Clinical and therapeutic features of polymorphous low-grade adenocarcinoma

Clinical and therapeutic features of polymorphous low-grade adenocarcinoma Steven D. Vincent, DDS, MS,a Harold L. Hammond, DDS, MS,b and Michael W. Finkelstein, DDS, MS,a Iowa City, Iowa DEPARTMENT COLLEGE

Polymorphous

OF

ORAL

PATHOLOGY

RADIOLOGY

AND

MEDICINE,

THE

UNIVERSITY

OF

IOWA,

OF DENTISTRY

low-grade

adenocarcinoma,

also known

as terminal

duct or lobular

carcinoma,

was first described

in

two clinical case series in 1983. Before that time most of these neoplasms were diagnosed as benign salivary gland neoplasms including pleomorphic adenomas, variants of monomorphic adenomas, or salivary malignant conditions including malignant pleomorphic adenomas, adenoid cystic carcinomas, and adenocarcinoma not otherwise stated. This neoplasm with few exceptions originates in minor salivary gland tissue of the posterior hard and soft palates or buccal mucosa. It is characteristically slow to enlarge; clinical reports show the neoplasm present for many years before diagnosis. We have evaluated the clinical and microscopic features of 15 cases from the archives of The University of Iowa Surgical Oral Pathology Laboratory and added these to published case reports. A total of 204 cases were evaluated with a female/male ratio of almost 2/l. Forty-nine percent originated in palatal mucosa. Polymorphous low-grade adenocarcinomas arising from pleomorphic adenomas or de novo have been reported within major salivary glands and outside the oral cavity. A 17% recurrence rate was found with a regional metastasis rate of 9%. Five cases had multiple recurrences, and 13 recurrences were at or beyond 5 years after the initial diagnosis. Regional node metastases were identified at the time of initial treatment or at the time of recurrence in 9% of cases in which followvp data were specified. (ORAL SURC ORAL MED ORAL PATHOL 1994;77:41-7)

First described by two groups of investigators in 1983 as terminal duct carcinoma’ and lobular carcinoma,* polymorphous low-grade adenocarcinoma is now a well-recognized malignant glandular neoplasm found most often in areas of minor salivary gland. This article adds 15 new cases to the literature and reviews the clinical features and therapeutic management of previously reported neoplasms. MATERIAL AND METHODS

The archives of the Surgical Oral Pathology Laboratory of The University of Iowa College of Dentistry were reviewed, and all cases of salivary gland neoplasms, diagnosed as polymorphous low-grade adenocarcinoma since 1984 were retrieved. In addition, all cases of salivary gland neoplasms accessioned before 1984 were reviewed. From these accessions, 15 cases were identified. The clinical features were recorded, and the case contributors were contacted for additional information concerning management and follow-up. This information is found in Table I. Among cases accessioned before 1984, three had been diagnosed as variants of monomorphic adenoma, one as a pleomorphic adenoma, and three as adenoid cystic carcinomas. One case, (no. 7) had been seen on aAssociate

Professor.

bProfessor. Copyright @ 1994 0030-4220/93/$1.00

by Mosby-Year Book, + .lO 7/14/50083

Inc.

consultation at three institutions and given three distinct diagnoses; basal cell adenoma, adenoid cystic carcinoma, and mucoepidermoid carcinoma. Information on therapeutic management was obtained for 13 cases. All were treated with local excision. One case (no. 6) also had a suprahyoid lymph node dissection, and two cases (no. 7 and 9) received radiation therapy. One case (no. 14) recurred at 2 years and was retreated with wide local reexcision of the floor of the mouth. Follow-up was obtained for 10 cases. Ail patients were reported free of disease for follow-up periods ranging from 3 months to 10 years. MICROSCOPIC

FEATURES

Clinically and at the time of surgery, these neoplasms often appear very well-demarcated. This may lead to the erroneous assumption that the tumor is encapsulated. However, microscopic evaluation will show areas of infiltration into adjacent structures. This infiltration has been described as an “Indian file” pattern with small islands or single rows of epithelial cells noted between layers of collagen at the periphery of the neoplasm (Fig. 1). Additional features indicative of a malignant condition include perineural (Fig. 2) and vascular space invasion (Fig. 3). Histopathologic features common to many benign and malignant salivary gland neoplasms characterize the bulk of these neoplasms. Foci of solid sheets or islands of cells characteristic of basal cell adenoma may be found. Ducts and cystic structures that contain in41

42

Vincent, Hammond, and Finkelstein

ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY

January I994

Fig. 1. Small nests of epithelial cells between collagen bundles at periphery of polymorphous low-grade adenocarcinoma referred to as “Indian file” pattern. (Hematoxylin-eosin stain; original magnification X63.)

