Canine Thymoma

Thymoma, a tumor originating from the thymic epithelium, represents the second most common cranial mediastinal tumor in dogs, although it is an uncommon disease in general.1-3 Even though the thymus is primarily active during puppyhood, thymomas are typically diagnosed in older medium to large breed dogs and Labrador and golden retrievers were overrepresented in a recent study.1,2 A clear sex predisposition has not been documented, nor have predisposing or etiologic factors.

The terms “benign” and “malignant” have been used to describe thymomas but are based on clinical rather than histologic features, and the classification is rather subjective. Specifically, “benign” thymomas are typically well encapsulated and more easily resectable whereas “malignant” thymomas are more invasive and difficult to remove surgically. Metastasis to regional lymph nodes, lungs, and pleura is rare but has been reported.1,2

Clinically, most patients present with some signs of respiratory distress (coughing, tachypnea, and dyspnea) related to the mass itself and/or secondary pleural effusion. In more severe cases, precaval syndrome (presenting as pitting edema of the head, neck, and forelimbs) may also occur secondary to obstruction of venous and lymphatic drainage. General constitutional signs reported include decreased appetite, weight loss, and lethargy. Common physical examination findings in dogs with thymoma include increased respiratory rate and effort and dull cardiopulmonary sounds.

Several paraneoplastic syndromes have been described with thymoma and a recent study2 reported that 34% of dogs with thymoma had hypercalcemia, 17% had signs of myasthenia gravis, 7% had a concurrent immune-mediated disease (including anemia, thrombocytopenia, myositis, keratoconjunctivitis sicca), 27% had another tumor at the time of thymoma diagnosis, and 14% of dogs developed a second non-thymic tumor at a later date. Peripheral T-cell lymphocytosis has also been an uncommonly reported paraneoplastic syndrome.4,5 Concurrent laryngeal paralysis is also a common finding in dogs with thymoma.2

DIAGNOSIS

Differential diagnoses for thymoma include mediastinal lymphoma, chemodectoma, branchial cyst, ectopic thyroid tumor, and primary or metastatic carcinoma, as all can present as a cranial mediastinal mass with or without pleural effusion.1

The diagnostic work up for a mediastinal mass typically includes routine laboratory tests (complete blood count/CBC, serum biochemical profile), thoracic radiography, thoracic ultrasound, computed tomography (CT), ultrasound-guided fine needle aspirate cytology or tru-cut biopsy, thoracoscopic-assisted biopsy, and flow cytometry.

Common changes noted on CBC and serum biochemical profile include anemia, thrombocytopenia (paraneoplastic immune-mediate destruction), neutrophilia, lymphocytosis (paraneoplastic), and hypercalcemia (paraneoplastic secondary to PTHrp).1,2,4,5

Thoracic radiographs typically reveal a mass or mass effect in the cranial mediastinum, lateral and dorsal displacement of the trachea and occasionally the heart, and caudodorsal displacement of the lungs (Figure 1). If present, pleural effusion may obscure the normal anatomy and ability to discern a discrete mass. Dilation of the esophagus may be seen in patients with paraneoplastic myasthenia gravis.

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Figure 1. Ventrodorsal and left lateral thoracic radiographs of a dog with a mediastinal mass that was later confirmed to be a thymoma.
Images courtesy of Chris Ryan, VMD, DACVR, Hope Veterinary Specialists.

It is generally not possible to differentiate thymomas from other mediastinal masses radiographically, however, certain ultrasonographic characteristics may be used to differentiate thymoma from lymphoma. A recent study found that many (57.1%) thymomas were sonographically cystic in appearance and nearly all (94%) were heterogeneous in echogenicity compared with lymphoma. Lymphomatous lymph nodes were more likely to be solid (80%) and were equally divided between hypoechoic (47%) and heterogeneous (53%) in echogenicity.6 Therefore, the sonographic findings of either an either cystic or heterogeneous echogenicity in a mediastinal mass may be suggestive of thymoma (Figure 2).

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Figure 2. Ultrasonographic image of a thymoma in the cranial mediastinum of a dog. Image courtesy of Chris Ryan, VMD, DACVR, Hope Veterinary Specialists.

Another study evaluating the use of computed tomography (CT) attempted to characterize mediastinal masses based on the presence or absence of contrast enhancement, internal architecture, size, extent of local invasion, presence of pleural fluid, and presence of regional vascular invasion. Although there appeared to be no clinically exploitable relationship between CT appearance and histologic characterization of mediastinal masses in this study, CT was found to provide reasonably accurate local staging information7 (Figure 3). CT has become a common prerequisite to surgery for thymoma.

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Figure 3. Multiple slices from a thoracic CT scan performed prior to surgical excision of a thymoma, which is highlighted by the green arrows in the left and middle images.
Images courtesy of Chris Ryan, VMD, DACVR, Hope Veterinary Specialists.

