Cribriform adenocarcinoma of the minor salivary glands: case report and literature review

Cribriform adenocarcinoma is a rare salivary basal cell adenocarcinoma, first recognised as a separate identity from the polymorphous low-grade adenocarcinoma in 1999 by Michal et al.¹ It represents less than 1% of salivary gland tumours and is defined as low-grade malignancy according to the World Health Organization histopathological classification of carcinomas of the salivary glands.² This neoplasm affects males and females equally and is more common in African and African-American individuals.³ The location of the primary tumour is often the tongue or the palate. These tumours may metastasise to the cervical lymph nodes. Despite this, the overall prognosis for patients is favourable.⁴

The cribriform adenocarcinoma has a lobulated infiltrative growth pattern. Microscopically, the tumour is non-encapsulated, typically with no cyst formation or presence of eosinophilic colloid material. Mitotic figures are uncommon, and cellular atypia is usually mild. The cribriform adenocarcinoma has characteristic pale overlapping nuclei arranged in a cribriform, solid or papillary pattern with a fibrous background stroma.⁵ They stain positive for cytokeratin markers (AE1-3, CK7, CK8, CK18, Cam 5.2), smooth muscle actin and S-100 protein calponin and vimentin. They return a negative stain for thyroglobulin and TTF-1.⁶

Case report

A 79-year-old male presented to the urgent care unit, Faculty of Dentistry, University of Otago, requesting the replacement of a broken filling. His past medical history included a cerebro-vascular accident (stroke), heart murmur and rheumatic fever, the latter diagnosed at the age of 10 years. He was taking atorvastatin (10mg OD), aspirin (100mg OD) and pantoprazole (10mg OD). He was a non-smoker and did not report consuming alcohol regularly. He had no known drug allergies but reported adverse reactions to amitriptyline, nortriptyline, gabapentin and codeine. He was afebrile on presentation and had no palpable cervical lymphadenopathy. Intra-oral examination revealed an incidental finding of a 2.5cm x 2.5cm mass near tooth 38 in the left retromolar trigone (Figure 1). The lesion appeared dark red–purple and was ulcerated, soft and non-tender to palpation. He was unaware of this lesion and had not experienced any pain or discomfort in the area. Clinical differential diagnosis was between a lymphoma or primary salivary gland neoplasm. An initial biopsy of the lesion under local anaesthetic in the dental chair revealed histopathological findings suggesting an unencapsulated infiltrative tumour with bland cytology. However, no definitive diagnosis was reached due to insufficient tissue from the initial biopsy. Computerised tomography (CT) revealed an expansile mass with the displacement of adjacent structures, including blood vessels located inferiorly (Figure 2). The mandibular cortex remained intact and unaffected. No metastases or lymphadenopathy were reported. The CT findings suggested a benign appearance of the lesion indicative of a possible haemangioma with the differential diagnosis of a nerve sheath tumour or, less likely, a paraganglioma.

An immediate referral was made to the multidisciplinary head and neck oncology service of the Dunedin Hospital, where a surgical excision was performed under general anaesthetic. The histopathological report showed eosinophilic columnar cells arranged in cribriform, tubular and micro-cribriform arrangements and scattered glomeruloid bodies. Peripheral hyperchromatic palisaded tumour cells were present in a collaganised background stroma. There was no evidence of lymphovascular, perineural or adjacent tissue invasion. A positive response to S100 and CK7 staining and variable response for glial fibrillary acidic protein and focal membranous positivity for CD117 was evident. Histopathological findings of the excised specimen were consistent with a diagnosis of cribriform adenocarcinoma of minor salivary gland origin (Figure 3). Surgical excision margins were reportedly tumour-free; thus, no adjunctive therapy was used. Twelve months after the surgery, the patient remains stable with no evidence of primary recurrence or metastases. The patient will be regularly reviewed and monitored for potential recurrent disease in the multidisciplinary head and neck cancer service’s outpatient clinic for at least 5 years.

