Urothelial carcinoma with tonsillar metastasis in a dog

Abstract

Given its unusual lymphatic drainage system, the tonsil is a rare site of metastasis, with few reports in the human and veterinary literature. Prognosis in cases of tonsillar metastasis is reportedly poor. We describe here a unique case of urinary bladder urothelial carcinoma (UC) with metastasis to the tonsil in an 11-y-old, spayed female, mixed-breed dog. At presentation, the patient had a history of a growing neck mass and increasing lethargy, hyporexia, weight loss, drooling, and diarrhea for 2 wk. A carcinoma was diagnosed by cytology. Given the poor prognosis, the patient was euthanized. Postmortem examination revealed masses in the inguinal region, cranioventral neck region including tonsil, and urinary bladder. Histologically, the masses were composed of large polyhedral cells arranged in dense sheets and nests with occasional large, clear, intracytoplasmic vacuoles. Neoplastic cells were multifocally positive for uroplakin III and cytokeratin 8/18 by immunohistochemistry. UC with metastasis to tonsil and lymph nodes was diagnosed.

The tonsils are a unique part of the hemolymphatic system because the tonsils do not have afferent lymphatics. Metastasis to the palatine tonsils is considered rare in humans, accounting for ~0.8% of all tonsillar neoplasia. ² In dogs, this percentage has been reported as high as 9%. ⁹ The typical route of cancer cell spread to the tonsils is unknown, but current theories include retrograde lymphatic and hematogenous spread. ¹⁵ In humans, types of neoplasia with tonsillar metastasis include melanoma, breast neoplasia, gastrointestinal neoplasia, and lung neoplasia.^8,12,14 Reports of metastases to the tonsil originating from the urogenital system include renal cell neoplasia and seminoma.^1,7,13 In dogs, tonsillar metastases have included melanoma, carcinoma, salivary carcinoma, adenocarcinoma, hemangiosarcoma, basal cell tumor, fibrosarcoma, malignant histiocytosis, and undifferentiated sarcoma, the majority of which originated in the head and neck region. ⁹ To our knowledge, metastasis of urinary bladder urothelial carcinoma (UC) to the tonsil has not been reported in the human or veterinary literature.

An 11-y-old, spayed female, mixed-breed dog was presented on emergency to the University of Missouri Veterinary Health Center (Columbia, MO, USA) because of a neck mass. The dog had a 2-wk history of hyporexia, lethargy, weight loss, drooling, and diarrhea; in-house cytology of the neck mass by the referring veterinarian was inconclusive. The referring veterinarian prescribed clindamycin (unknown dosage) 1 wk prior to presentation. The patient had a history of presumed epilepsy that was reportedly well-controlled on phenobarbital (32.4 mg PO q12h), plus hypothyroidism was being treated (Thyro-Tabs, Lloyd; 0.5 mg PO q12h).

On physical examination, the dog was quiet, alert, and responsive, and weighed 23.5 kg with a body condition score of 5 of 9. Vital parameters (heart rate, respiratory rate, and body temperature) were within normal limits. Cardiothoracic auscultation was unremarkable. Oral examination was apparently painful, and there was a swollen ulcerated lesion, possibly a mass, in the left caudal aspect of the oral cavity involving the palatine tonsil. Cranial nerve examination was normal. There were irregular, fixed, firm, masses surrounded by local edema along the ventral neck region at the level of the larynx and over the salivary glands. The abdomen was soft on palpation. The popliteal and prescapular lymph nodes were soft and small. Inguinal lymph nodes were firm, irregular, and enlarged but freely moveable.

CBC and serum chemistry were unremarkable. Cytology of the left ventral neck mass revealed occasional clusters of epithelial cells with ovoid central nuclei, coarsely stippled chromatin, 1–3 variably sized round nucleoli, and small-to-abundant amounts of variably basophilic cytoplasm that displayed perinuclear vacuolation occasionally. Occasional binucleation, rare multinucleation, and rare mitotic figures were encountered. No cytologic evidence of lymphoid tissue was observed. These findings were consistent with carcinoma. Cytology of the retropharyngeal and mandibular lymph nodes revealed similar polygonal neoplastic epithelial cells in the background of various lymphoid cells, suggesting a metastatic carcinoma. Tonsillar squamous cell carcinoma with multiple lymph node metastases was suspected based on physical examination and cytology. The owners elected euthanasia, and postmortem examination was performed.

On autopsy examination, there was a soft, mottled tan-and-red, multilobular mass (1.5 × 0.5 × 0.5 cm) in the urinary bladder just distal to the trigone. Bilaterally, there were 2, firm, irregular, freely moveable masses in the left (2 × 2 × 4 cm) and right (5 × 3.5 × 1.5 cm) inguinal subcutis. Within the cranial left neck, there were coalescing, firm, tan-and-red multinodular masses with the largest mass measuring 6.5 × 4 × 3.5 cm. The left tonsil was mildly enlarged (1 × 2 × 2 cm) and multifocally ulcerated.