Definitive diagnosis of thymoma without surgical biopsy can be difficult and differentiation from mediastinal lymphoma poses the biggest challenge, as a considerable proportion of thymomas are lymphocyte-rich and can cytologically appear similar to lymphoma. Both fine needle aspirate cytology and tru-cut biopsy of thymoma carry the risk that only a lymphocyte-rich, necrotic, or cystic sample is obtained, leading to non-diagnostic or equivocal results. However, transthoracic fine needle aspiration for cytologic preparations is a simple and safe procedure and if the epithelial component of thymoma is obtained along with a population of mature lymphocytes, it is often possible to differentiate thymoma from lymphoma8. A recent study showed substantial to an almost perfect agreement between cytology and histology of mediastinal masses in dogs and cats9. Interestingly, ~50% of thymomas will also contain mast cells8 (Figure 4).  Cytologic evaluation of pleural effusion from patients with thymoma may yield mature lymphocytes as opposed to larger lymphoblasts seen with lymphoma, however, this distinction can sometimes be difficult with intermediate cell lymphomas.

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Figure 4. Cytologic preparations of two canine mediastinal masses. The image on the left is from a thymoma and illustrates the three cell types typically present in this tumor type (epithelial cells, small lymphocytes, mast cells). The right image illustrates the lymphoblasts that typically characterize large cell lymphoma of the mediastinum.
Image courtesy of Casey LeBlanc, DVM, PhD, DACVP (Clinical Pathology), Eastern VetPath.

Recently, the utility and accuracy of flow cytometry as a tool to differentiate lymphoma from thymoma was described10 and it was found that the two tumor types could be unambiguously differentiated by flow cytometry in all cases examined (n=13). Specifically, all cases of thymoma consisted of ≥ 10% lymphocytes coexpressing CD4 and CD8 (a phenotype that is characteristic of thymocytes), whereas 6 of 7 lymphomas contained < 2% CD4+CD8+ lymphocytes. Furthermore, the single CD4+CD8+ lymphoma could be readily distinguished flow cytometrically from thymoma by light scatter properties.10

Therefore, flow cytometry is considered a useful and relatively non-invasive test to help determine mediastinal tumor type, especially when routine cytology results are lymphocyte-rich and equivocal.

Ultimately, confirmation of thymoma diagnosis via histology is preferred and typically achieved if and when definitive therapy (surgical excision) is instituted. Different histologic subtypes of thymoma have been described including differentiated epithelial, lymphocyte-rich, and clear cell), and a higher component of lymphocytes has been inconsistently shown to correlate positively with survival.2,3

TREATMENT

Surgery

The definitive therapy for thymoma is surgical removal1-3, typically via a median sternotomy.  A CT scan is often performed prior to surgery in order to determine local invasiveness and vascular involvement for surgical planning, although no preoperative test is 100% reliable in predicting resectability. Invasive and malignant thymomas are typically adherent to surrounding tissues, especially major nerves, veins, trachea, pericardium, and esophagus, making removal difficult. Complete surgical excision is the ultimate goal of a thoracotomy, although debulking of invasive thymomas can be performed with the intent of alleviating symptoms of the physical mass effect. If the mass is deemed non-resectable at the time of surgery, then multiple biopsies should be taken in order to obtain a definitive diagnosis and characterize the tumor histologically.

A 2008 study evaluating dogs and cats undergoing surgical excision of thymomas determined a median survival time of 790 days for dogs, with a 1-year survival rate of 64% and a 3-year survival rate of 42%.3  Percentage lymphocyte composition of the mass was the only factor that was significantly correlated with survival time, where animals whose tumor had a high percentage of lymphocytes lived longer.

A more recent study evaluating 84 dogs undergoing surgical excision of thymoma documented a 17% tumor recurrence rate. However, the prognosis after second surgery was still quite good. The median survival time for dogs undergoing surgery was 635 days, yet only 76 days for the 32 dogs not undergoing surgery. Factors associated with shorter survival included lack of surgical removal, higher pathological stage, and the presence of another tumor at the time of thymoma diagnosis. Interestingly, hypercalcemia, presence of myasthenia gravis, histopathologic subtype, and tumor development at a later date were not associated with survival time.

Radiation Therapy

Radiation therapy may be considered as an alternative local therapy for thymoma if the tumor is non-resectable or if surgical excision is declined by the owner. There are no large-scale studies evaluating the use of radiotherapy for canine thymoma, however, a small retrospective study11 showed an overall response rate of 75%. Complete responses were rare, but another small group of patients that only achieved stable disease still had improvement in clinical signs. Thus, there was high chance of palliation with this modality, regardless of whether or not the tumor decrease in size. The median survival time for dogs in this study was 248 days. Shortcomings of this study included that several patients underwent surgery and/or received concurrent steroids or chemotherapy and that radiation protocols varied amongst patients.

Radiation therapy also has a role in the adjuvant setting for patients where the residual disease remains following surgery, a common risk with this invasive tumor type. In these cases, full course (Monday-Friday for 15-18 treatments) radiation therapy would be indicated and the goal would be for long-term disease control (i.e. curative intent). Another use of radiotherapy is in the neoadjuvant setting, where the intent would be to shrink the mass to allow for more straightforward surgical excision. Stereotactic radiosurgery is now available as a more novel radiotherapy approach that can deliver a comparable total dose to traditional full-course radiotherapy but in a highly conformal and coarsely fractionated (1-3 treatments) manner.

