Correspondence *Division of Hematology/Oncology, Department of Medicine, University of Rochester Medical Center, 601 Elmwood Avenue, PO Box 704, Rochester, NY 14642, USA

Email manish_kohli@urmc.rochester.edu

The case

A 68-year-old male in clinical remission following a left nephrectomy for localized renal cell carcinoma, clear-cell type, with no capsular or renal-vein invasion and clean surgical margins, presented with a 2-month history of a new, mid-line growth at the junction of the hard and soft palate. The only presenting symptom was progressive difficulty in swallowing food. The patient reported a 30 pack-year history of smoking, but no history of epistaxis, cough or bleeding from the oral cavity. A year after nephrectomy, small-volume, unilateral pulmonary metastases were detected. These were treated by radiofrequency ablation with no further evidence of disease recurrence in the chest or any other site in the following year. Details of the size and locations of the metastasis, as well as reasons for radiofrequency ablation performed at a different facility, were available only from the patient history.

Significant comorbidities included stable angina and an early Parkinsonian tremor, which was well controlled with minimal doses of neuroprotective medications. Examination of the palate revealed a fleshy, 25 mm 25 mm soft lesion, fixed to the roof of the oral cavity but freely mobile in all directions (Figure 1A). No cervical or systemic lymphadenopathy was palpable. Thin-cut, contrast-enhanced CT and MRI scans of the palate, nasal cavity and nasopharynx revealed the presence of a localized lesion extending through the roof of the oral cavity anterior to the nasopharynx. No separate extrapalatal tumor lesion or growth was identified on clinical examination and radiologic imaging.

Figure 1 Serial clinical response of palatal lesion to interferon injections.

(A) Day 0 (first injection). (B) Day 29. (C) Day 59. (D) Day 92. Abbreviations: T, tongue; UL, upper lip.

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Following a discussion with the patient, a fine-needle biopsy of the palatal lesion was performed in order to establish a diagnosis. The biopsy revealed clear cell carcinoma cytology, consistent with the renal primary tumor (Figures 2 and 3A). Flexible nasopharyngeal and laryngeal endoscopy, performed by a head and neck specialist, revealed a 1.5 cm exophytic lesion at the junction of the hard and soft palate with posterior extension to the soft palate, 3–3.5 cm in greatest dimension. The lesion also extended to the posterior edge of the bony nasal septum and to the nasal surface of the soft palate. No hypopharyngeal or laryngeal lesion was noted. A CT scan of the chest, abdomen and pelvis did not detect any evidence of tumor recurrence. In the absence of any clinically detectable metastasis, other than the palatal lesion, a diagnosis of palatal oligometastasis from primary renal cell carcinoma was made.

Figure 2 Hematoxylin and eosin immunohistochemistry of palatal lesion (20).

Arrows point to subsquamous epithelium tumor-cell infiltration. Abbreviations: SE, subsquamous epithelium; TC, tumor cell.

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Figure 3 Pretreatment and post-treatment hematoxylin and eosin immunohistochemistry and microvessel counts (400).

(A) Pretreatment hematoxylin and eosin immunohistochemistry. Arrows show cancer cells. (B) Pretreatment CD34⁺ microvessel count: 85 per high-power field (averaged count from five different fields). (C) Post-treatment hematoxylin and eosin immunohistochemistry. Arrows show necrosis in a field of scattered tumor cells. (D) Post-treatment CD34⁺ microvessel count: 58 per high-power field (averaged count from five different fields). Abbreviations: N, necrosis; TC, tumor cells.

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The patient was treated with low-dose, subcutaneous (5 /m²) interferon 2b (IFN-2b) every other day with the intention of increasing the dosage over time. The patient also applied a mixture of IFN-2b and viscous lidocaine to the lesion several times a day, via a swab. Follow-up after 4 weeks revealed no increase in the size of the lesion, but the patient was suffering from grade 3 fatigue, grade 2 myeloid suppression, and grade 2 renal insufficiency; subcutaneous IFN-2b was immediately discontinued. In order to continue the trial of immunotherapy without systemic side effects, topical applications of the interferon–lidocaine solution were continued, and a new monthly schedule of small volume (0.3–0.4 ml), 5 MU/ml IFN-2b injected into and surrounding the palatal lesion was substituted for subcutaneous IFN-2b. A surprisingly rapid reduction in the size of the lesion from 25 mm 25 mm to 3 mm 2 mm was observed over only 3 months (Figure 1). An excisional post-treatment biopsy of the residual lesion (Figure 1D) revealed extensive necrotic tissue with scattered tumor cells (Figure 3C). The patient was followed up with repeat physical examinations and serial imaging every 3 months. No oropharyngeal tumor regrowth was observed on close surveillance, including serial nasopharyngeal endoscopy.