Table I. Clinical

University Case

KEY:

and therapeutic features of 15 cases of polymorphous of Iowa Surgical Oral Pathology Laboratory Gender

Age

Site

Duration

I

Size

I

13

2 3 4 5 6

59 78 70 66 50

Male Female Male Male Female Female

Upper lip Upper lip Upper lip Lower lip Palate Tongue

I year 6 years NS NS 1 year NS

1.4 cm 1.5 cm 1.5 cm 1.5 cm 2 cm 1 cm

7

39

Male

Buccal mucosa

NS

3 cm

8 9 10 11 12 13 14

69 75 55 41 NS 52 86

Male Female Female Female Male Male Male

Palate Palate Palate Upper lip Palate Palate Floor of mouth

1 month NS NS 7 years NS 6 months NS

2.5 cm NS 2.5 cm 1 cm NS 1.2 cm 2 cm

15

54

Female

Palate

3 months

1.2 cm

cGy (centiGray),

NED

(No

evidence

of disease),

NS (Not

low-grade adenocarcinoma Treatment

Excision Wide excision Excision Excision Wide excision Glossectomy and suprahyoid node dissection Wide excision 6120 cGy Wide excision Excision and radiation NS Wide excision NS Wide excision Excision Recurrence at 2 years Wide excision NS

from The Follow-up

NED NED NED NS NS NED

9 months 4 years 3 months 10 years

NED 3 years NED NED NS NED NS NED

-

5 years 32 months 7 years 6 years

NED 3 years NS

stated).

spissated secretory material may be noted. Cribriform areas have caused diagnostic confusion with adenoid cystic carcinomas (Fig. 4). A background of myxomatous, mucoid, fibrous, or hyalinized stroma together with the above described epithelial features suggest pleomorphic adenoma (Fig. 5): The cytologic features include little dysplasia and few mitotic figures. The cells show a wide variety of features at-

tributable to both epithelial (cuboidal, columnar, secretory, squamous) and myoepithelial (spindled, plasmacytoid) differentiation. Special stains can be of academic value but are usually not of significant diagnostic importance as most cases are now diagnosed on the basis of recognition of the above described features. However, Gnepp et a1.3 reported that the variable staining pat-

ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY

Vincent, Hammond,and Finkelstein 43

Volume 77, Number 1

Fig. 2. Perineuralinvasioncharacteristicof polymorphouslow-gradeadenocarcinoma (N, nerve). (Hematoxylin-eosin stain; original magnificationX63.)

Fig. 3. Vascular spaceinvasionby epithelialcellsof polymorphouslow-gradeadenocarcinoma. (Hematoxylin-eosinstain; original magnificationX63.)

terns of carcinoembryonic antigen and epithelial membrane antigen may be of value in distinguishing adenoid cystic carcinomas from polymorphous lowgrade adenocarcinoma. Polymorphous low-grade adenocarcinomas have been shown to retain immunologic markers for high and low molecular weight cytokeratins, epithelial membrane antigen, S- 100 protein, carcinoembryonic antigen, and muscle specific actin. Some reports distinguish papillary and nonpapillary subtypes of polymorphous low-grade adenocar-

cinema. Recognizing that papillary areas can be identified within polymorphous low-grade adenocarcinemas, we believe that if the microscopic features are predominantly papillary, the lesion should be referred to as a low-grade papillary adenocarcinoma or papillary cystadenocarcinoma.5-7 Papillary cystadenocarcinomas have been reported more often in males. More importantly, published cases suggest that papillary cystadenocarcinomas recur locally more often and metastasize more often when compared with polymorphous low-grade adenocarcinomas.

44

Vincent, Hammond,

and Finkelstein

ORAL SURGERY ORAL MEDfClNE ORAL PATHOLOGY January 1994

Fig. 4. Cribriform pattern makessomepolymorphouslow-gradeadenocarcinomas difficult to distinguish from adenoidcystic carcinoma.(Hematoxylin-eosinstain; original magnificationX63.)

Fig. 5. Focusof polymorphouslow-gradeadenocarcinomaconsistsof tubulesand ductal structureswithin myxomatousmatrix. Featuressuchof thesehavecontributedto somepastcasesof polymorphouslow-grade adenocarcinomas beingmisdiagnosed aspleomorphicadenomas.(Hematoxylin-eosinstain; original magnification ~63.) REWEWOF PREVIOUS CASE REPORTSAND DlSCUSSTON We have added our 15 cases to the previously reported casesle3’ 8-31in an effort to further clarify the

behavior and response to therapy for this low-grade malignancy. The total number of cases identified was 204. For 184 cases the gender was recorded; 121 were females and 63 were males for a ratio of almost 2 to 1. The location was recorded for 173 neoplasms; the majority occurred in palatal mucosa (Table II). The age at initial diagnosis was most often between

