⁵⁶ GISTs are distinguished by high vimentin immunoreactivity, low alpha smooth muscle actin reactivity, CD117 (Kit) reactivity, and a site predilection for the large intestine (compared to the stomach for leiomyoma).^31,57 Activating mutations were identified in Kit exon 11 encoding the juxtamembrane domain in two of four cases examined.³¹ CD117 reactivity is considered a major diagnostic criteria and in many studies is used to distinguish GISTs from leiomyosarcomas.^58,59 When stratified as such, 28 of 42 leiomyosarcomas in dogs were reclassified as GISTs and only 2 of the 28 cases of GIST metastasized (7%). These investigators also found that GISTs were significantly more likely to occur in the large intestine, specifically the cecum, and leiomyosarcomas in the stomach and small intestine.⁵⁸ Considering these findings, the incidence of true leiomyosarcoma is likely low because many previously reported cases may have actually been GISTs. Leiomyomas occur more commonly in the stomach but have also been reported in the esophagus, small intestine, and colorectum.³¹

Intestinal lymphoma in dogs occurs in the stomach and small intestine equally and more often in both of these sites than the large intestine. Lesions are typically diffuse, and neoplastic cells infiltrate the submucosa and lamina propria. Additional visceral and systemic involvement may be seen.

Intestinal lymphoma in cats was originally thought to be predominantly of B-cell origin, resulting from its origin in Peyer’s patches and germinal centers; however, some reports suggest that the incidence of T-cell lymphoma may equal or exceed that of B-cell lymphoma.^20,34,44 IHC and PCR for antigen receptor rearrangement (PARR) can be useful in identifying predominant immunophenotype and clonality, as well as distinguishing lymphoma from severe inflammation.^60,61 There is no clear association between the presence of FeLV antigens in tissue and clonality (B-cell versus T-cell).⁴⁴ Incidence of feline intestinal lymphoma appears to have increased over the past 2 decades to an extent that may exceed that attributed to an aging cat population.⁶² Within a diagnosis of intestinal lymphoma, subtype also impacts behavior. In one series, cats with lymphocytic/small cell lymphoma experienced a 69% complete remission rate with prednisone and chlorambucil for a MST of nearly 2 years, whereas cats with lymphoblastic lymphoma had only an 18% complete remission rate with combination chemotherapy for a MST of less than 3 months. Cats with lymphoblastic lymphoma were more likely to have a palpable abdominal mass and require surgery for intestinal obstruction than cats with lymphocytic lymphoma.³⁵

Other unique subsets of feline intestinal lymphoma include epitheliotropic and LGL lymphoma. Most of these cats are serologically negative for FeLV. Immunohistochemical evaluation of feline epitheliotropic lymphoma shows these tumors to be strictly T-cell in origin and 80% small/lymphocytic.^34,63 In one study, although great overlap of values occurred, there was a significantly greater percentage of intraepithelial lymphocytes in neoplastic compared to normal cats and inflammatory bowel disease cases. The determination of epitheliotropism depends on the pathologist’s interpretation. As with epitheliotropic cutaneous lymphoma, microabscesses are often seen. Intraepithelial lymphocytes are richer in villous than crypt epithelium, suggesting that this diagnosis may be reliably made with endoscopic biopsies. This disease may represent a continuum from inflammatory bowel disease.³⁴

By contrast, LGL lymphoma of the intestine (also called globule leukocyte and granulated round cell tumor) often has a rapidly progressive and fatal course.^64,65 These tumors are distinguished by heterogeneous cytoplasmic granules (azurophilic on cytology and eosinophilic on histopathology with routine hematoxylin and eosin [H&E] staining) and are commonly seen in the intestinal tract (especially jejunum), occasionally with leukemic cells.^66,67 Perforin-like immunoreactivity has been demonstrated and may help distinguish these from other lymphomas.¹⁴

Extramedullary plasmacytoma (EMP) refers to solitary tumors with no evidence of systemic multiple myeloma. Case reports of GI EMP in dogs and cats exist, though uncommon. In one series, one-fourth of EMPs were found in the digestive system, most in the mouth.⁶⁸ One case report in a dog with EMP of the colon and rectum was associated with monoclonal gammopathy.⁶⁹ Another uncommon tumor type is extraskeletal osteosarcoma, which has been reported in the duodenum of a cat. This cat had no evidence of metastasis at diagnosis but did well for only 4 months after surgery when clinical signs recurred and the cat died.⁷⁰ Three of 55 extraskeletal and 145 total cases of feline osteosarcoma were of intestinal origin.⁷¹ A series of four cats was reported with intestinal hemangiosarcoma arising from four different locations within the intestines, with none surviving greater than 1 week.⁷² Finally, one dog was diagnosed with ganglioneuroma of the rectum and experienced long-term survival following surgical resection.⁷³

Intestinal mast cell tumors are cited as the third most common tumor following lymphoma and adenocarcinoma in cats, but incidence and behavior are poorly reported. They have been confused with carcinoids but are distinct.¹² They may present as an eosinophilic enteritis, and conversely, eosinophilic enteritis may mimic intestinal tumors.^74,75 Intestinal sclerosing mast cell tumor in the cat is a potentially aggressive variant characterized by moderate-to-abundant dense stromal tissue, marked eosinophilic infiltrates, and some cases with tryptase and c-kit immunoreactivity. Ultrasonographic changes were transmural, and tumors were most commonly located in the small intestine. Outcome was reported for 25 of 50 cats, and survival was less than 2 months for 23/25; however, outcome was unknown for the remaining 25 cats.⁷⁶ In dogs, intestinal mast cell tumors occur primarily in the stomach and small intestine, are typically poorly granulated, and are often immunohistochemically positive for toluidine blue, c-kit, and tryptase. Mucosal mast cells may be structurally distinct from cutaneous mast cells.⁴¹

