Sinonasal tract seromucous adenocarcinomas: a report of 12 cases

Sinonasal Tract Seromucous Adenocarcinomas: A Report of 12 Cases A.G. Neto, MD, K. Pineda-Daboin, MD, and M.A. Luna, MD Sinonasal seromucous adenocarcinomas may originate from the surface epithelium or from the submucosal glands. We reviewed the clinicopathologic material from 12 patients with sinonasal tract seromucous adenocarcinomas at the University of Texas M. D. Anderson Cancer Center (Houston, TX). There were nine men and three women age 30 to 87 years (mean age, 56.3 years). The clinical presentation included nasal obstruction, nasal mass, and epistaxis. Eight tumors were located in the nasal cavity, three in the ethmoidal sinuses, and one involved the nasal cavity and ethmoid. Histologically, in nine cases the neoplastic glands were lined by a single cell type, arranged back to back without intervening stroma and often inducing desmoplastic reaction. The remaining three tumors also had a cribriform and papillary pattern. All patients were treated by surgical resection. Three patients had recurrences, which occurred at 36, 36, and 48 months after initial therapy. Their treatment involved surgery and irradiation. Eleven patients are alive and free of disease at 36 to 108 months after diagnosis. One patient died 48 months after diagnosis of another cause. Sinonasal tract seromucous adenocarcinomas arise purely from submucosal seromucous glands. The diagnosis is facilitated by their anatomic location, the absence of tumor within the mucosal surface epithelium, and the striking similarity to terminal tubules of the seromucous glands. Ann Diagn Pathol 7: 154-159, 2003. © 2003 Elsevier Inc. All rights reserved. Index Words: Sinonasal tract; seromucous glands; seromucous adenocarcinoma

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INONASAL adenocarcinomas can be separated into two groups: those whose origin can be traced unequivocally to the surface mucosal epithelium and those of seromucous gland origin.1 The majority of neoplasms in the latter group have a histologic phenotype analogous to those of salivary gland neoplasms found in the major salivary gland or oral cavity (ie, adenoid cystic carcinoma, mucoepidermoid carcinoma, and pleomorphic adenoma, among others).2 There is a distinctive type of adenocarcinoma arising in the region of the middle turbinate and ethmoid that is composed of neoplastic glands closely resembling the normal sinonasal seromucous glands. Kleinsasser named this neoplasm “ter-

From the University of Texas Medical School, Houston, TX; Military Hospital “Carlos Arvelo”, Caracas, Venezuela; and the University of Texas M. D. Anderson Cancer Center, Houston, TX. Address reprint requests to Mario A Luna, MD, Department of Pathology and Laboratory Medicine, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030. © 2003 Elsevier Inc. All rights reserved. 1092-9134/03/0703-0003$30.00/0 doi:10.1016/S0192-9134(03)00012-1

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minal tubulus adenocarcinomas of the nasal seromucous glands”.3 In a later publication, he called these adenocarcinomas papillary-tubular-cylinder cell type.4 Only a few series of this neoplasms have been reported in the English literature to date.2-6 In this report, we describe the clinical findings of 12 patients with sinonasal tract seromucous adenocarcinoma, illustrate the tumor pathologic features, and discuss the histologic differential diagnosis. Materials and Methods Twelve cases of sinonasal seromucous adenocarcinoma were retrieved from the files of the Department of Pathology at The University of Texas M. D. Anderson Cancer Center (Houston, TX) covering a period from January 1, 1992 to December 31, 1999. Clinical and surgery reports and follow-up data were examined. In all case, hematoxylin-eosin stained histologic sections were available for review. Two to 18 slides (mean, eight slides) per case were reviewed, and the light microscopic features were evaluated. Sections from four cases were stained with mucicarmin, alcian blue at pH 2.5, periodic acid Schiff with and without diastase digestion.

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Table 1. Summary of Clinicopathologic Findings of 12 Cases of Sinonasal Seromucous Adenocarcinomas Case

A/R/S

Symptom

Site

Histology

Treatment

Follow-up

1

44/W/F

Mass/sinusitis

ES

Crib ⫹ Pap*

Surg ⫹ XRT

ES

Tub-cyst

Surg ⫹ XRT

MT MT⫹ES MT MT

Tub-cyst Tub-cyst* Tub-cyst* Tub-cyst*

Surg Surg Surg Surg ⫹ XRT

Tub-cyst Onc metaplasia Tub-cyst* Tub-cyst Tub-cyst Onc metaplasia

Surg Surg Surg Surg Surg Surg

Rec 48 mos NED 60 mos Rec 36 mos NED 84 mos NED 108 mos DOC 48 mos NED 84 mos Rec 36 mos NED 36 mos NED 42 mos NED 72 mos NED 80 mos NED 50 mos NED 35 mos NED 100 mos

