ABSTRACT
Hyalinizing clear cell carcinoma (HCCC) is a rare low-grade malignant tumor of the minor salivary glands of the head and neck. It can also arise in the nasopharynx in rare cases. Only a few cases of nasopharyngeal HCCC (NHCCC) have been reported in the literature, and most patients are in their sixth decade of life. Due to this disease’s rarity, there is no consensus on its optimal treatment. Surgical excision is the mainstay of treatment. However, the role of postoperative radiotherapy is unknown. Herein, we report on a case of NHCCC in a 14-year-old female, treated successfully with sur-gical resection and adjuvant radiotherapy. This patient is the youngest case of NHCCC reported in the literature.
Introduction
Hyalinizing clear cell carcinoma (HCCC) is a rare low-grade malignant tumor of the head and neck salivary glands which was first described in detail by Milchgrub et al. (1) in 1994. HCCC represents 1% of all salivary gland tumors (1, 2). They arise mainly from the palate, base of the tongue, and floor of the mouth and also in the nasopharynx, maxilla, oral mucosa, or nasal cavity in rare cases (1-4).
HCCCs are low-grade malignant tumors, and they have an indolent course. Most patients are in their sixth decade of life and have a female predominance (3). They usually present with painless mass and manifest site-specific symptoms such as epistaxis, tinnitus, or nasal obstruction due to the local mass effect (2, 3).
Its definitive diagnosis is based on histological examination. HCCC has a broad differential diagnosis which includes other clear cell-containing head and neck tumors (3). Hence, it is sometimes challenging to distinguish HCCC from the other salivary gland tumors with clear cell variants based on a small biopsy sample. Antonescu et al. (5) identified a consistent Ewing sarcoma breakpoint region 1 (EWSR1) - activating transcription factor-1 fusion gene in HCCC, and this molecular signature is not present in the other clear cell tumors. Shah et al. (6) recently found that EWSR1 rearrangements were not a feature in the other salivary gland tumors, suggesting that this EWSR1 rearrangement is specific to HCCC and so it can be used to distinguish this lesion from other salivary gland neoplasms.
There have been only a few cases of nasopharyngeal HCCC (NHCCC) reported in the literature. Due to this disease’s rarity, there is no consensus on its optimal treatment. Surgical excision is the mainstay of treatment. However, the role of adjuvant radiotherapy remains unknown. Although there is no standardized treatment regimen, positive surgical margins and particularly aggressive tumors are frequently treated with radiotherapy in order to decrease the risk of recurrence (4).
Case Report
A fourteen-year-old female patient presented with nasal congestion and epistaxis for three months. On her physical examination, a large polypoid mass obliterated the left nasal cavity. Her head and neck examination showed no other lesions or lymphadenopathy. Magnetic resonance imaging showed a protruding nasopharyngeal mass measuring 3x2.5x2 cm in diameter, arising from the left lateral and posterior wall, obstructing the entire nasopharynx, and extending to the Rosenmüller fossa and torus tubarius (Figure 1). A homogeneous contrast enhancement was apparent. There were also bilateral retropharyngeal and cervical lymph nodes of less than 1 cm.
A biopsy was performed, and it showed submucosal diffuse infiltration by neoplastic epithelial cells with clear cytoplasm, round-oval nuclei, and inconspicuous nucleoli. Tumor cells were positive for periodic acid schiff with diastase soluble in histochemistry. Immunohistochemistry revealed that the neoplastic cells were positive for epithelial membrane antigen (EMA), cytokeratin (AE1/AE3), but no expression of DOG1, SOX-10, or p63. This was compatible with clear cell carcinoma. To rule out metastasis from the kidney, a positron emission tomography (PET) scan and abdominal ultrasonography (USG) were performed. The PET scan revealed an abnormal accumulation of fluorodeoxyglucose (SUVmax: 2.5) in the nasopharyngeal mass without any tumors in other sites of the body. Abdominal USG was normal. Tumor markers, such as alpha-fetoprotein, human chorionic gonadotropin and neuron specific enolase were within normal limits. The tumor stage was pT2N0M0. Following this, the patient underwent complete tumor resection.
The tumor originated from the left Rosenmüller fossa, and the boundaries of the resection were the base of the sphenoid sinus superiorly, the lateral nasopharyngeal wall laterally, and the midline posterior nasopharyngeal wall medially. The Torus tubarius and cartilaginous Eustachian tubes were included in the resection. The deep surgical margin was clear along longus capitis and longus colli muscles. An endoscopic partial nasopharyngectomy was performed using the transnasal route (Figure 2).
