Adenoid cystic carcinoma.A clinicopathological study

ADENOID CYSTIC CARCINOMA A Clinicopathological S t u d y JOHN

M. BECKER, M.D.,~: LUTHER W. BRADY, M.D.,~ J. MORAN, M.D., STANLEY AND V. BIRCH RAMBO, M.D."

T

HE PATHOLOGICAL features and natural history of adenoid cystic carcinoma have been clearly described in several excellent reviews during the past 20 years. Despite these publications, this group of neoplasms continues to be frequently misdiagnosed and inadequately treated by some physicians. Adenoid cystic carcinoma is still often mistaken for a benign tumor. Many surgeons fail to appreciate the lethal nature of this tumor and thus lose the initial opportunity for a curative procedure. Therefore, a total of 38 cases of adenoid cystic carcinoma, available to us at the Hospital of the University of Pennsylvania, Philadelphia, Pa., was reviewed in regard to pathological and clinical features, long term follow-up, and the results of various modes of therapy.

adenomyoepithelioma, indicating their belief that this neoplasm was composed chiefly of myoepithelial cells rather than cylindrical cells. Dockerty and Mayo8 used the term adenocarcinoma, cylindroma type, to designate this group of neoplasms. Foote and Frazell12 expressed their preference for the name adenoid cystic carcinoma and used this term in their fascicle on tumors of the major salivary glands in the Atlas of Tumor Pathology. Other names implying the relationship of this neoplasm to mixed tumors or basal cell Carcinoma are unsatisfactory, since they are misnomers and obsolete according to the current concepts. T h e term adenoid cystic carcinoma, as suggested in the Atlas of Tumor Pathology, will be used throughout this paper.12

REVIEW OF NOMENCLATURE The term cylindroma was first applied to this type of tumor in 1859 by Billroth.6 In 1945, Bauer and Fox4 introduced the name From the Laboratory of Pathological Anatomy, Department of Radiology, and Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pa. This study was supported by the Penn Mutual Life Insurance Foundation for the Study of Neoplastic Disease and by the Harrison Department of Surgical Research. The authors are indebted to the people listed for the opportunity to review histological material on the following cases: case 3, Dr. Allan D. Wallis, Episcopal Hospital, Philadelphia, Pa., and Dr. Stephen P. Dachi, School of Dentistry, University of Pennsylvania, Philadelphia, Pa.; c a m 2, 4, and 16, Dr. William Beckfield, Philadelphia General Hospital, Philadelphia, Pa.; case 33, Dr. James Butcher, Presbyterian Hospital, Philadelphia, Pa., and Dr. John Culberson, U. S. Naval Hospital, Philadelphia, Pa.; and case 7, Dr. Norman H. Rickles, Dental School, University of Oregon, Portland, Ore. * Present address: Jefferson Medical College Hospital, Philadelphia, Pa. t Present address: Bradford Hospital, Bradford, Pa. $ Fellow of the American Cancer Society, Inc., 19581959. 3 Present address: Hahnemann Medical College and Hospital, Philadelphia, Pa. Present address: Grace Hospital, Banner Elk, N.C. Received for publication Jan. 11, 1961.

THE

LITERATURE

I t is not the purpose of this paper to present a comprehensive review of the many papers on adenoid cystic carcinoma. Rather, it is our purpose to describe briefly the historical background and to compare the findings in some of the larger reviews with those in our present series of cases. In 1859, Billrothe first used the term cylindroma for a tumor arising in the accessory nasal sinuses and penetrating the orbit. He described the histological appearance of these tumors as resembling thyroid follicles composed of cylinders of hyalin and mucin surrounded by tubes of epithelial cells. At first he regarded the cells of the parenchyma as epithelial in origin, but later he described them as connective tissue cells. Among a group of 22 cases of tumors of the salivary gland that he reviewed at that time, 4 cases were diagnosed adenoid cystic carcinoma. One of these tumors recurred 9 times after excision during a period of 20 years. In spite of the repeated recurrences, Billroth found no evidence of lymph node or visceral involvement. After Billroth's accurate description of both the pathological and the clinical features of adenoid cystic carcinoma,6 many writers pro-