2

44/W/F

Bleeding

3 4 5 6

67/W/M 61/U/F 50/U/M 69/W/M

Mass/sinusitis Obstruction Bleeding Obstruction

7 8 9 10 11 12

30/As/M 67W/M 52/W/M 50/W/M 55/W/M 87/W/M

Obstruction Mass Mass Obstruction Obstruction Obstruction

ES MT MT MT MT MT

Abbreviations: A, age; As, asian; Crib, cribriform; DOC, died of other cause; E S, ethmoidal sinus; M T, middle turbinate; NED, no evidence of disease; Onc, oncocytoid; Pap, papillary; R, race; Rec, recurrence; S, sex; Surg, Surgery; Tub-cyst, tubulo-cystic; U, unspecified; W, white; XRT, radiation. *Cases with bone invasion.

Results The clinicopathologic findings in the 12 cases reviewed are summarized in Table 1. Patients’ ages ranged from 30 to 87 years (mean age, 56.3 years). Nine patients were white, one Asian, and race was unspecified in two cases. The ratio of men to women was 9:3. The most common presentation was nasal obstruction (six cases), with the remaining patients presenting with mass/sinusitis (four cases) and bleeding (two cases) as the primary complaint. The duration of the symptoms ranged from months to years. The site most frequently involved was the middle turbinate (eight cases), followed by the ethmoidal sinus (three cases). One case involved the nasal cavity and ethmoidal sinus. Histologically, the neoplasms were composed of tubular glands lined by a single cell type (Fig 1). The cells were cuboidal or low columnar and showed regular round to oval nuclei situated at the basal portion. The chromatin was clumped or vesicular, and the nucleoli was prominent (Fig 2). The cytoplasm was slightly eosinophilic and granular. Scattered clear-appearing cells with scanty secretory granules were also observed. Occasional goblet cells were present. The size, shape, and staining of the neoplastic tumor cells was very regular. Pleomorphism, atypia, and increased mitotic activity were present in a few cases, and were focal

when observed. No myoepithelial cells were observed. Stratified high columnar cells, signet ring cells, or pools of mucin with floating malignant cells were not seen. Histologic transition from normal surface epithelium to neoplasia could not be discerned. The glands grew in a “back to back” pattern without intervening stroma (Fig 3), and often inducing desmoplastic reaction (Fig 2). Alternating with these glandular structures were dilated cysts

Figure 1. Tubular architecture with a single row of cuboidal cells with moderate atypia in a low-grade seromucous adenocarcinoma.

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Figure 2. High-power view of a low-grade adenocarcinoma showing cells with eosinophilic cytopasm, vesicular nuclei, and prominent nucleoli. Note the desmoplastic stromal reaction.

Figure 4. Tubulo-cystic pattern. Note the cuboidal and low cylindric cells lining the cysts.

lined by flat cells. Nine cases showed this classic “tubulo-cystic” pattern (Fig 4). When the tubulocystic structures were cut vertically, a trabecular pattern was observed (Fig 5). The remaining three cases showed additional cribriform and papillary areas (Fig 6); two with oncocytoid metaplasia (Fig 7). In situ component or significant dysplasia of the surface mucosa was not identified, nor was transition from tumor to normal mucosa observed. All tumors were invasive without capsular formation. Bone invasion was present in five cases. Nerve and/or lymphovascular invasion was not observed. Occasional intracytoplasmic mucin drops were observed with the help of alcian blue stain but not with the nucicarmin technique. Both mucin stains

showed scanty mucinous material in the lumen of large cysts and glands and thin secretory streaks at the cell surface. The initial treatment consisted of local excision with free surgical margins (eight cases), lateral rhinotomy (three cases) to craniofacial resection (one case). Of the 12 patients with available followup, the disease recurred in three patients at 36, 36, and 48 months after the initial treatment, respectively. These patients underwent surgery and radiation therapy. One patient died of metastatic breast carcinoma 48 months after the initial diagnosis. Eleven patients are alive and free of disease 36 to 108 months following initial diagnosis.

Figure 3. Glands growing “back to back” without intervening stroma.

Figure 5. Clear cells with small uniform nuclei arranged in a trabecular pattern.

Sinonasal Tract Seromucous Adenocarcinomas

Figure 6. (A) Well-differentiated seromucous adenocarcinoma with intraductal papillary formations. Inset shows high magnification of papillae. (B) Cribriform pattern in seromucous adenocarcinoma.