Samples of various tissues were collected and fixed in 10% neutral-buffered formalin, processed routinely, and 4-µm sections were stained with H&E. Immunohistochemistry (IHC) was performed on the tonsil, urinary bladder mass, and cervical and inguinal lymph nodes using rabbit polyclonal anti-uroplakin III (UPIII) antibody (1:100; Bio SB) and mouse monoclonal anti-cytokeratins 8/18 (CK8/18) antibody (clone 5D3, 1:100; Leica). For antigen retrieval for UP III IHC, a heat-induced method was performed using a retrieval solution (Diva Decloaker; Biocare Medical). For CK8/18, the slides were pretreated with proteinase K (Dako) for 5 min. Immunoreactivity was visualized by using Romulin AEC chromogen (Biocare Medical), and hematoxylin was used for counterstain.

Microscopically, the urinary bladder was infiltrated by a neoplasm that arose from urothelium. The tumor consisted of large polyhedral cells arranged in densely cellular sheets and nests supported by collagenous stroma. Neoplastic cells had large round vesicular nuclei, 2 or 3 nucleoli, and moderate-to-abundant, lightly vacuolated, eosinophilic cytoplasm with distinct cellular outlines. Occasional multinucleate cells were noted. Some tumor cells had a large, clear, intracytoplasmic vacuole. Anisocytosis and anisokaryosis were marked. Mitotic activity was high (26 mitotic figures in 2.37 mm²). Many lymphatic vessels contained tumor emboli. Urinary bladder UC was diagnosed.

In the tonsil, unencapsulated, poorly demarcated, neoplastic islands were composed of polyhedral neoplastic cells arranged in nests supported by thin collagenous connective tissue (Fig. 1). The neoplastic cells had morphologic characteristics similar to the tumor cells in the urinary bladder. A few lymphatic vessels contained tumor emboli. The inguinal, retropharyngeal, and mandibular lymph nodes had similar metastatic carcinomas.

Figure 1.

Urothelial carcinoma (UC) with metastasis to a tonsil in a dog. A. Aggregates of neoplastic epithelial cells in the tonsil. H&E. B. Neoplastic cells exhibited positive immunostaining for UPIII, confirming UC metastasis. C. Neoplastic cells exhibited positive immunostaining for CK8/18. D. Neoplastic cells arising from the urinary bladder epithelium and adjacent normal urothelial cells exhibited positive immunostaining for UPIII. Inset: the urinary bladder UC. H&E.

The neoplastic cells in the urinary bladder and tonsil exhibited multifocally strongly positive immunoreactivity against UPIII and CK8/18. The IHC results supported the diagnosis of UC with a primary location of the urinary bladder and metastasis to the tonsil and lymph nodes. Squamous cell carcinoma was ruled out because oral squamous cells are negative for UPIII. Normal oral squamous mucosa does not express CK8/18; however, CK8/18 expression has been detected in human oral squamous cell carcinomas with a poor prognosis. ³

The rarity of tonsillar metastasis is attributed to the unique lymphatic drainage system of the tonsil. In humans and dogs, although efferent lymphatics drain to the medial retropharyngeal lymph nodes, there is no afferent lymphatic input.^4,5 Skull indirect computed tomography lymphangiography used in conjunction with contrast injection around a primary tumor of the head to evaluate drainage showed that, in the 53 dogs studied, the palatine tonsils did not contain contrast drainage; however, a lymphatic vessel coursed around the tonsil in 4 dogs. ⁹ Without afferent lymphatics, the presumed route for many cases of tonsillar metastasis is hematogenous spread. Indeed, metastasis of urogenital tumors, including UC, to the head and neck region has been reported in humans with suggested possible hematogenous routes including the paravertebral venous plexus. ¹⁰

Metastatic UC can be notoriously aggressive in dogs, and more than half with UC have distant metastases at death. ⁶ In our case, metastasis to the inguinal, retropharyngeal, and mandibular lymph nodes is likely the result of afferent lymphatic spread. Rare cases of retrograde lymphatic metastasis or direct implantation of tumor cells following diagnostic procedures have been implicated in metastasis of carcinoma to the tonsils. ¹¹ Except for the lymphoid tissues, no vascular-rich internal organs including lungs, liver, and kidneys contained metastases, and no tumor emboli were found in blood vessels in those tissues. In the tonsil, there were small islands of neoplastic cells in presumed lymphatic vessels, given that none of the spaces were obvious blood-filled channels. This pattern might provide a support for retrograde lymphatic spread in our case.

Metastasis should be a differential diagnosis for head and neck tumors with a concurrent history of urogenital tumors. Although primary tonsillar neoplasia is far more common than metastatic neoplasia, IHC may be warranted when multiple tumors are present. To date, there is no consensus regarding therapeutic approaches in cases of palatine tonsillar metastasis in the human literature. ¹⁴