1235

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CANCER November-December 1961

Vol. 14

ceeded to confuse this neoplasm with benign HISTOGENESIS mixed tumors and other neoplasms of salivary glands. T h e confusion as to the precise nature T h e theory that adenoid cystic carcinoma of salivary gland tumors is seen in the writings arose from the mucous gland was first proposed of many authors of this period. Fry13 in 1927, by Billroth in 1859.6 Ribbert,ZBin 1907, stated in reporting on the structure and origin of the the origin to be from the mucous gland ducts. “mixed” tumors of the salivary glands, con- Sheldon,28 in describing the origin of so-called cluded that: “Some of the tumours show vary- mixed tumors of the salivary gland, described ing degrees of malignancy; there is n o definite invasive tumors arising from secretory epithedividing line between innocent and malig- lium and invading nerve sheaths. These tunant, and some of the more malignant may mors presumably were adenoid cystic carcishow many of the features typical of the in- nomas in view of their unique tendency to nocent type of tumour.” I n 1936, M ~ F a r l a n d , ~invade ~ nerves. Bauer and FOX,^ in 1945, conafter studying 300 cases of salivary gland tu- cluded that these tumors arose from the basket mors, stated that there was no significance in or myoepithelial cells of the intercalated ducts the many variations in the histological appear- of palatal mucous glands. Russel127 stated that ance of these lesions. His opinion of the nature they arise from dilated mucous glands of the of this group of tumors varied in his publica- anterior foregut, with the epithelium of these tions from all “malignant . . . i n varying de- ducts undergoing degenerative metaplasia g r e e ~ ” ~to3 “inherently benign.”22 from cuboidal cells into small polygonal cells Heschll7 in 1877 described the first case of having very little cytoplasm. I n 1959, Azzowhat he termed “cylindroma of the lung.” pardi and Smith,2 after a histochemical study After his report, this entity became confused of the mucins in salivary gland tumors, conwith the carcinoid type of bronchial adenoma, cluded that adenoid cystic carcinoma arises and both were grouped together under the from the intercalated ducts. These conflicting term bronchial adenoma.l* Harnperl,l5 in views can well be summarized by Foote and 1937, differentiated between the carcinoid and Frazell’slZ statement that “conclusive evidence cylindroma types of bronchial adenoma. Again of the precise source of origin of these tumors in 1954, Enterline and Schoenberglo pointed is yet to be presented.” out that the use of the term bronchial adenoma to include both carcinoid and adenoid cystic INCIDENCE carcinomas was very unfortunate in view of Adenoid carcinoma is a relatively uncomthe decided difference in their behavior and mon neoplasm. I t is impossible to find a n prognosis. Further confusion resulted when, in 1908, over-all figure to indicate its frequency in all Krompecherls classified adenoid cystic carci- locations because most reports in the literanoma with basal cell carcinoma of the skin. ture are confined to a specific organ or region. S p i e ~ , ~ing 1930, finally clearly differentiated I n reviewing salivary gland tumors seen in adenoid cystic carcinoma of noncutaneous ori- the Laboratory of Surgical Pathology of the gin from the epithelioma adenoides cysticum Hospital of the University of Pennsylvania, it was found that this tumor accounted for of skin origin. I n 1942, Dockerty and Mayos in reviewing about 6.01, of all salivary gland neoplasms and a group of $1 tumors of the submaxillary gland 21.0/, of the malignant neoplasms of salivary designated 15 of them as adenocarcinoma, cyl- gland. indromatous type. They clearly summarized all I n a review of 877 major salivary gland of the important features that characterize this tumors from Memorial Sloan-Kettering Canneoplasm-including the prominence of pain cer Center, New York, N.Y.,lZ adenoid cystic in many of the cases, invasive growth, predilec- carcinoma constituted about 4.01, of all tution for invasion of nerves, frequent recur- mors and 14.601, of the malignant lesions. rences, later regional lymph node metastasis, Kirklin and his co-workersls found this neoand general poor prognosis. From this time on, plasm to constitute 4.% of a group of 909 an increasing number of reports have appeared parotid tumors. Dockerty and Mayo,s in 1942, in the literature accurately describing the ma- found 15 cases (18.%) in 81 cases of tumor of lignant nature of these tumors, but many of the submaxillary gland. I n a recent review by the cases reported lack adequate follow-up Fine and his associates,ll this tumor constituted IS.% of a group of 79 minor salivary data.

