Primary Colonic -Type Adenocarcinoma of the Base of the Tongue: a Previously Unreported Phenotype

Abstract

Primary lingual adenocarcinomas are rare and typically of salivary or seromucinous glands origin. Similarly, metastatic adenocarcinoma from distant primary sites to the tongue is an uncommon event, with only three cases from a colonic primary site reported. We present, for the first time, two primary colonic-type adenocarcinomas of the base of the tongue and discuss their putative origin and the clinicopathologic characteristics.

INTRODUCTION

Primary lingual adenocarcinomas are rare and predominantly of salivary or seromucinous glands origin (1–5). Similarly, metastatic adenocarcinomas to the tongue are uncommon and comprise approximately 35% of all secondary tumors at this location (3, 6–16). Of the latter, only three instances of colonic adenocarcinoma to the tongue have been reported (9, 12, 14).

We present, for the first time, two primary colonic-type adenocarcinomas of the base of the tongue and discuss their putative origin, clinicopathologic characteristics, and the differential diagnosis.

CASE REPORTS

Case #1

A 58-year-old male presented with recent oral bleeding and a tongue mass. The patient’s significant medical history included hypertension and a long history of smoking. Physical examination revealed a firm mass occupying the base of the tongue with extension into the oral tongue (Fig 1). No lymphadenopathy was identified on examination. A biopsy was taken and revealed colonic-type adenocarcinoma. Extensive examination (colonoscopy, PET/CT) failed to identify any gastrointestinal primary tumor. Induction chemotherapy was initiated, and after 6 weeks with no noticeable response the patient underwent total glossectomy and left neck dissection. On gross examination, the mass was 3 cm in size and centrally located in the submucosa of the base of tongue with extension into mobile tongue. The tumor showed a light-tan appearance and was firm with infiltrative ill-defined margins. Lymph node examination revealed microscopic metastatic carcinoma in only one level 3 lymph node. The postoperative course was uneventful and the patient has remained free of recurrence and metastasis to the last follow-up (13 months).

Fig. 1.

CT of the neck with IV contrast showing an enhancing tongue mass (case #1).

Case #2

A 58-year-old male presented with a history of bilateral neck adenopathy, macroglosia, pain, hoarseness, and slurred speech of one year’s duration. The patient’s significant medical history included hypertension and a long history of smoking. On physical examination an irregular ulcerated submucosal indurated mass in the base of the tongue and bilateral lymphadenopathy was noted. A biopsy of the tongue mucosa was taken and an adenocarcinoma with colonic features was diagnosed. A chest x-ray and CT-scan revealed multiple bilateral lung nodules. PET/CT scan and lower and upper gastrointestinal endoscopy showed no evidence of gastrointestinal primary tumors, and no other metastatic lesions were identified. Induction chemotherapy was initiated but due to progression of the disease at the primary site and regional nodes, the patient underwent total glossectomy and bilateral neck dissection. Grossly, a 4.5 cm firm and ill-defined mass was located in the base of tongue submucosa with extension in the anterior two thirds of the tongue (Fig. 2). Metastatic carcinoma to bilateral multilevel lymph nodes was found. The patient has remained free of recurrence and metastasis to the last follow-up (11 months) with excellent quality of life and return of function.

Fig. 2.

The 4.5 cm firm tumor with ill-defined infiltrative boundaries was located in the submucosa (carcinoma #2).

Methods

Immunohistochemistry (IHC)

Immunohistochemically, the following primary antibodies were used by the ABC-method: CDX2, CK7, CK20, and beta-catenin. Microsatellite instability status was also assessed by IHC for hMLH1, hMSH2, hMSH6, hPMS-2 mismatched repair proteins (17, 18).

DNA analysis

DNA was isolated from paraffinized normal and tumor tissues using microdissection. The isolated DNA was of good purity, as judged by the fact that the A₂₆₀/A₂₈₀ value of approximately 1.8. K-ras was amplified by polymerase chain reaction (PCR). The purified PCR products were applied to the fluorescent dye terminator cycle sequencing reaction (Perkin Elmer, Rodgau, Germany). Analysis of the product of the sequencing reaction was performed on an ABI Prism 310 sequencer (Applied Biosystems, Darmstadt, Germany). Nucleotide sequence alignment was performed with DNA Star software (DNASTAR, Inc, Madison, WI). All sequence reactions were performed in both directions and tested for concordance.

Results

a) Histopathology

Tumors in both patients were invasive well to moderately differentiated colonic-type adenocarcinomas (Figs. 3, 4). The colonic malignant epithelial cells forming tubular and glandular structures with intra-glandular necrosis were dominantly observed in both tumors, with a significant mucinous component found in the tumor from patient #2 (Fig. 4).

Figs 3–4.