When tumors of the GI system metastasize, sites of predilection in decreasing frequency include mesenteric lymph nodes (especially adenocarcinoma), liver (especially leiomyosarcoma), mesentery, omentum, spleen, kidney, bone, peritoneum/carcinomatosis, and lung.^11,32,37,53 Interestingly, metastasis from intestinal adenocarcinoma was discovered in three dogs initially presented for testicular masses.⁷⁷ One dog was presented for multiple cutaneous masses that suggested round cell or epithelial malignancy on cytology but for which IHC confirmed epithelial origin. A primary small intestinal adenocarcinoma with additional visceral metastasis was identified at necropsy.⁷⁸ Lymphoma is often a systemic disease, and one-fourth of dogs and four-fifths of cats with GI lymphoma will have concurrent involvement of other organs.^13,22

History and Clinical Signs

The duration of clinical signs prior to presentation typically averages 6 to 8 weeks but can range from less than 1 day to several months.^11,22,23 Clinical signs include (in varying order of frequency): weight loss, diarrhea, vomiting, and anorexia and less frequently melena, anemia, and hypoglycemia (with smooth muscle tumors).* Clinical signs often relate to location of the tumor within the GI tract. Proximal lesions more commonly result in vomiting, small intestinal lesions in weight loss, and large bowel lesions in hematochezia and tenesmus.^30,32 Although carcinoids may secrete endocrine substances, clinical signs do not always reflect hypersecretion.⁷ Dogs and cats may present with clinical signs relating to intestinal obstruction, such as anorexia, weight loss, and vomiting. Although uncommon, perforation and septic peritonitis can occur.³⁴ Smooth muscle tumors are located within the muscular layer of the intestines and not within the lumen and evidence of GI bleeding is often absent, but anemia and melena have been reported.^23,24

Diagnostic Techniques and Work-Up

Therapy and Prognosis

Prognostic Factors

Intestinal perforation does not appear to be a negative prognostic factor for leiomyosarcoma because dogs surviving the perioperative period enjoyed prolonged survival in one series.²³ For colorectal tumors, treatment is prognostic with local excision significantly better than palliative care. Gross appearance, although not statistically examined, may determine outcome because dogs with annular, obstructing masses survived a mean of 1.6 months; nodular or cobblestone masses 12 months; and single, pedunculated masses 32 months.⁵²

For nonlymphomatous small intestinal tumors in dogs, metastasis at the time of surgery resulted in significantly shorter survival times (3 months versus 15 months). One-year survival for dogs with lymph node metastasis was 20% as compared to 67% without.¹¹ In another study, however, dogs with and without visceral metastasis from leiomyosarcoma survived equally long following surgical resection (21 months).²³ In one study, males fared significantly better than females for small intestinal adenocarcinoma, although the number of females was small.³⁰

The strongest prognostic factor for cats with intestinal lymphoma is response to treatment. Cats achieving a complete resolution of clinical signs typically fare significantly better than those that do not.^20,118 For cats with epitheliotropic lymphoma, those that did not achieve remission (euthanized within 3.5 months) had a worse survival than those that achieved remission (median 11 months).³⁴ For 103 cats with lymphoma, 28 of which were intestinal, negative prognostic factors were FeLV positivity (median survival 3 months if positive, 17 months if negative for early stage disease, not prognostic for advanced stages) and advanced stage of disease.²⁶ FeLV status did not affect outcome in other studies.^20,25 For large intestinal neoplasia, cats with surgery for lymphoma fared equally poorly with and without adjuvant chemotherapy (median survival of just over 3 months in both groups). Cats with adenocarcinoma, however, survived significantly longer if they were treated with subtotal colectomy (138 days versus 68 days with mass excision), received postoperative doxorubicin (280 days with versus 56 days without), and had negative lymph nodes at surgery (259 days negative versus 49 days positive).¹⁸

Comparative Aspects

Although cancer of the large intestine and rectum is well characterized in humans, small intestinal neoplasia is rare. Theories for this discrepancy include more rapid small intestinal transit time as compared to the large intestine (creating less contact time for carcinogens), dilution of carcinogens with fluid as compared to solid stool, differences in pH, relative lack of bacteria to allow transformation of procarcinogens, presence of detoxifying enzymes, and increased presence of immunoglobulin A promoting local immunosurveillance of damaged cells as a result of increased lymphocytes in the small intestine. Intake of red meat, salt-cured foods, and fat are associated with an increased risk of small intestinal neoplasia, although tobacco and alcohol use were not.¹¹⁹ This is in contrast to veterinary medicine where in cats and sometimes dogs, malignant neoplasia is more common in the small than the large intestine. This may reflect differences in physiology, diet, or genetics among species. The difference in species may also be a matter of proportion in that humans develop a large number of colorectal cancers as a result of diet and genetic influences. As in animals, tumors of the small intestine of humans are usually malignant. Diagnostic evaluation is similar to that described in animals, although advanced imaging such as CT is more often used. Most diagnoses are made at surgery and 5-year survival rates average just over 20%.¹¹⁹