Discussion The normal sinonasal mucosa is covered by a pseudostratified columnar ciliated epithelium with goblet cells. The luminal lining of ciliated and goblet cells in varying proportions is separated from flattened basal cells by one or more layers of intermediate cells.7 Beneath the epithelium is the submucosa with the seromucous glands of the nasal respiratory tract, which are referred to as the “glandulae nasals.”7 These glands consist of irregularly branching tubules that often end blindly and occasionally terminate in a slight distension, the acinus. The clear-cut structural subdivision of the major salivary glands into acinus, intercalated, and striated ducts is missing in the nasal glands. The secretory epithelium of the tubules differs only slightly from the acinar cells when either light or electron microscopy are performed. There are nu-

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merous gradients between the tubular and acinar cells, and it seems to be most appropriate to call these glandular segments the “terminal tubules.”3 Malignant neoplasms of the nasal cavity and the paranasal sinuses are rare and represent approximately 15% of the neoplasms in the upper aerodigestive tract.5 In this region, 80% to 90% of malignancies are squamous cell carcinoma and tumors of minor salivary gland origin; other glandular neoplasms constitute between 4% to 8% of malignant neoplasms of this site.8 Of the salivary gland type of sinonasal carcinomas, adenoid cystic carcinomas is by far the most common, followed by the adenocarcinomas type non-specified (NOS), mucoepidermoid carcinomas, and other unusual types such as epimyoepithelial carcinomas, carcinoma ex pleomorphic adenomas, and others.2 The adenocarcinomas NOS group constitute a heterogenous subset of neoplasms that can be subclassified into several morphologic subgroups (ie, papillary, mucinous, seromucous, tubular, among others).5,6 In reality, a malignant salivary gland carcinoma that does not fit any of the classic tumors of the salivary glands is usually classified as adenocarcinomas NOS.5 Therefore, the frequency of sinonasal seromucous adenocarcinoma remains unknown. Furthermore, this problem is compounded by the fact that in many series they are not separated into surface origin or salivary gland type.2,8 In reviewing the available literature, only a few descriptions of these distinctive nasal adenocarcinomas could be found. The most complete clinicopathologic description was made by Kleinsasser in

Figure 7. Oncocytoid-appearing cells in a low-grade seromucous adenocarcinoma.

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1985.3 However, he admitted that the adenocarcinomas were originally confused with cystadenomas or adenomas by several authors.3 Heffner et al2 also agreed that the literature in recent decades contains little reference to adenomas of the sinonasal tract and, aside from pleomorphic adenomas of the nasal cavity, tends to regard all glandular neoplasms of this anatomic region as malignant. Many of the neoplasms of this type may be found in the Armed Forces Institute of Pathology2 series where they were categorized as “low-grade adenocarcinomas” (Fig 1). Seromucous adenocarcinoma should be distinguished from the respiratory epithelial adenomatoid hamartoma, the seromucous gland hamartomas, inverted papillomas, antrochoanal polyps, and other types of adenocarcinomas. The respiratory epithelial adenomatoid hamartomas described by Wenig and Heffner,9 as their names imply, are formed of ciliated glands of the respiratory-type, originating from the surface epithelium of the sinonasal tract. The seromucous gland hamartomas are composed of a proliferation of small seromucous glands alternating with cysts and blood vessels.9,10 In contrast with the adenocarcinomas, these hamartomas show two types of cells lining the small glands, and lack a cribriform pattern, a desmoplastic reaction, and the invasive characteristic of the adenocarcinomas. Inverted papilloma, especially the cylindrical cell type, should not be confused with seromucous adenocarcinoma. The cylindrical-cell papilloma show stratification of cylindrical cells with eosinophilic cytoplasms resting in a thick basement membrane; intraepithelial cysts are also observed. In addition, the cells have an oncocytoid look.9 The presence of infarcted areas, proliferation of blood vessels, edema, inflammatory cells, and scanty gland in addition to the radiographic appearance characterizes the antrochoanal polyp. Sinonasal seromucous adenocarcinoma also must be distinguished from the high-grade intestinal type adenocarcinomas because of the more aggressive clinical course of the latter, with 80% of deaths occurring within 3 years of diagnosis.11 The distinction is usually straightforward, given the intestinal appearance of the cells, the nuclear stratification of tall cylindric cells, and the nuclear pleomorphism in the enteric high-grade adenocarcinomas. The salivary gland neoplasms of the usual type can be easily separated from the seromucous adenocarcinoma, because their morphology is