ADENOID CYSTIC CARClI N O M A

No. 6

TABLE1 S I T E OF ORIGIN OF ADENOID CYSTIC CARCINOMA IN 38 PATIENTS Site origin

No. pt.

Hard palate Parotid gland Submaxillary gland Lacrimal gland Trachea Base tongue Upper lip Soft palate Lacrimal duct Posterior pharynx(?) Bronchus Nostril wall Tongue

1 1 -

38

TOTAL

gland tumors and 35.y0 of the malignant tumors arising in these structures. I n a group of 339 malignant tumors of the nose, throat, and mouth reviewed by McDonald and Havens21 in 1948, adenoid cystic carcinoma comprised about 25.70 of the entire group. T h e incidence of this tumor in the trachea and bronchus is even more difficult to determine except in relationship to other types of so-called bronchial adenomas. I n a recent study by Payne and his asso~iates,~4 a group of 162 bronchial adenomas were studied and adenoid cystic carcinomas comprised 8 . x of this group. MATERIALS AND METHODS

*

Moran et al.

1237

tid and submaxillary glands, with 6 cases originating in each area. T h i s agrees with the finding of Foote and Frazell12 in which the tumors were equally distributed between the parotid and submaxillary glands. Harrisorr16 reported that 66.70 of the adenoid cystic carcinomas in a group of 46 patients had their site of origin outside of the major salivary glands. A similar distribution is apparent in the present group of cases, with 6 9 . x originating outside of the major salivary glands. Other frequent sites of origin included the lacrimal gland, the trachea, the base of the tongue, and the lip. Patient Sex. Harrison16 found in a group of 46 cases of adenoid cystic carcinoma, twothirds of the patients were female. Wawro and McAdams30 also found a preponderance of female patients. Other authors, including Quattlebaum and co-workers25and Payne and his associate^,^^ failed to find any sex predilection. No sex predilection was apparent in our group of patients, i n which 19 were male and 19 female. Patient Race. One of the patients in the present group was Mongolian, 8 were Negroes, and the remainder were Caucasians. Patient Age. T h e age range at the time of diagnosis was from 17 to 83 years (Table 2). T h e tumor is most frequent between ages 30 and 60 years, reaching a peak in the fourth and fifth decades. T h e average age is 48 years. Only 1 case was diagnosed when the patient was less than 22 years old (case 22). Gross Appearance. T h e size of the primary tumor i n the present group of cases varied from 0.5 to 4.5 cm. in largest diameter at time of resection. Wawro and M ~ A d a m sstated: ~~ “There is nothing distinctive about the macroscopic ap-

T h e material consisted of 38 cases of adenoid cystic carcinoma-representing the total experience with this neoplasm at the Hospital of the University of Pennsylvania during the period 1925 to 1960-plus 6 cases treated at other institutions. T h e histological material and clinical data on the additional 6 cases were made available in order to complete this study. TABLE 2 Clinical follow-up data are available for 36 of AGE AT DIAGNOSIS I N ADENOID these cases. CYSTIC CARCINOMA* T h e study was confined to the cases of adenoid cystic carcinoma arising in the up0-10 0 per and lower respiratory tracts, mouth, sali11-20 1 vary glands, and lacrimal region. “Cylindroma- 21-30 3 tous tumors” arising in other locations includ- 31-40 10 10 ing skin and breast were not included because 41-50 51-60 6 they are believed to be basically different neo- 61-70 5 plasms from those previously mentioned. 71-80 2 1 Site of Origin. T h e hard palate is the most 81-90 _. common site of origin, with the neoplasm arisTOTAL 38 ing in that site in 9 cases in this series (Table *The average age in this group of patients was 48 1). T h e next most common sites were the paro- years.