40 and 70 years of age (Fig. 6). The duration of the primary tumor was reported for 48 cases and averaged 2 years 9 months; 6 casesreportedly were present for more than 7 years (Fig. 7). The primary tumor size was most often between 1 cm and 3 cm in greatest dimension; the largest reported case was 6 cm and was located in the floor of the mouth (Fig. 8). A few case reports of polymorphous low-grade adenocarcinoma that appeared as the malignant component of carcinoma ex-pleomorphic adenomas in major salivary glands have been published.23, 29,31

Vincent, Hammond,

ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY Volume 77, Number 1 Table II. Primary

Table III. Original

tumor location

Palatal mucosa Hard Soft Not stated Buccal mucosa Labial mucosa Upper Lower Not stated Retromolar trigone Tongue Floor of mouth Nasal antrum Parotid gland Nasopharynx Total

Table IV. Primary

The difficulty in diagnosing this neoplasm is illustrated by the finding that 42 cases of polymorphous low-grade adenocarcinoma that were originally given an alternative benign or malignant diagnosis (Table III). Some of these cases were published recently and include two cases in our series treated in 1986 and 1989. This indicates a continuing difficulty in diagnosing this neoplasm. Recently published cases of polymorphous low-grade adenocarcinoma arising in major salivary glands25, 27 or elsewhere in the upper aerodigestive tract 1% 18, 19,*8,30 show that the neoplasm is not restricted to oral minor salivary glands. Initial therapy was recorded for 93 cases with excision or wide excision as the treatment of record for 57 (Table IV). Radiation was used in eight cases at doses that ranged from 3820 to 6120 cGy. Of the original 204 cases, 116 reported follow-up. Twenty cases recurred for an overall recurrence rate of 17%. This compares favorably with the 24% Armed Forces Institute of Pathology recurrence rate among 84 cases recently reviewed by Wenig and Gnepp.4 Time from initial treatment to recurrence ranged from 1 to 19 years. Primary tumor recurrence sites included 11 palatal, two buccal mucosal, and three floor-of-mouth neoplasms. Sixteen cases that recurred reported the initial management as follows: nine excisions, three wide excisions, two excision and radiation, one excision with radiation and chemotherapy, and one excision and regional lymph node dissection. Five cases had multiple recurrences, and 13 recurrences were at or beyond 5 years after initial diagnosis. Regional node metastases were identified at the time of initial treatment or at the time of recurrence in 9% of cases reporting follow-up. This is slightly more than the 6% reported by Wenig and Gnepp.4

doses:

3800 5000 6000 6120

11 10 9 7 5 42

tumor therapy

Excision Wide excision Hemisection. maxilla/mandible Excision and radiation Excision, radiation, and lymph node dissection Excision, radiation, and chemotherapy *Radiation

45

microscopic diagnoses

Monomorphic adenomas Adenoid cystic carcinoma Malignant pleomorphic adenoma Adenocarcinoma NOS Pleomorphic adenoma Total

9 2 14 38 4 1 16 11 6 4 3 4 1 173

and Finkelstein

31 26 9 20* 5* 2

(2) (4)

SUMMARY

Polymorphous low-grade adenocarcinoma most often appears as an asymptomatic soft tissue enlargement of posterior palatal mucosa. The neoplasm’s clinical features, including rate of growth, often simulate characteristics of benign salivary gland neoplasms. Microscopically, the neoplasm shows histopathologic features characteristic of many benign and malignant salivary gland neoplasms that continues to make diagnoses difficult. Infiltrative margins and perineural and vascular space invasion contribute to the diagnosis of malignant disease in this otherwise benign-appearing neoplasm. Many additional case reports need to be added to the literature in an effort to further characterize the behavior of this neoplasm. Several case reports now indicate that this neoplasm can be identified in major salivary glands as well as elsewhere in the upper aerodigestive tract. Wide local excision with close evaluation of surgical margins seems to be the most appropriate initial therapy. Because past published case reports strongly suggest that 5-year follow-up is not adequate to rule out recurrent disease, patients diagnosed with polymorphous low-grade adenocarcinoma may need to be followed yearly for the remainder of their lives. Initial therapy may have been adversely affected for several of these cases, especially the 42 cases that were initially interpreted as benign or as some other malignant salivary gland neoplasm. Therefore future primary tumor recurrence rates for this neoplasm may be significantly altered by a correct diagnosis before initial therapeutic management. Our additional 15 cases mimic the overall pattern of this neoplasm. Most occurred in the palatal mucosa

46

Vincent, Hammond,

and Finkelstein

ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY January 1994

28

30 25

q Femafe N=64 Avg. 52.2 n Male N=41 Avg. 57.7

20

5 0 O-IO

II-20

21-30

31-40

41-50

51-60

61-70

71-80

81-90

91-100

Fig. 6. Age at initial diagnosisfor 105casesof polymorphouslow-gradeadenocarcinoma.Ordinate axis: Number of cases.Abscissaaxis: Age in years.