In contrast to the rarity of small bowel neoplasia, large bowel/colorectal cancer is one of the most frequently diagnosed cancers in both men and women. Risk factors include genetic predisposition/familial history, tobacco and alcohol intake, advanced age, and predisposing medical conditions, among others. Colorectal cancer development may further be influenced by intake of red meat (especially fried), low-fiber and/or high-fat diet, obesity, fecal pH, and fecal mutagens. Among genetic risk factors, polymorphism in colonic enzymes and mutations leading to familial adenomatous syndromes are uncommon but are important as models of carcinogenesis. In most familial polyposis syndromes, the adenomatous polyposis coli (APC) gene is mutated. The multistage progression from benign polyp to carcinoma is well understood and underscores the importance of early detection.¹²⁰ In contrast, hereditary nonpolyposis colon cancer (HNPCC) develops without known premalignant polyps. It is inherited via autosomal dominance with high penetration and is characterized by microsatellite instability.¹²¹

Severe celiac disease in humans is associated with an increased risk of lymphoma. Progression to lymphoma from inflammatory bowel disease (IBD), especially in cats, has been postulated but not confirmed. Two of 97 cats with lymphoma had a history of IBD in a population of cats examined for comparison to a group of cats with IBD at one institution during the same time period.¹²²

The most clinically important aspects of comparative oncology when considering intestinal neoplasia in humans are the use of COX inhibitors in treatment, the prevention of colorectal neoplasia, and the use of TKIs. In people, KIT mutations in GI stromal tumors have led to the use of imatinib mesylate, a TKI that inhibits KIT.¹²³ This illustrates the notion of therapy directed at the molecular defect rather than the histologic diagnosis. KIT is mutated in some canine GISTs, and thus TKIs may benefit this population as well.

COX inhibition by NSAIDs will decrease the incidence of colorectal cancer and decrease mortality by 40% to 50%.¹²⁴ Among the proposed mechanisms of action, prostaglandin production is thought to be related to tumor progression and therefore inhibition leads to cancer prevention. Additionally, non-COX pathways include inhibition of transcription factors and induction of nuclear hormone receptors that lead to cellular differentiation.¹²⁴ Interestingly, a recent retrospective study found a significantly reduced incidence of cancer in dogs with a history of NSAID use (71% reduced risk).¹²⁵

Therapy in humans is similar to that in companion animals. Surgical resection is the primary mode of therapy, with adjuvant targeted or traditional chemotherapy in many cases, especially if patients present with lymph node metastasis or unresectable disease. Transanal endoscopic resection is used when possible for rectal tumors, and this technique has been performed with some success in dogs. TKIs may improve prognosis for unresectable and metastatic GISTs.¹²³ Adjuvant chemotherapy is used in colon cancer, with 5-FU–based combinations providing the best control often in combination with a platinum agent, with some studies showing decreased local recurrence but not increased overall survival.¹²⁶ RT is used primarily for areas of the GI tract that are not very mobile, such as the stomach and rectum.

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119. Coit, DG. Cancer of the small intestine. In DeVita VT, Hellman S, Rosenberg SA, eds.: Cancer: principles and practice of oncology, ed 6, Philadelphia: Lippincott Williams & Wilkins, 2001.

120. Skibber, JM, Minsky, BD, Hoff, PM. Cancer of the colon. In DeVita VT, Hellman S, Rosenberg SA, eds.: Cancer: principles and practice of oncology, ed 6, Philadelphia: Lippincott Williams & Wilkins, 2001.

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Incidence and Risk Factors

Perianal adenomas (circumanal, hepatoid tumors) represent the majority, 58% to 96%, of canine perianal tumors.^1,11 Development and progression of these benign tumors appear to be sex hormone–dependent, with growth stimulated by androgenic hormones and depressed by estrogenic hormones.^1,12,13 The older, intact male is at high risk.^1,11,12 The mean reported age is 10 years.¹¹ A high incidence of associated testicular interstitial cell tumors has been reported for males with adenomas, supporting testosterone production as a cause.¹² However, a true cause-and-effect relationship has not been clarified since interstitial cell tumors are a common incidental finding in non–adenoma-bearing, older intact males. Perianal adenomas in the female occur almost exclusively in ovariohysterectomized animals in which low levels of estrogen do not suppress tumor growth. Rarely, testosterone secretion from the adrenal glands, occasionally accompanied by signs of hyperadrenocorticism, may stimulate perianal adenoma formation in the female.^14,15 Cocker spaniels, beagles, bulldogs, and Samoyeds may be predisposed.^1,12

Perianal adenocarcinoma, a malignant tumor of the perianal glands, occurs much less frequently than its benign counterpart, representing only 3% to 21% of all tumors in this region.^1,11 Average age of affected dogs is 11 years.^11,16 Tumors occur in castrated or intact males, as well as in females, implying no hormonal dependency; however, this does not preclude earlier hormonal initiation.^12,16 Large-breed males appear to be overrepresented.¹⁶

Apocrine gland adenocarcinoma of the anal sacs occurs at relatively low frequency in the dog, representing 17% of perianal malignancies and 2% of all skin and subcutaneous tumors.^11,17 A breed survey of a large cohort of British dogs with anal sac adenocarcinoma suggests that spaniels, in particular English cocker spaniels, are at increased risk.¹⁸ Earlier reports suggested a female predilection^11,19-21; however, approximately equal sex distribution has been shown in multiple larger series.^18,22-24 In male dogs, it has been proposed that neutering may be associated with increased incidence of anal sac apocrine gland adenocarcinoma.¹⁸ The average age of dogs diagnosed with this disease is 9 to 11 years.^{11,19,20,22-26} Dogs as young as 5 years have been reported,^{19,20,23,25,27} suggesting that evaluation of the perineum and palpation of the anal sacs should be a routine part of the physical examination in every adult dog.²³ Benign tumors of the anal sac are very rare.