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CANCER November-December 1961

Vol. 14

FIG. 1. Case 15. A, Radical re-excision of recurrent adenoid cystic carcinoma of submaxillary gland, including the contents of the floor of the mouth, the mandible, part of the tongue, and regional lymph nodes. B, Closer view of an area of poorly demarcated tumor.

pearance of a cylindroma, and it is dangerous to attempt to differentiate it from any ordinary mixed tumor or from an adenocarcinoma on the basis of its gross pathology." Almost all of these tumors were described as composed of pale-gray or pink tissue. Some of the lesions appeared rather sharply circumscribed, but the use of the term encapsulated that was so common in the older literature is not justified. I n many cases, the infiltrative growth and attachment to adjacent structures is quite apparent on gross examination (Fig. 1A and K). Small cystic and hemorrhagic areas were noted in a few cases. Probably the most important feature of the gross appearance of these neoplasms is the difficulty in demarcating the extent of the tumor at the time of surgery. Figure 2 represents the microscopic presence of tumor along the primary lines of excision in a palatal lesion, which grossly was thought to be completely excised. The insidious infiltrative growth of this tumor makes the exact extent of this tumor impossible to recognize grossly. The use of rapid frozen section at time of surgery is of great value in determining if portions of the line of excision are free of tumor. It is also of greatest importance for the pathologist in the final examination of the specimen to determine whether the entire margin of excision is free of tumor. Experience with

this present group of cases makes it obvious that this is one of the most important steps in ensuring the success of surgical treatment. Microscopic Features. Adenoid cystic carcinoma is composed of groups of small cells having darkly staining round or oval vesicular nuclei that are generally uniform and have only rare mitotic figures. The cytoplasm is scant, with no clearly defined cell borders. These cells are usually arranged in 3 basic patterns: glandular (Fig. 3), solid cords (Fig. 4), and relatively solid areas with varying-sized spaces scattered throughout (Fig. 5). These groups of epithelial cells are separated by poorly cellular fibrous tissue (Fig. 6). The spaces in the described areas and in the lumina frequently contain pink or bluish material when stained with hematoxylin and eosin preparations. This material is variable in its affinity for mucin and periodic acid-Schiff stains. The growth pattern is distinctly invasive (Fig. 7). Invasion of perineural lymphatics (Fig. 8) and nerve sheaths (Fig. 9) is one of the characteristic features of this neoplasm. Nerve invasion was present in 23 of 27 cases in which histological material was adequate for evaluation. Diflerential Diagnosis. Although the histological appearance of this tumor is rather characteristic, in 9 of the 38 cases, the original pathological diagnosis made elsewhere was incorrect. The 3 sources of error were in the separation of adenoid cystic carcinoma from

ADENOID CYSTICCARCINOMA Moran et al.

No. 6

basal cell carcinoma, mucoepidermoid carcinoma, and mixed tumor. Certain areas of cylindroid or adenocystic

FIG. 2. FIG. 3. FIG. 4. FIG. 5.

Case Case Case Case

1239

variants of basal cell carcinoma may be indistinguishable fronl adenoid cystic carcinoma. Differentiation can be made on the basis of

5. Residual tumor along a recent primary line of excision. (x97.7.) 1. Typical small gland and cord pattern. (~290.1.) 11. Small uniform basophilic cells arranged in solid cords and small glands. (xS01.3.) 26. Characteristic solid masses of epithelial cells, with varying size spaces. (x145.1.)

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CANCER November-December 1961

the cutaneous origin of basal cell carcinoma as opposed to the mucosal glandular origin of adenoid cystic carcinoma. Most basal cell car-

Vol. 14

cinomas having a cylindroid pattern can be seen to merge with more typical areas of basal cell carcinoma by adequate scrutiny.

FIG. 6. Case 21. Typical small gland pattern with atypical pattern in the upper field. (X130.3.) FIG. 7. Case 31. Invasive growth pattern, as seen in tumor extension from a lacrimal gland into periorbital fibromuscular tissue. ( ~ 9 7 . 7 . ) FIG. 8. Case 5. Perineural lymphatic invasion in an adenoid cystic carcinoma of the hard palate. (X97.7.) FIG. 9. Case 11. Extensive invasion of the nerve sheath, perineural region, and lingual nerve. (X129.1.)