Chemotherapy

There are no formal studies evaluating the use of chemotherapy for treatment of canine thymoma, however, anecdotal evidence suggests that some may respond to various agents. In particular, similar protocols to those that are used for canine lymphoma (doxorubicin, vincristine, cyclophosphamide) may be employed with some benefit along with other agents more typically used for the treatment of epithelial tumors (e.g. carboplatin, alkylating agents). It is likely that the majority of the tumor regression seen with thymomas treated with radiation therapy and/or chemotherapy is due to the die-off of the secondary lymphocyte population, rather than the cancerous epithelial cells themselves.

Another commonly used medical therapy for thymoma is corticosteroids, as the lymphocyte component of these tumors is highly responsive to this class of drugs. Some durable and rare complete responses of thymomas to steroids have been anecdotally reported.1,2

PROGNOSIS

The prognosis for dogs undergoing surgical removal of minimally invasive thymomas is typically very good and long-term remissions and cures can be expected in dogs without megaesophagus or aspiration pneumonia. Myasthenia gravis, if present, generally requires treatment with immunosuppression or anticholinesterase drugs but may not be reversible, even following surgical tumor removal. Symptomatic treatment of the megaesophagus may be attempted in hopes of decreasing the prevalence of regurgitation and aspiration pneumonia.

The long-term outlook for canine patients with non-resectable thymomas remains poor, although radiation therapy (and possibly chemotherapy) may be beneficial in reducing clinical signs and could play a role in both the neoadjuvant (shrinking the tumor to make it surgically resectable) and adjuvant (eradicating residual tumor cells after incomplete resection) settings.

Submitted by Christine Mullin, VMD, DACVIM (Oncology)

References

  1. de Mello Souza CH. Thymoma. In: Withrow SJ, Vail DM, Page R, Eds. Small Animal Clinical Oncology, 5th St. Louis, MO: Saunders/Elsevier; 2013:688-691.
  2. Robat CS, Cesario L, Gaeta R, DVM et al. Clinical features, treatment options, and outcome in dogs with thymoma: 116 cases (1999–2010). J Am Vet Med Assoc 2013;243:1448–1454. http://avmajournals.avma.org/doi/abs/10.2460/javma.243.10.1448?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed
  3. Zitz JC, Birchard SJ, Couto GC et al. Results of excision of thymoma 
in cats and dogs: 20 cases (1984–2005). J Am Vet Med Assoc 2008;232:1186–1192. http://avmajournals.avma.org/doi/abs/10.2460/javma.232.8.1186?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed
  4. Burton AG, Borjesson DL, Vernau W. Paraneoplastic T-cell lymphocytosis associated with thymoma in a dog. J Small Anim Pract 2010;51:491–494. http://onlinelibrary.wiley.com/doi/10.1111/j.1748-5827.2010.00962.x/abstract;jsessionid=1ED8D30E5170178F44F138B8304337A5.f04t01
  5. Batlivala TP, Bacon NJ, Avery AC et al. Thymoma-associated lymphocytosis in a dog. Vet Clin Pathol 2014;43/4:584–588. http://onlinelibrary.wiley.com/doi/10.1111/vcp.12196/abstract
  6. Patterson M and Marolf AJ. Sonographic Characteristics of Thymoma Compared With Mediastinal Lymphoma. J Am Anim Hosp Assoc 2014; 50:409–413. http://jaaha.org/doi/10.5326/JAAHA-MS-6132?url_ver=Z39.882003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed
  7. Yoon J, Feeney DA, Cronk DE et al. Computed tomographic evaluation of canine and feline mediastinal masses in 14 patients. Vet Radiol Ultrasound 2004;45(6):542-6. http://onlinelibrary.wiley.com/doi/10.1111/j.17408261.2004.04093.x/abstract
  8. Rae CA, Jacobs RM, Couto CG. A comparison between the cytological and histological characteristics in thirteen canine and feline thymomas. Can Vet J 1989;30:497-500. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1681127/
  9. Pintore L, Bertazzolo W, Bonfanti U et al. Cytological and histological correlation in diagnosing feline and canine mediastinal masses. J Small Anim Practice 2014;55, 28–32. http://onlinelibrary.wiley.com/doi/10.1111/jsap.12161/abstract
  10. Lana S, Plaza S, Hampe K et al. Diagnosis of mediastinal masses in dogs by flow cytometry. J Vet Intern Med 2006;20(5):1161-5. http://onlinelibrary.wiley.com/doi/10.1111/j.19391676.2006.tb00716.x/abstract
  11. Smith AN, Wright JC, Brawner WR. Radiation Therapy in the Treatment of Canine and Feline Thymomas:
A Retrospective Study (1985-1999). J Am Anim Hosp Assoc 2001;37:489–496. http://jaaha.org/doi/10.5326/15473317-37-5-489?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed
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