20 1

16

15

10

5

0 *I

I<2

2~3

3<4

4<5

5<6

6~7

>7

Fig. 7. Primary tumor durationreportedfor 48 caseof polymorphouslow-gradeadenocarcinoma. Ordinate axis: numberof cases.Abscissaaxis: years.


I<2

2~3

3*4

445

5<6

6~7

27

Fig. 8. Primary tumor size for 66 casesof polymorphouslow-gradeadenocarcinoma. Ordinate axis: number of cases.Abscissaaxis: greatesttumor dimensionin centimeters.

with an average age of patients at the time of diagnosis of 62 years, a slow rate of growth, and a low recurrence rate (one case) after wide local excision. No case has metastasized. Our male to female ratio of

approximately 1: 1 is probably an aberration because of the relatively small numbers of cases. All patients for whom we have follow-up are alive and well without evidence of recurrent diseaseat the present time.

Vincent, Hammond,

ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY Volume 77, Number 1 REFERENCES 1. Batsakis JG, Pinkston GR, Luna MA, Byers RM, Sciubba JJ, Tillery GW. Adenocarcinomas of the oral cavity: a clinicopathologic study of terminal duct carcinomas. J Laryngol Otol 1983;97:825-35. 2. Freedman PD, Lummerman H. Lobular carcinoma of intraoral minor salivary glands. ORAL SURG ORAL MED ORAL PATHOL 1983;56:157-65. 3. Gnepp DR, Chen JC, Warren C. Polymorphous low-grade adenocarcinoma of minor salivary gland: an immunohistochemical and clinicopathologic study. Am J Surg Path01 1988;12: 461-8. 4. Wenig BM, Gnepp DR. Polymorphous low-grade adenocarcinomas of minor salivary glands. IN: Ellis GL, Auclair PL, Gnepp DR, eds. Surgical pathology of the salivary glands, Vol. 25. Maior nroblems in oathologv. Ch. 23. Philadelnhia: W.B. Saundeis, 1991:390-411. I-’ 5. Mills SE, Garland TA, Allen MS. Low-grade papillary adenocarcinoma of palatal salivary gland origin. Am J Surg Path01 1984;8:367-74. 6. Mostofi R, Wood RS, Christinson W, Talerman A. Low-grade papillary adenocarcinoma of minor salivary glands. ORAL SURC ORAL MED ORAL PATHOL 1992;73:591-5. 7. Ellis GE, Auclair PL, Gnepp DR, Goode RK. Other malignant neoplasms. IN: Ellis GL. Auclair PL, Gnepp DR, Surigcal pathology of the salivary glands. Vol. 25, Major problems in pathology, Ch. 27. Philadelphia: W.B. Saunders, 1991:455-88. 8. Evans HL, Batsakis JG. Polymorphous low-grade adenocarcinoma of minor salivary glands. Cancer 1984;53:935-42. 9. Frierson HF, Mills SE, Garland TA. Terminal duct carcinoma of minor salivary glands. Am J Clin Path01 1985;84:8-14. 10. Aberle AM, Abrams AM, Bowe R, Melrose RJ, Handlers JP. Lobular (polymorphous low-grade) carcinoma of minor salivary glands. ORAL SURG ORAL MED ORAL PATHOL 1985; 60:387-95. 11. Zarbo RJ, Regezi JA, Batsakis JB. S-100 protein in salivary gland tumors: an immunohistochemical study of 129 cases. Head and Neck Surgery 1986;8:268-75. 12. Frierson HF. Pathology quiz Case 1. Arch Otolaryngol Head and Neck Surg 1986;112:568. 13. Slootweg PJ, Muller H. Low-grade adenocarcinoma of the oral cavity: a comparison between terminal duct and papillary type. J Craniomaxillofac Surg 1987;15:359-64. 14. Nicolatou 0, Kakarantza-Angelopoulou E, Angeloupoulos AP, Anagnostopoulou S. Polymorphous low-grade adenocarcinomaof the palate. JOral MaxillofacSurg 1988;46:1008-13. 15. Kennedy KS, Healy KM, Taylor RE, Strom CG. Polymorphous low-grade adenocarcinoma of the tongue. Laryngoscope 1987;97:533-6. 16. Scally CM, Irwin ST, Nirodi N. Low-grade polymorphous adenocarcinoma of a minor salivary gland. J Laryngol Otol 1988;102:284-7. 17. Waldron CA, El-Mofty SK, Gnepp DR. Tumors of the intraoral salivary glands: a demographic and histologic study

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Steven D. Vincent, DDS, MS Department of Oral Pathology, Radiology, and Medicine College of Dentistry, DSB 356 The University of Iowa Iowa City, Iowa 52242