Anal gland apocrine gland adenocarcinoma occurs rarely in the cat, representing 0.5% of all feline skin and subcutaneous neoplasms.⁷ Median age of affected cats is 12 years, although animals as young as 6 years have been reported.^7,10 Siamese cats may be at higher risk.⁷

Pathology and Natural Behavior

Almost any tumor can occasionally affect the perianal region, including lymphoma, soft tissue sarcoma, SCC, melanoma, leiomyoma, transmissible venereal tumor, and mast cell tumor. However, the most common tumors in the dog are those that arise from the sebaceous glands of the perineum. The histologic distinction between perianal adenoma and adenocarcinoma may not always be clear, and clinically there may be an intermediate condition called invasive perianal adenoma, which may look benign microscopically, yet be moderately invasive in the patient.

Perianal adenomas follow a benign clinical course. The tumors are slow-growing, and although local disease may be extensive, metastasis does not occur.^1,11,12

Perianal adenocarcinoma is generally associated with a low rate of metastasis (15%) at the time of original diagnosis.¹⁶ It has been suggested that metastasis is most likely to develop later in the course of disease as the primary tumor becomes larger and more invasive.¹⁶ The most frequent site of metastasis is the regional sublumbar and pelvic lymph nodes, including the iliac, hypogastric, and sacral nodes.^1,16 Distant metastases may rarely affect lungs, liver, kidney, and bone.^12,16 These tumors tend to be more rapidly growing, fixed, and firmer than the more common benign perianal adenomas.

Anal sac apocrine gland adenocarcinoma in the dog is distinct from perianal sebaceous gland adenocarcinoma clinically and histologically. Usually, only one anal sac is affected; however, bilateral tumors can occur.^19,20,25,28 The metastatic potential of this tumor is well established with most reports identifying about 50% metastasis (range 46% to 96%) at the time of initial presentation.^11,20-26,28 Regional sublumbar lymph nodes and pelvic nodes are by far the most common sites of metastasis early in the course of disease.^22-26,28 The primary anal sac tumor may be as small as 0.5 cm, with greatly enlarged metastatic nodes. Distant metastatic sites, including lungs, liver, spleen, bone, and, less commonly, heart, adrenal glands, pancreas, kidneys, and/or the mediastinum, may rarely develop later.^{11,19,20,22-25} The association between anal sac apocrine gland adenocarcinoma and paraneoplastic hypercalcemia of malignancy, mediated by tumor secretion of parathyroid hormone–related peptide,^29-31 has been well documented.* Incidence of hypercalcemia is approximately 27% based on an analysis of 113 dogs with anal sac adenocarcinoma.²³ Along with lymphoma, plasma-ionized calcium concentrations tend to be higher with this tumor than with other types of neoplasia.³⁴

The pathogenesis of canine perianal tumors is not known. In a large study evaluating tumor growth characteristics of 240 perianal gland tumors, cell proliferation and apoptosis were quantified by proliferating cell nuclear antigen (PCNA) staining and microscopic detection of apoptotic corpuscles.³⁵ An increase in both parameters was observed in malignant lesions compared to benign ones.³⁵ Various other immunohistochemical studies have attempted to elucidate possible molecular mechanisms involved in canine perianal gland tumorigenesis. Using a single polyclonal antihuman antibody, nuclear p53 accumulation was detected in 50% (8 of 16) of perianal sebaceous gland adenocarcinomas in one study, suggesting that expression of a mutated p53 tumor suppressor protein may play a role.³⁶ Discordant results were reported in another study in which p53 reactivity was found in none of 11 perianal gland adenocarcinomas and in only a small percentage of adenomas.³⁷ In the same tumor samples, Mdm2 expression was observed in both adenomas and adenocarcinomas.³⁷ A study that evaluated androgen receptor expression found no difference between perianal adenomas and their malignant counterparts; the authors concluded that the mechanism by which androgens may influence carcinogenesis is still unknown.³⁸ Finally, another proposed mediator of tumor growth or evolution is growth hormone. Growth hormone was detected immunohistochemically in 96% (23 of 24) of perianal adenomas and 100% (5 of 5) of perianal sebaceous gland adenocarcinomas.³⁹ With respect to anal sac adenocarcinoma, expression of E-cadherin, a protein known to mediate adhesion and communication between cells and the extracellular matrix, was evaluated in tumor biopsies from dogs using a polyclonal antihuman antibody that has been validated for use in canines.²⁶ E-cadherin expression correlated with the presence of metastasis and shorter survival time, suggesting that it may play a role in tumor progression.²⁶ p53 expression has been detected immunohistochemically in a low-to-moderate proportion of anal gland adenocarcinoma tissue biopsies; however, no clinical implications have come from these findings.³⁶ A recent genetic analysis study in English cocker spaniels showed an association between tumor development and major histocompatibility complex haplotype (DLA-DQB1 allele), suggesting that a genetic factor may play a role in tumor development in this at-risk breed.⁴⁰

The biologic behavior of anal sac apocrine gland adenocarcinoma in the cat has not been clearly defined. Most reports suggest that it is a locally invasive disease associated with a moderate-to-high risk of tumor recurrence following surgery.^5-8,10 The rate of metastasis is variable between studies ranging from low to high.^6,7,10 Described sites of metastasis include sublumbar lymph nodes, liver, diaphragm, and lungs.^6,7,10 Paraneoplastic hypercalcemia is not a common complication of this disease in cats.^7,10 Bilateral tumors have not been reported.