No. 6

ADENOID CYSTIC CARCINOMA * Moran el al.

1241

FIG. 10. (A-17892). Mucoepidermoid carcinoma of the parotid misdiagnosed as an adenoid cystic carcinoma. Shown are the presence of squamous areas and pale-staining glands as the diagnostic features. ( ~ 1 3 0 .3 .) FIG. 11. (188046). Cylindromatous pattern in a benign mixed tumor of the parotid misdiagnosed as an adenoid cystic carcinoma. The typical mixed tumor pattern is present in the upper right field. (~134.9.)

Mucoepidermoid carcinoma may be differentiated on the basis of glandular structures composed of rather pale or eosinophilic cuboidal epithelium as apposed to the usual small dark basal type cells that form the structures in adenoid cystic carcinoma (Fig. 10). In addition the presence of areas of squamous cells confirms the diagnosis of mucoepidermoid carcinoma. The last and most frequent tumor to be confused with the adenoid cystic carcinoma is the benign mixed tumor. T h e difficulty usually results from the presence of small duct or cord structures composed of basal type cells similar to those seen in adenoid cystic carcinoma (Fig. 11). The most helpful feature in the differentiation of these 2 tumors is the presence or absence of the other typical features of mixed tumor, including myxoid or pseudocartilagenous stroma as opposed to the poorly cellular collagenous stroma of the adenoid cystic carcinoma. Other features that confirm the diagnosis of adenoid cystic carcinoma are the highly invasive growth pattern and the tendency to invade nerves. Most of the difficul-

ties in differential diagnosis are obviated by examination of adequate material from these tumors. The clinical and pathological findings in the 38 cases of adenoid cystic carcinoma are summarized in Table 3. The following are a group of case histories illustrating some of the more characteristic features of this neoplasm. CASEREPORTS Case 5. A 48-year-old white man was seen at the Hospital of the University of Pennsylvania in April, 1953, complaining of an ulcer of the hard palate of 4 to 5 weeks' duration. A biopsy specimen showed adenoid cystic carcinoma of the hard palate. During the period from April 3, 1953, to May 25, 1953, the patient received a tumor dose of 3,950 rads of external irradiation through an intraoral port. T h e tumor response was recorded as good, but the following year a palatal biopsy revealed recurrent tumor. In December, 1954, the patient was admitted to the Hospital of the University of Pennsylvania, and a radical excision of the right maxilla was performed. Pathological ex-

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CANCER November-December 1961

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TABLE 3 CLINICAL AND PATHOLOGICAL FINDINGS I N 38 CASES OF ADENOID CYSTIC CARCINOMA Case no. Site

1 Hard pal. 2 Hard pal. 3 Hard pal.

Pt. sex Race

Ageat diag., yr.

M N M

Dufat. prior treat.

Init. sympt.

LOC. recur.*

Metast.

Outcome

Mass

3. yr.

LOC.excis.

7.3 yr.

7. yr.

?

70

1. yr.

Mass

...

X ray

4. yr.

3. yr.

?

52

2. yr.

Mass

8. yr.

LOC.excis.

10. yr.

8. yr.

Lung

68

?

Swelling 2. yr. (occas. painful) 8. mo. Ulcer aft. rapal. diother. Tender ... mass ... Mass

?

3. yr.

Lung

Died tumor Died tumor Liv. with tumor Liv. with tumor

9. mo.

6. yr.

...

Liv. without tumor Liv. without tumor Died tumor

5 Hard pal.

M W

48

4.3. Wk.

6 Hard pal.

43

3. mo.

49

4. yr.

Hard pal.

F W M W

8 Hard pal.

F W

79

1. yr.

9 Hard pal.

M \n:

36

2 yr.

Ulcer pa!. & pain ?

10 Submax. gland 11 Submax. gland 12 Submax. gland 13 Submax. gland 14 Submax. gland

F W

59

2. yr.

Pain

M N

83

6. mo.

Mass

M N

41

4. mo.

Tender mass

M

32

1.9 yr.