identical to their counterpart in the major salivary gland.6 Metastasis should be always a consideration in the differential diagnosis. In the clinical presentation of our cases there was an absence of facial deformity, the symptoms were of long duration, and there was a minimal incidence of pain, suggesting the low-grade nature of the neoplasm. The anatomic location of the tumors in these cases, as well as that of the “low-grade carcinomas” reported by Heffner et al2 and Kleinsasser3 indicates that the adenocarcinomas are primarily nasal (ie, turbinate, middle concha) or ethmoidal in origin. The most frequent symptom and sign, nasal obstruction and epistaxis, were also observed in our cases. Despite their usually low-grade histopathologic appearance, seromucous gland adenocarcinomas can recur and their recurrences can have a lethal behavior. Heffner et al2 noted a 30% recurrence rate, similar to the findings in our series in which three of 12 patients (25%) had tumor recurrence. In the Kleinsasser3 series, one patient died of the disease, with lung metastasis and intracraneal extension 2 years after initial treatment. In the Armed Forces Institute of Pathology series, one patient died of the disease with cranial base invasion and metastasis to the oropharynx and larynx.2 Because these tumors are low-grade adenocarcinomas, a longer follow-up period is needed. Regarding treatment for the seromucous gland adenocarcinoma, we found that surgery alone appeared to be the treatment of choice; however, for the more malignant spectrum of the tumor and for recurrent lesions, surgery and radiation appear to be the best approach. This conclusion is concurrent with what has been written in the literature. The histogenesis of these sinonasal adenocarcinomas remains controversial. Kleinsasser,3 in his original description of the terminal tubulus adenocarcinomas, thought that they arose from the nasal seromucous glands. The uncertainty over whether sinonasal gland neoplasms originate at the surface epithelium versus the seromucous gland has led investigators to classify the malignant variants as only high grade or low grade on the basis of their histologic appearance.2 The fact is that the epithelium of the seromucous glands, excretory ducts, and surface epithelium all have a common ectodermal embryologic origin and should have the potential to give rise to histologically similar neoplasms.

Sinonasal Tract Seromucous Adenocarcinomas

Pathologists should classify these adenocarcinomas by their histologic features reminiscent of their normal-appearing counterparts, ie, intestinal type and nonintestinal type such as seromucous and salivary gland adenocarcinomas, adding the degree of differentiation. In our study, no in situ component was identified; rather, we observed normal surface epithelium with no transition between normal epithelium and neoplastic glands. Therefore, we speculated that the neoplastic glands originated from the seromucous glands within the mucosa. No cases arising from the surface mucosa were observed. In conclusion, the neoplastic glands of seromucous adenocarcinomas correspond morphologically and almost exactly to the normal nasal terminal tubules, and tubular formations appear to be the predominating pattern. Therefore, it seems to be justified to use the name “sinonasal tract seromucous adenocarcinoma,” given their similar appearance to the sinonasal seromucous glands, as described early in this article. The diagnosis of these tumors is facilitated by their anatomic location, absence of tumor in continuity with the mucosal surface epithelium, lack of numerous goblet cells, stratified high columnar cells, and the striking similarity to the terminal tubules of the seromucous glands.

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References 1. Manning JT, Batsakis JG: Pathology consultation. Salivarytype neoplasms of the sinonasal tract. Ann Otol Rhinol Laryngol 1991;100:691-694 2. Heffner DK, Hyams VJ, Hauck KW, et al: Low-grade adenocarcinoma of the nasal cavity and paranasal sinuses. Cancer 1982;50:312-322 3. Kleinsasser O: Terminal tubulus adenocarcinoma of the nasal seromucous glands. A specific entity. Arch Otorhinolaryngol 1985;241:183-193 4. Kleinsasser O, Schroeder HG: Adenocarcinomas of the inner nose after exposure to wood dust. Morphological findings and relationships between histopathology and clinical behavior in 79 cases. Arch Otorhinolaryngol 1988;245:1-15 5. Goepfert H, Luna MA, Lindberg RD, et al: Malignant salivary gland tumors of the paranasal sinuses and nasal cavity. Arch Otolaryngol 1983;109:662-668 6. Gnepp DR, Heffner DK: Mucosal origin of sinonasal tract adenomatous neoplasms. Mod Pathol 1989;9:365-371 7. Busuttil A, More IA, McSeveney D: A reappraisal of the ultrastructure of the human respiratory nasal mucosa. J Anat 1977;124:445-458 8. Robin PE, Jean Powell D, Stansbie JM: Carcinoma of the nasal cavity and paranasal sinuses: Incidence and presentation of different histological types. Clin Otolaryngol 1979;4:431-456 9. Wenig BM, Heffner DK: Respiratory epithelial adenomatoid hamartomas of the sinonasal tract and nasopharynx: A clinicopathologic study of 31 cases. Ann Otol Rhinol Laryngol 1995;104:639-645 10. Cook-Graeme F, Pilch BZ: Hamartomas of the nose and nasopharynx. Head Neck 1992;14:321-327 11. Barnes L: Intestinal-type adenocarcinoma of the nasal cavity and paranasal sinuses. Am J Surg Pathol 1986;10:192-202