History and Clinical Signs

The history for benign perianal adenoma is that of a slow-growing (over months to years) mass or masses that are nonpainful and usually asymptomatic. These may be single, multiple, or diffuse (similar to generalized hyperplasia or hypertrophy of the perianal tissue; Figure 22-29).¹ Most occur on the hairless skin area around the anus, although they may extend to haired regions and can develop on the prepuce, scrotum, or tail head (stud tail or “caudal tail gland”).¹ Benign lesions may ulcerate and become infected but are rarely adherent or fixed to deeper structures.¹ They are usually fairly well circumscribed, on average 0.5 to 3 cm in diameter, and elevated from the perineum.¹

The male perianal adenocarcinoma may look similar to adenomas but tends to grow more rapidly, be more firm, become ulcerated, adhere to underlying tissues, recur following conservative surgery, and generally be larger than its benign counterpart.¹⁶ Obstipation, dyschezia, or perianal pain/irritation can be seen with larger masses.¹⁶ Rarely, signs are related to obstruction of the pelvic canal by lymph node metastasis. Tumors can be multiple.¹⁶ Castrated males with new or recurrent perianal tumors should raise the suspicion for malignant rather than benign disease because adenocarcinomas are not hormonally dependent.

Clinical signs of dogs with anal sac adenocarcinoma are often referable to either the presence of the primary mass (perianal discomfort, swelling [Figure 22-30], bleeding; scooting), to obstruction of the pelvic canal by regional nodal metastasis (tenesmus, constipation [Figure 22-31]), or to hypercalcemia (polyuria, polydipsia; anorexia; lethargy; vomiting).^22,23 In as many as 39% of dogs, the primary tumor can be an incidental finding on physical examination.²³ Rarely, regional bone metastasis or direct extension of tumor from sublumbar lymph nodes into the lumbar vertebrae with associated pain or fracture may be seen.

In cats, the most common history and clinical signs associated with anal sac adenocarcinoma are related to the presence of local disease. Like dogs, cats may be presented for tenesmus, constipation, scooting, presence of a mass, hemorrhagic discharge, or excessive grooming of the perineal area.^6-8,10 Lethargy and/or inappetence may be secondary to severe constipation.⁵ Not all cats present with clinical signs, and tumors can be detected incidentally during a routine physical examination.⁷ Clinicians should recognize anal sac adenocarcinoma as a distinct clinical entity in the cat and include it as a differential diagnosis for animals with anal sac disease.⁷ It is not uncommon for anal sac adenocarcinoma to be misdiagnosed as an anal sac abscess based on the presence of a mass, ulceration, or a fistulous tract in the perineal region.⁷

Diagnostic Techniques and Work-Up

In the intact male with suspected perianal adenoma, a routine geriatric work-up prior to anesthesia is desirable. Thoracic radiographs to evaluate for lung metastasis may not be cost effective unless indicated for other cardiopulmonary evaluation given the benign biologic behavior of these tumors. Evaluation of regional lymph node size is indicated if one suspects perianal adenocarcinoma based on signalment (neutered male), recurrent disease, or physical examination characteristics of malignancy. Ultrasonographic evaluation of regional lymph nodes is a superior staging tool in comparison to plain radiography which can both underestimate and overestimate lymph node disease.⁴¹ Although distant metastasis is uncommon, thoracic radiographs to evaluate for lung metastasis are recommended in dogs with perianal adenocarcinoma. FNA and cytology to differentiate benign from malignant tumors in the male can be unrewarding, although they are helpful in ruling out other forms of cancer or mass development. Tissue biopsy is necessary to make the distinction in most cases, and the most important histologic criteria supporting a diagnosis of perianal sebaceous gland adenocarcinoma is invasiveness of tumor cells into surrounding tissue.⁴² Disorderly arrangement of cells, increased nuclear pleomorphism, and increased numbers of mitotic figures also favor a diagnosis of malignancy.⁴² The use of monoclonal antibodies, MAbs4A9 and 1A10, developed against a canine mammary cell line and screened for reactivity with perianal adenocarcinoma, has been proposed as a diagnostic tool to help distinguish benign perianal tumors from adenocarcinoma when routine light microscopy is not conclusive.⁴³ Clinical validation is needed to confirm the utility of this approach.