Sixteen months after the initiation of local immunotherapy, the patient presented with symptoms of nasal stuffiness, speech difficulties, and episodic epistaxis. Nasophrayngeal endoscopy detected an exophytic lesion on the midline of the posterior aspect of the vomer, resting on the upper surface of the palate. After obtaining histologic confirmation of renal cell carcinoma, the lesion was treated locally, with IFN-2b injected directly into and surrounding the lesion, administered by nasal endoscopy. The first injections resulted in a rapid improvement in breathing and speech symptoms after less than a week, and the injections were administered twice more, at monthly intervals. Repeat endoscopy confirmed that the growth had shrunk to a clinically undetectable size, as had been observed with the palatal lesion. At the time of recurrence in the nasal cavity, unstable angina and small-volume pulmonary metastatic disease were also diagnosed. Over the following 30 months, local immunotherapy was repeated, and low-dose, subcutaneous IFN-2b therapy was reinstated for pulmonary metastasis. The latter was administered intermittently over the following months because of treatment-related adverse events. A deterioration of global health status—attributable to the cancer, worsening Parkinson's disease symptoms, and unstable anginal symptoms—precluded aggressive medical or surgical treatments for any of the conditions, and the patient died 52 months after his initial presentation with the palatal lesion.

Discussion of diagnosis

Head and neck metastases and palatal metastases that originate from renal cell carcinoma are unusual,^{1, 2, 3, 4, 5} accounting for just 6% of all head and neck metastases.⁶ Common sites of metastatic renal cell carcinoma in the head and neck area include the paranasal sinuses, the parotid gland, the eye, the orbital rim, the inner ear, the external auditory meatus, the mandible, and only rarely the palate.⁷ Given this patient's history of heavy smoking and the relatively long time period before developing palatal metastasis following nephrectomy, therefore, a second primary tumor of oropharyngeal origin was suspected.

The differential diagnosis for primary oropharyngeal tumors considered for the patient's palatal lesion included squamous cell carcinoma of the palate (the most common malignant tumor of the palate), minor salivary-gland lesions such as adenoid cystic carcinoma and adenocarcinoma, extranodal B-cell and T-cell lymphomas, and other rare soft-tissue neoplasms, such as mucosal melanoma, soft-tissue sarcoma and plasmacytoma. This differential diagnosis prompted a diagnostic work-up that included multiple imaging studies and a biopsy of the palatal lesion. Imaging studies were performed for local evaluation of the lesion as well as for the assessment of distant disease: for example, focused-view CT scans (coronal sections) of the head and neck, including a view of the paranasal sinuses, and MRI scans to assess the depth of invasion. Distant metastatic disease was evaluated in the chest, abdomen, and pelvis via body CT scans. Histopathologic assessment of a fine-needle biopsy specimen was compared with the histopathology of the original nephrectomy specimen. The biopsy specimen showed distinct features of clear-cell morphology that were consistent with the primary nephrectomy histopathology; on the basis of these findings, metastasis from renal cell carcinoma to the palate was confirmed. No evidence was found of squamous cell carcinoma, adenoid cystic carcinoma or spindle-shaped tumor cells. A fine-needle biopsy of the lesion, rather than a core biopsy, was the procedure of choice, because of the potential for excessive bleeding from possible renal-cell-carcinoma metastases, which are typically vascular lesions.

Treatment and management

The traditional treatment for metastatic renal cell carcinoma is systemic immunotherapy in the form of interferon or interleukin-2 (IL-2). The efficacy of IFN-2b monotherapy has been explored in several well-conducted, randomized trials of a variety of doses and schedules, with modest results.⁸ An overall response rate of 15% has been observed in most studies, with limited durability of response periods. High-dose bolus IL-2 immunotherapy, on the other hand, has provided impressive, durable responses in a limited subset of patients (approximately 7% long-term complete response rate), albeit at a high level of toxicity.⁹ In addition to specific immunotherapeutic interventions, metastasectomy in renal cell carcinoma for oligometastasis has been a well demonstrated therapeutic strategy in selected patients.¹⁰ Therefore, patient selection in metastatic renal cell carcinoma markedly influences survival rates. For example, in a multivariate analysis of 278 patients with recurrent renal cell carcinoma undergoing curative or noncurative resection without systemic immunotherapy,¹¹ the highest overall survival rate was observed in the subset of patients undergoing curative metastasectomy. In this and other studies, the strongest predictors of survival included a single metastatic site, a disease-free interval of greater than 1 year, and a good performance status.