The carcinomas in both patients were a well to moderately differentiated colonic-type adenocarcinoma, with characteristic columnar malignant epithelial cells forming tubular and glandular structures, and with intra-glandular necrosis (Figs. 3, 4). The carcinomas of patient #2 exhibited considerable mucinous component (Fig. 4). Both carcinomas manifested strong positive staining for CK20 and CDX2 (Figs 3, 4). No CK7 staining was noted in carcinoma #2 (Fig 4) but in carcinoma #1 a focal staining was noted in tumor cells (Fig. 3).

b) Immunohistochemistry

Both tumors manifested strong positive membranous/cytoplasmic staining for CK20 and beta-catenin, and nuclear staining for CDX2. CK7 staining was negative in carcinoma #2 (Fig. 4) and focally positive in tumor #1 (Fig. 3) (Table 1). Tumor cells in both cases showed nuclear staining for hMLH1, hMSH2, hMSH6, and hPMS-2 mismatch repair proteins.

Table 1.

Immunomarkers in Invasive Intestinal-Type Adenocarcinoma of Tongue

Case #	CK7	CK20	CDX-2	β-Catenin
1	-*	+	+	+
2	-	+	+	+

^*Focal positivity in few cells; -: Negative; +: Positive

c) K-ras Analysis

DNA sequencing of codons 12, 13, and 61 of the K-ras revealed no mutations.

DISCUSSION

We report a previously undocumented primary colonic-type adenocarcinoma of the base of the tongue in patients who had no prior or concurrent evidence of primary intestinal malignancy. The tumors were located in the submucosa of the base of the tongue and manifested histopathologic features and immunohistochemical profiles characteristic of primary colonic adenocarcinoma with a mucinous component. Interestingly, in both patients neck lymph node metastasis similar in distribution to those of primary base tongue carcinoma of squamous origin were found: the first patient had a single microscopic metastatic focus, while the second patient had widespread bilateral neck disease. The lack of primary colonic carcinoma and the anatomic restriction of metastasis to the neck lymph nodes supported the primary lingual origin of these tumors.

The primary clinical and pathologic issue in both cases was the exclusion of metastasis from a colonic primary site, especially with positive immunohistochemical staining for CK20 and CDX2 in both tumors. Moreover, all reported metastatic colonic carcinomas to the tongue were also submucosal and presented at a similar lingual location (Table 2). In contrast to our cases, all metastatic colon carcinoma to the tongue were preceded by colonic primary tumors (9, 12, 14). Taken together, the lack of colonic primary tumors and the selective metastasis to the neck nodes formed the basis for the primary lingual origin of our cases. Interestingly, the recent finding of an adenocarcinoma in a foregut duplication cyst of the floor of the mouth of a 61-year-old male may suggest an alternative origin for this phenotype (19). No evidence of a preexisting rudimentary cystic structure was found in our cases.

Table 2.

Clinicopathologic Features Intestinal-Type Adenocarcinoma in Tongue

Status	Age	Sex	Size (cm)	Site	Location	Time to mets	Disseminated disease
Metastasis
Colon	54	M	2.5	LT	SM	3 months	UK
Rectum	68	M	2.5	BOT	SM	36 months	Yes
Colon	53	F	1.5	BOT	SM	7 months	Yes
Primary
1	59	M	2.5	BOT	SM	Conc.	LN
2	59	M	3.5	BOT	SM	Conc.	LN, Lung

BOT: Base of Tongue; SM: Submucosal; LT: Lateral tongue; LN: Lymph node; UK: Unknown; Conc.: Concurrent

The histogenesis of both tumors is uncertain but an origin from a transformed minor salivary duct epithelium at this location is a likely possibility (20–25). This is supported by the IHC findings in both tumors and by studies of primary intestinal-type adenocarcinoma of the sinonasal tract where evidence of respiratory epithelium transformation to an intestinal phenotype have been noted in the adjacent non-neoplastic epithelium (18, 26–29). The transdifferentiation of the respiratory to the intestinal type epithelium was associated with a reversal of the CK7/CK20 expression in the metaplastic epithelium which was maintained in the developing carcinoma (5, 18, 28). It is interesting, however, that similar primary phenotype in the lung manifested an immunoprofile consistent with primary adenocarcinoma and were negative for CK20 and CDX2 (30). These differences could be related to epigenetic differences between upper and lower respiratory epithelium.

Our analysis of the molecular alteration common to colonic adenocarcinoma in these tumors revealed a lack of alteration in the K-ras gene and hMLH1, hMSH2, hMSH6, hPMS-2 mismatch repair protein expression. Studies of similar tumors in the sinonasal tract have also shown infrequent alterations of these genes (18); only a single K-ras mutation was identified in one of the six tumors studied.

The small number of tumors analyzed, however, precludes any definitive conclusion on the involvement of these alterations tumors from extra-colonic. Although none of our patients developed either local or distant disease one year after surgery, the clinical outcome should be guarded.