Since dogs with anal sac adenocarcinoma may present with signs unrelated to perianal disease (i.e., polyuria, polydipsia due to hypercalcemia), assessment of animals with suspicious clinical signs requires a careful rectal examination, including palpation of the anal sacs and evaluation for possible regional lymphadenopathy. Definitive diagnosis must be made cytologically or histologically, but a strong presumption of anal sac adenocarcinoma can be made for animals in which rectal examination identifies the presence of a firm and discrete mass in the area of the anal sac. This tumor has a characteristic cytologic appearance and is made up of polyhedral cells that have uniform round nuclei and light blue-gray, slightly granular cytoplasm. Features of malignancy may be subtle. In addition to suggesting the presence of cancer in the anal sacs, FNA is valuable for ruling out infection or inflammatory disease of the anal sac. The clinician should be aware that anal sac tumors can become secondarily infected or inflamed. Staging of disease includes thoracic radiographs for rare detection of pulmonary or mediastinal involvement. Abdominal radiographs may reveal regional lymphadenopathy in advanced cases (see Figure 22-31). Ultrasonographic evaluation of regional lymph nodes is a superior staging evaluation because plain radiography can both underestimate and overestimate lymph node disease.⁴¹ A recent study evaluating sonographic features of abdominal lymph nodes found that alterations in shape, contour, cavitation, echogenicity and parenchymal uniformity do not reliably distinguish neoplastic from benign nodes. The only significant difference identified between neoplastic and benign lymph nodes was size.⁴⁴ Ultrasound also allows for evaluation of other possible sites of abdominal metastasis, particularly liver and spleen. Advanced imaging, including CT and MRI, may yield a more complete assessment of abdominal involvement.⁴⁵ In rare instances, pulmonary metastasis can be present without obvious regional lymph node disease. Lameness or bone pain should be evaluated with radiography and/or nuclear scintigraphy to rule out bone metastasis. Work-up also includes complete blood count, serum chemistry panel, and urinalysis. Hypercalcemia of malignancy can result in renal damage, which may modify prognosis and anesthetic risk. Medical management of hypercalcemia or impaired renal function may be necessary prior to surgery (see Chapter 5).

Careful rectal examination should be performed on all dogs with perianal tumors to detect the clinical degree of fixation prior to surgery, the probability of resection, and the risk of postoperative complications, particularly incontinence, although this is very rare with even aggressive unilateral resection. It is also important to palpate for the presence of enlarged sacral lymph nodes located along the ventral surface of the vertebrae because these are not easily detectable by ultrasound due to their position in the caudal pelvic canal.

Similarly to dogs, feline anal sac adenocarcinoma can be diagnosed cytologically and histologically. Complete staging of this tumor in cats includes thoracic radiographs to evaluate for pulmonary metastasis and abdominal imaging.^4-6,8 Abdominal ultrasound is more sensitive than radiography for detection of metastasis involving abdominal organs or lymph nodes. Positive immunoreactivity with anticytokeratin monoclonal antibody, CAM 5.2, was recently reported in a series of 12 cats with anal sac adenocarcinoma.⁷

Therapy and Prognosis

Due to the hormonal dependence of perianal adenomas, the vast majority of these tumors will regress (at least partially) following castration, and recurrence is uncommon.¹² Surgery is recommended in males with ulcerated tumors or recurrence, as well as in females with typical small and focal masses.¹² For diffuse or large benign lesions situated on or in the anal sphincter, castration followed by an observation period of several months to allow reduction in tumor volume may permit safer and easier mass removal. This will only be effective for benign lesions that are hormone dependent. Over 90% of male dogs will be cured with castration and mass removal.^1,12 Adenomas can be excised with minimal margins. In addition to standard surgical techniques, mass removal can be achieved using cryosurgery or carbon dioxide laser, which should only be used for focal lesions less than 1 to 2 cm in diameter.^46,47 Use of either of these techniques precludes evaluation of the surgical margins for completeness of excision, which may be acceptable for benign masses; however, as the most consistent criterion for malignancy is invasiveness, lack of margin assessment is not without risk. Hyperthermia and RT have also been used successfully.^48,49 The cost, added morbidity, and limited availability of these techniques make them a poor alternative to standard blade excision. Electrochemotherapy has been recently described^50,51 and consists of intratumoral injections of chemotherapy (cisplatin and/or bleomycin in recent reports) followed by local delivery of electric pulses to potentiate drug uptake. Treatments are delivered in one or two weekly sessions. Based on limited studies, the reported overall response rate is greater than 90%, with 65% complete responses.^50,51 Smaller tumors (<5 cm) generally respond better than larger tumors.^50,51 Larger tumors are more likely to develop local complications, including focal necrosis, erythema, and inflammation.^50,51 Systemic effects are not reported.^50,51 Castration and surgical excision remain the treatments of choice for adenomas. Adenomas may also regress following estrogen therapy; however, its use is contraindicated by the risk of myelosuppression. Cyclosporin is reported to have had a palliative effect in a single dog with multiple ulcerated perianal adenomas and a measurable reduction in tumor size was observed.⁵²

Perianal sebaceous gland adenocarcinoma is more locally invasive than its benign counterpart and generally does not respond to castration.¹² Aggressive surgical removal with adequate margins is indicated. Removal of one-half or more of the anal sphincter is possible with only rare transient loss of continence. Recurrent disease becomes more difficult to resect. Unfortunately, most perianal adenocarcinomas are not suspected or known until after a conservative resection, which contaminates further tissue planes and can make the second resection problematic. Due to common local recurrence, this tumor is difficult to cure and may require numerous palliative resections over several years. Preoperative diagnosis of malignancy (i.e., incisional biopsy) and more aggressive initial resection should improve local control and should be strongly encouraged. The utility of postsurgical RT should also improve local control; however, data for this approach are lacking. The use of electrochemotherapy has been reported in a small series of dogs.⁵¹ Although the study suggested a favorable outcome in the adjuvant setting, additional clinical studies are needed for validation of the efficacy of the approach.⁵¹