The resection of the tumor demonstrated the same histological features as the biopsy. Immunohistochemistry showed that neoplastic cells with clear cytoplasm expression of cytokeratin (AE1/AE3) and EMA, but no expression of p63, alpha-smooth muscle actin, S100, PAX8, TFE-3, DOG1, or SOX-10. The Ki-67 proliferation index was approximately 15% in the neoplastic epithelial cells. Chromogenic in situ hybridization (CISH) for Epstein-Barr virus-encoded small RNA was negative. Fluorescence in situ hybridization (FISH) revealed EWSR-1 gene rearrangement in the neoplastic cells. Given the morphology, immunophenotype, CISH, and FISH, the exact diagnosis was clear cell carcinoma (Figure 3). Since the patient had no evidence for the involvement of the renal tissue, besides immunohistochemically, and with TFE-3 being negative in the tumor, renal cell carcinoma was excluded.
After discussing adjuvant treatment at the tumor board, the patient underwent an intensity-modulated radiation therapy of 66 Gy targeting the nasopharynx. There was no recurrent or residual disease after 4 years of follow-up.
Discussion
HCCCs are rare low-grade malignant tumors, and they have an indolent course. To date, 50 cases of NHCCC have been reported in the literature (Table I) (4-24). Due to the rarity of this tumor, most of these reports are clinical case reports. As of 2023, only 21 cases had been reported in the literature. However, in October 2023, Zhai et al. (24) published the largest case series to date, reporting on 26 cases from a single institution. Of these 50 cases, only 43 had detailed information on clinical presentation, treatment, and follow-up. The mean age of the reported 43 patients was 52 years (18-82 years), and twenty-six (60%) were female. To our knowledge, our patient is the youngest patient reported in the literature to date.
Most of the time, HCCCs have an excellent prognosis (4). Local or distant metastases at presentation are uncommon in HCCC. Solar et al. (7) reviewed 52 cases of HCCC independent from localization, reported local lymph node metastasis at 23%, and recommended careful evaluation of the neck and the removal of regional lymphatics. There were no cases of NHCCC presenting with distant metastases in the literature - only seven patients from 43 cases (16%) presented with local cervical lymph node involvement (8, 23, 24).
There is currently no consensus on the standard treatment. The recommended treatment for HCCC is a wide surgical resection, followed by partial or modified neck dissection in the presence of cervical lymph node metastases (4, 8). The effects of chemotherapy and irradiation after surgery are controversial because of the rarity of HCCC.
In the 17 single case reports, four patients were treated with complete surgical excision, and six were treated with surgery and postoperative adjuvant radiotherapy. Of these six patients, five had an excellent prognosis with no evidence of mortality. Only Tang et al. (9) reported a patient who experienced multiple recurrences; however, this case had an incomplete initial surgical excision. Of the 17 reported cases, six presented with extensive disease, and two had local lymph node metastasis (8, 10, 21-23). These six cases were treated with chemotherapy, surgery, and radiotherapy.
We evaluated the study by Zhai et al. (24) separately from the others because it is the largest case series in the literature, consisting of 26 cases reported retrospectively from a single center. Of the 26 patients included in their study, the treatment details of 23 patients were available. Of these 23 patients, 14 had surgery alone, 5 had combined surgery and radiotherapy, 3 had only radiotherapy, and one was treated with chemotherapy and surgery due to advanced disease. In this cohort, tumor recurrence and death occurred in 2 of the 14 patients who underwent surgery alone. Tumor recurrence was detected in 3 of the 5 patients treated with surgery and radiotherapy, but all survived. Three patients who received only radiotherapy died due to progressive disease.
According to these results, complete surgical resection is the mainstay of treatment, and the role of radiotherapy remains uncertain. Case reports both with and without adjuvant radiotherapy are limited. The average follow-up for the single case reports was one year (9 weeks-3 years), excluding one case reported by Tang et al. (9) (with multiple recurrences over 11 years). These follow-up times are too short to assess the role of radiotherapy.
When compared with the literature, Zhai et al. (24) reported a high recurrence rate (23%) (6/26 patients). However, their study has longer follow-up periods (6-192 months) compared to the other single-case reports.
In the present case, we employed endoscopic partial nasopharyngectomy and adjuvant radiotherapy. An adequate safety margin could not be obtained due to the anatomical complexity of the nasopharynx, and the long-term risk of recurrence remains unknown. Albergotti et al. (2) reviewed patients with head and neck clear cell carcinomas treated by surgical resection without documented positive margins or evidence of metastasis at resection, reporting a 20.4% risk of recurrence. There was one case of recurrent NHCCC among the 17 single case reports in the literature, and no patients died from disease progression. However, as mentioned earlier, there are limited cases of NHCCC, and the follow-up periods in these reports are too short. When reviewing the study by Zhai et al. (24) it is evident that the risk of seeing relapse and/or mortality becomes higher with longer-term follow-ups. As a result, long-term follow-ups of these patients are necessary.
The case presented here highlights the importance of a detailed evaluation for a definitive diagnosis. In the treatment of NHCCC, wide local excision is recommended. Despite ongoing controversy regarding the role of radiation in its treatment, adjuvant radiotherapy should be recommended when total surgical removal of the primary tumor is not achieved or for clinically aggressive tumors. Since the reported cases of NHCCC are rare, more cases are needed in order to discuss the role of postoperative radiotherapy, and long-term follow-ups of these patients are essential.