In our patient, a metachronous oligometastasis with low tumor volume provided an opportunity for attempting a metastasectomy. In light of the patient's presentation with a solitary metastasis, surgery seemed the best option; however, this would potentially have involved the removal of more than half of the soft palate, as well as a portion of the hard palate and, possibly, the posterior wall of the maxillary sinus. After discussing the treatment options with the patient and explaining the surgical approach, the patient opted for a trial of systemic immunotherapy instead of surgery because of the patient's concern about the high postoperative morbidity burden from reconstructive palatal surgery. Surgery was reserved as a second option, to be considered in the event of immunotherapy failure.

Treatment was begun with low-dose, subcutaneous IFN-2b, administered every other day, with the intention of increasing the dosage over time. Since the oral lesion was easily accessible, an attempt was made to treat it directly, with the patient applying an interferon–lidocaine solution to the lesion with a swab. It had been hypothesized, in reports of patients receiving inhaled IL-2 therapy for isolated pulmonary metastasis from renal cell carcinoma, that local delivery of interferon to the tumor lesion, in addition to systemic treatments, might increase treatment efficacy and the likelihood of a response.¹² Initial stabilization of tumor growth after 4 weeks was taken as a sign of response to IFN-2b therapy. This response was, however, accompanied by systemic toxicity. As subcutaneous treatment had resulted in toxicity, submucosal injections with small-volume IFN-2b were attempted, with a view to increasing efficacy at a lower cost of systemic side effects. A rapid decrease in the size of the lesion was reported by the patient after initiation of direct IFN-2b injections, and this strategy seemed to have been successful.

An excisional biopsy of the remaining lesion, performed as a therapeutic and diagnostic procedure, provided a rare opportunity to grade histologic response to interferon treatment in metastatic renal cell carcinoma. The patient's major, but incomplete, response is evident from the extensive necrosis with scattered renal cell carcinoma seen after immunotherapy that replaced the extensive infiltration by tumor cells seen at presentation (Figure 3). Post-treatment immunohistochemistry revealed expression of a diffuse CD3⁺ lymphocytic infiltrate that had not been evident at presentation (Figure 4), as well as a reduction from 85 microvessels per high-power field at presentation to 58 microvessels per high-power field after treatment (Figure 3); these findings are not surprising, as interferons are known to modulate cellular immune function and to downregulate cancer angiogenesis.^{13, 14} Interestingly, CD3⁺ lymphocytes did not coexpress CD56 (a marker used for detecting expression of natural killer cells or neural-cell adhesion molecules), which was, instead, detected on tumor cells after treatment (Figure 4). It is possible that the post-therapy CD56⁺ tumor nests might be result from the expression of neural-cell adhesion molecules by an aggressive and interferon-unresponsive subclone of tumor cells,¹⁵ or from a resistance mechanism acquired by previously interferon-responsive tumor cells.

Figure 4 Pretreatment and post-treatment CD3 and CD56 expression (1000).

(A) Pretreatment CD3^- immunohistochemistry. (B) Tumor cells with CD56^- immunohistochemistry in pretreatment biopsy specimen. (C) CD3⁺ diffuse lymphocytic infiltrate in post-treatment specimen. (D) Tumor cells expressing CD56 in post-treatment specimen. Abbreviations: L, lymphocytic infiltrate; TC, tumor cell.

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Conclusion

The accessibility of the solitary palatal metastasis and the desire to limit systemic interferon toxicity in this patient prompted an unconventional treatment strategy that combined daily topical application and monthly injection of IFN-2b. This resulted in a rapid decrease in tumor size without accompanying systemic adverse effects. While this strategy proved reasonably successful in providing tumor control without increasing systemic side effects in this case, it is not known whether direct, target-based local immunotherapy intervention in patients demonstrating initial response to systemic immunotherapy will be an appropriate strategy in managing other metastatic renal carcinoma patients. Such a strategy could be explored in patients unable to undergo surgical or medical treatments who present with accessible lesions.

At present, a targeted approach to treat solitary metastasis in renal cell carcinoma with metastasectomy remains the better-established and more reasonable therapeutic alternative. This typically involves surgical resection without systemic therapy, followed by close clinical monitoring for progression, as it is not yet clear whether a strategy of early additional systemic immunotherapy enhances disease control. Depending on the site of metastasis and disease volume, a trial of a less-invasive, lesion-directed strategy might be equally successful in controlling local growth, as well as in maintaining quality of life. As with metastasectomy, such a strategy—if successful—must always include a rigorous follow-up program, as a role for immediate systemic immunotherapy in such circumstances remains undefined.

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Subject areas under which this article appears: Urologic oncology (nonprostatic)