In a series of 41 dogs with perianal adenocarcinoma, stage of tumor had a significant influence on DFI and overall survival (Figure 22-32).¹⁶ Tumors less than 5 cm in diameter (T2) were associated with 2-year tumor control rates in excess of 60%, suggesting that surgical removal of these masses at an early stage is relatively successful with respect to disease control. Fifteen percent of dogs had evidence of metastasis at the time of diagnosis, which related negatively to survival (see Figure 22-32).¹⁶ MST for dogs with lymph node or distant metastasis was 7 months; however, aggressive treatment was not attempted in five of six cases.¹⁶ If present, regional lymph node metastasis may be excised. Large nodal volume is not a contraindication to caudal abdominal exploratory and lymphadenectomy because some nodes “shell out” readily, whereas others are invasive. Enlarged lymph nodes should be considered for removal, especially if they are causing obstruction of the pelvic canal. The use of radiation and/or chemotherapy, including actinomycin D, has been reported anecdotally, but their role in local or distant control is largely undefined.^16,53,54 Controlled clinical trials have not been performed. It has been suggested that nuclear size measured by computer-assisted image analysis in cytologic tumor samples may correlate with biologic behavior in this tumor type.⁵⁵

Apocrine gland adenocarcinoma of the anal sac is generally locally invasive, and aggressive surgical excision is recommended. Recurrence rate is high after marginal surgery alone.^20,22 Complete resection of large perianal malignancies is difficult due to proximity to the rectum and poor definition of perineal tissue to define an adequate margin. Metastasis is present at the time of diagnosis in approximately 50% to 80% of cases,^{19,20,22,23,25} with regional lymph nodes being the most common site.

Enlarged lymph nodes should be considered for removal, especially if they are causing obstruction of the pelvic canal or contributing to hypercalcemia. Radiation and/or chemotherapy may be used adjuvantly or as the sole treatment.^22-25,28

Large-scale studies controlled for tumor stage and treatment are lacking in dogs with anal sac adenocarcinoma. There is discordance in the outcome and prognosis reported in the literature. Earlier small studies suggest a MST of 6 to 12 months.^20,22,27 This is in contrast to recent reports in which the MST ranges from 16 to 18 months.^23,24 These later studies involve larger groups of dogs (113 dogs and 80 dogs, respectively).^23,24 However, there is variability in stage of disease and treatment in the study populations that leads to difficulty accurately predicting the prognosis of individual dogs with this tumor type. Negative prognostic indicators gleaned from these and other studies include increasing primary tumor size,^23,24 presence of lymph node metastasis,²⁴ presence of distant metastasis,^23,24,26 advanced clinical stage,²⁴ nonpursuit of surgery,²³ treatment with chemotherapy alone,²³ and lack of any therapy at all.²⁴ In one study, extirpation of involved sublumbar lymph nodes in dogs without distant metastasis correlated with improved survival compared to animals in which nodal metastases were not removed.²⁴ E-cadherin expression detected immunohistochemically in tumor biopsies has also been suggested to directly correlate with survival.²⁶ These prognostic variables should be confirmed in controlled clinical trials.

Although chemotherapy and RT are generally considered standard adjuvant treatment options for anal sac adenocarcinoma, the role of these modalities alone or in combination is not well defined. Chemotherapy is theoretically indicated given the high rate of metastasis. Chemotherapeutics with demonstrated antitumor activity in the gross disease setting include carboplatin, cisplatin, and actinomycin D.^22,24,52 Other drugs reported in the adjuvant setting include mitoxantrone and melphalan.^25,28 Gross tumor responses have not been described for these agents when used alone, and their true role in combination therapies is not known. Toceranib phosphate, a TKI, has been associated with modest tumor responses with median response durations of 19 to 25 weeks in a series of 33 dogs with multiple prior failed therapies.⁵⁶ This antitumor effect may be mediated through inhibition of the platelet-derived growth factor receptor β (PDGFR-β) based on immunoreactivity of tumor biopsies to anti-PDGFR antibody.⁵⁷ Controlled clinical trials are needed to determine the role of toceranib in the treatment of anal sac adenocarcinoma. Adjuvant electrochemotherapy using cisplatin is reported in a single dog following an incomplete primary tumor excision.⁵⁸