Discussion

There is much debate about whether cribriform adenocarcinoma is distinct from polymorphous low-grade adenocarcinoma. The current 5th edition of the World Health Organization Classification of Head and Neck Tumours identifies it as a distinct subtype of polymorphous adenocarcinoma.^2,7 There is a recognition of different characteristics, including the typical location of the primary tumour, cytology, architecture, early nodal metastases and local behaviour. We found only 149 cases reported in published literature since Michal et al. (1999) first described the cribriform adenocarcinoma as a separate entity.^{1,3–6,8–39}

The commonest primary site is the tongue, and only four cases have been reported previously for the retromolar region.^8,10,20,26 Recurrence rates reported are low at 8.8% for local recurrence following treatment, but long-term follow-up of cases is not well documented in the literature.³¹

In total, 149 reported cases of cribriform adenocarcinoma have been previously described in the literature (Table 1).^{1,3–6,8–39} Gender data for the 149 cases showed 62 (59.62%) were females and 42 (40.38%) were males. The location of the primary tumour was described in 107 cases. The most common site affected was the tongue (n=47, 42.93%), followed by the palate (n=30, 28.04%), the tonsil (n=6, 5.61%), the maxillary sinus/nasal region (n=5, 4.67%), retromolar regions (n=5, 4.67%), buccal mucosa (n=4, 3.74%), parotid gland (n=4, 3.74%), upper lip (n=2, 1.87%) and one tumour (n=1, 0.93%) each was found in the submandibular region, gingiva, epiglottis and floor of the mouth. Of the 107 cases describing location, 42 (39.25%) had lymph node metastases at diagnosis. Fourteen cases (13.08%) reported tumour recurrence during follow-up in local, regional or distant regions. One case involved partial resection of the tumour due to patient factors. One individual died due to cribriform adenocarcinoma metastases. Initially, the cribriform adenocarcinoma was thought to only occur at the base of the tongue. However, this has since been disproved.^5,6,10 De Luca et al. described the location of cribriform adenocarcinoma affecting the tongue, which comprised nearly 60% of cases.³¹ Other sites included the palate (19.6%), tonsil (7.1%), buccal (3.6%), reticular mucosa (3.6%), lip (3.6%), retromolar pad (1.7%) and floor of the mouth (1.7%).³¹ The literature review in this case report found 42.93% of cases reportedly arose in the tongue, while 28.04% occurred on the palate. De Luca et al. found cribriform adenocarcinoma to have a high risk of lymph node metastases (71.7% of cases reported), whereas this study found it to be lower at 39.25%.³¹

The 5th edition of the World Health Organization Classification of Head and Neck Tumours has incorporated molecular data and cytological findings in most sections.⁷ Fine needle aspiration (FNA) has been recognised as important in these tumours’ initial diagnostic workup. However, the FNAs and even core needle biopsies can fail to produce diagnostic specimens, especially lacking architectural information and assessment of the tumour’s interface with surrounding tissues. Diagnosing low-grade malignancies from benign tumours can be difficult with FNA and core needle biopsies.

The polymorphous adenocarcinoma typically contains a single tumour cell type arranged in trabeculae or tubules, swirling or concentrically wrapped around nerves or vasculature.¹⁶ In contrast, the cribriform adenocarcinoma has a multinodular growth pattern, separated by fibrous septae forming a cribriform and microcystic architecture. The low-grade polymorphous adenocarcinoma has a heterogenous histological and molecular profile. Translocations in genes PRKD1, PRKD2 and PRKD3 (protein kinase D) have been identified in about 80% of cases of cribriform adenocarcinoma.²⁷ Whether the cribriform adenocarcinoma remains a distinct subtype or becomes a separate entity in future classifications is unknown.²⁷ Both low-grade polymorphous adenocarcinoma and cribriform adenocarcinoma are associated with the activation of PRKD1, but via different mechanisms.⁴ Surgical excision is the recommended first-line therapy with lateral neck dissection of involved lymph nodes yielding successful results. Adjunctive radiotherapy was performed on nearly 50% of cases. Evidence suggests that cribriform adenocarcinoma is sensitive to radiation therapy.³¹ Chemotherapy is uncommon, and no regime has been validated for cribriform adenocarcinoma.³¹

Conclusion

This case report outlines the identification of the rare cribriform adenocarcinoma of the minor salivary glands located in an uncommon site, emphasising the need to be vigilant to recognise incidental pathology when performing clinical examination. Further, it endorses the value of complete surgical resection for establishing a definitive histopathological diagnosis.

View Table 1, Figure 1–3.