The optimal combination of therapies for anal sac adenocarcinoma is not known. In three clinical studies with controlled treatment regimes, MSTs ranged from 17 to 31 months.^24,25,28 A study of 14 dogs that underwent surgical excision and melphalan chemotherapy reported an overall MST of 20 months (95% CI, 11.6 to 28.4 months).²⁸ Seven dogs had known nodal metastasis at the time of diagnosis, and nodal metastasis was not prognostic for survival in this small study. A significant relationship between a modified clinical staging scheme and survival was found in a study of 50 dogs treated prospectively according to a predetermined management algorithm.²⁴ Treatment included various combinations of surgery, carboplatin chemotherapy, and hypofractionated (9 Gy × 4 weekly fractions) RT. Fifteen dogs had sublumbar lymphadenopathy and/or distant metastasis at the time of treatment. MST was 17 months (95% CI, 7 to 27 months). Toxicity associated with the treatment was not reported. The third study utilized a standardized RT protocol with concurrent chemotherapy in a cohort of 15 dogs.²⁵ Dogs were treated with combination surgery (primary tumor ± metastatic lymph nodes), curative-intent radiation (3.2 Gy × 15 daily fractions for a total dose of 48 Gy) to the primary tumor site and regional lymph node beds, and mitoxantrone chemotherapy. Seven dogs had lymph node metastasis at diagnosis. Median event-free survival was 9 months (range: 2.5 to 35 months), and overall survival was 31 months (range: 5 to 47 months). Measurable responses were observed in bulky metastatic lymph nodes. The relative importance of radiation versus mitoxantrone chemotherapy is not clear from this study. Without more rigorously controlled clinical trials, strong statements about the “best” treatment and prognosis are difficult to support. In a case series of five dogs selected for resectability of metastatic lymph nodes, a MST of 20 months was achieved with surgery alone.⁵⁹ One dog underwent repeated lymph node debulking surgeries and survived for 54 months. Another dog survived 18 months following omentalization of cystic sublumbar lymph node metastasis for palliation of tenesmus and dysuria.⁶⁰ Taken together, these findings of prolonged survival, despite varying tumor stages and varying treatments, strongly suggest the need for prospective, controlled clinical trials to elucidate any benefits of treatment modalities, such as radiation, chemotherapy, molecular-targeted drugs, and their combinations. Identification of reliable prognostic criteria predictive of outcome or treatment response is also needed. It has been suggested in a small study using computer-assisted analysis that nuclear size of tumor cells may correlate with biologic behavior; nuclear size parameters were larger in metastatic anal gland adenocarcinomas than in nonmetastatic tumors.⁶¹ Further validation of this approach is needed before it can be considered clinically useful. Finally, when short-term palliation is the therapeutic goal, treatment options include surgery, palliative RT, chemotherapy and/or toceranib, even though efficacy of these approaches has not been definitively established.

Curative-intent RT of the perineal and pelvic regions is associated with self-limiting, acute radiation effects, including mild-to-severe moist desquamation, colitis, and perineal discomfort lasting 2 to 4 weeks posttherapy. Radiation prescriptions should be designed to minimize the risk of late effects, including rectal stricture or perforation. Two studies have demonstrated that radiation doses of less than 3 Gy per fraction should be used to minimize this risk.^62,63 In the only report of standardized curative-intent RT for anal sac adenocarcinoma,²⁵ none of the side effects were reported as life-threatening, and all dogs maintained reasonable quality of life as assessed by owners. Chronic complications included tenesmus and narrow stool, diarrhea, and rectal stricture. The daily radiation dose in this study was 3.2 Gy. Future studies should be designed with daily radiation doses of less than 3 Gy to reduce the risk of chronic complications.

There is discordance in the data reported regarding the prognostic significance of hypercalcemia of malignancy accompanying anal sac adenocarcinoma. Hypercalcemia has generally been associated with shorter survival^20,23; however, other studies have not supported this finding.^22,25,26,28 Complete or near-complete removal of the tumor results in reversal of hypercalcemia. Return of hypercalcemia after therapy usually signals recurrence or metastasis.

Prognosis associated with feline anal sac adenocarcinoma has not been clearly established and some reports are conflicting. Local recurrence after surgical resection appears relatively common. The reported rate of metastasis is variable. In a study involving 39 cats that underwent incisional biopsy or tumor resection, survival time ranged from 0 to 23 months.⁷ Eighty-five percent of cats succumbed to local disease or presumptive metastasis. MST in this group was 3 months; 1- and 2-year survival rates were 19% and 0%, respectively.⁷ This is in contrast to a recent retrospective study of 23 cats that reported a median DFI and survival time of over 300 days.¹⁰ The role of chemotherapy and RT is not known. A short-lived partial response to carboplatin was reported in a cat with recurrent anal sac adenocarcinoma.⁸ In another report, outcome following concurrent adjuvant curative-intent RT (48 Gy) and chemotherapy (carboplatin) resulted in local recurrence and/or metastatic disease within 6 months of treatment in two cats.⁶ In both cases, RT was well tolerated with minimal acute effects.⁶ Although these survival data are not encouraging, more studies are needed to determine the true role of radiation and chemotherapy in this disease. Based on individual cases of long-term survival, it has been suggested that early detection and completeness of excision may positively impact outcome.^6,7

Comparative Aspects^64-66

No similar hormonally dependent perianal disease state exists in humans. The most common cancer of the anal margin is squamous cell (epidermoid) carcinoma. These tumors arise from the junction of haired skin and mucous membrane of the anal canal. Risk of developing cancer in this location is positively correlated with sexual activity, and most tumors are associated with human papillomavirus infection. Precancerous changes (dysplasia) in the epithelium of the anal canal may precede tumor development. Regional lymph nodes are the most common site of metastasis. Previously considered a surgical disease requiring a permanent colostomy, improved outcomes have been achieved with definitive chemoradiation. The standard approach to therapy is concomitant radiation and chemotherapy using 5-FU and mitomycin C. Surgery is reserved for locally recurrent or persistent disease. Mean 5-year disease-free survival and overall survival are 60% and 75%, respectively. Size and degree of invasion of the primary tumor, regional lymph node involvement, and presence of distant metastases are important prognostic factors. Identification of biomarkers that may serve as predictors of outcome or targets for therapy is being explored.

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