Pain

I . yr. aft. radiat. 6 . yr. aft. surg. 3. yr. aft. surg. 3. yr. aft. surg. 1. yr. aft.. loc. excis. 2. mo.

69

2. yr.

Mass

5. yr.

33

5. yr.

Pain & mass

M

50

Mass

N M

4. yr.

Irnmed. aft. loc. surg. 1. yr.

46

10. yr.

Mass

2. yr.

M

58

?

Mass

6. yr.

M W

35

5. yr.

Mass

5. yr. & 6. yr.

F W

54

5. yr.

Tender mass

...

15 Submax. gland 16 Soft pal. 17 Base tongue 18 Parotid gland 19 Parotid gland 20 Parotid gland

Followupaft. treat.

4. mo.

Hard pal.

7

Tot. durat. turn.

38

N F W F N

4

Proced. &/or treat.

Rad. excis. & X ray X ray & rad. excis. Rad. excis. Kad. excis. & X ray

3. mo.

3. yr.

...

4.6 yr.

8. mo.

X ray

3. yr.

2. yr.

Lungs, brain, liver, skull, vertebra, & ribs ?

11. yr.

8. yr.

Lungs & rib

Liv. with tumor

6. yr.

3. yr.

...

Liv. with tumor

Rad. excis.

6.5 yr.

6. yr.

?

Liv. with tumor

LOC.escis. & rad. reexcis. LOC.excis.

8. yr.

6. yr.

...

Liv. without tumor

6. pr.

5. yr.

Pituitary

Died tumor

6. yr.

7. yr.

Lung

Died tumor

6 . yr.

9. mo.

...

Liv. without tumor

9. yr.

4. yr.

17. yr.

6. yr.

Lung & brain Brain (clin.)

Died tumor Died tumor

9. yr.

9. yr.

Died tumor

LOC.excis. 11. yr. & ‘ad. excis. Rad. ex5. yr.

6. yr.

Lungs & brain (X ray) ...

2. yr.

...

Liv. without tumor

Rad excis. & X ray Rad. exCIS.

W F

W M

W

w

LOC.excis., rad. reexcis., & radium LOC.excis. & rad. reexcis. X ray

X ray, radon, & radium X ray

W

CIS.

Died tumor

(3

Liv. with tumor

*After diagnosis.

amination of the specimen showed tumor to extend to the lines of resection (Fig. 2). Six days later, a re-excision of the right maxilla was performed, and the margins were found to be free of tumor. The patient is €ree of tumor -6 years after operation.

Case 9. I n 1952, a 36-year-old man underwent a resection of the hard palate, left antrum, and gum for an adenoid cystic carcinoma of the hard palate known to be present for about 2 years. He did well until 1958, when he was seen at the Hospital of the Uni-

1213

ADENOID CYSTIC CARCINOMA * Moran et al.

No. 6

TABLE 3 (Concluded) CLINICAL AND PATHOLOGICAL FINDINGS IN Case Pt. Ageat Dufat. no. sex diag., prior Init. LOC. Site Race yr. treat. sympt. recur.* 4. yr., Mass 3. yr. 25 F 21 2. yr., & N Parotid 3. yr. gland

22 Parotid gland 23 Parotid gland 24 Bronchus

F W

17

7. mo.

Pain

1.3 yr. & 3. yr.

F

76

4. yr.

Painful mass

4. yr.

M W

31

1. mo.

DYSPnea

7. yr.

25 Trachea

F W

53

7. mo.

DYSPnea

...

26 Trachea

M W

50

9. mo.

Dyspnea

...

27 Trachea 28 Rase tongue

M

29

2. yr.

Pain

F W

44

10. days

Mass

F

50

5. yr.

Mass

M N

40

6. mo.

F

26

3. yr.

Painful protrus. eYe Pain eye

F W

46

6. yr.

Pain

M

36

3.-4. mo.

32

?

Proptosis rt. eye Mass

?

65

?

Mass

4. yr.

M W

37

4. yr.

Tinnitus 1.3 yr. & pain

F W

49

4.-5. mo.

Swelling ?

F

70

6. yr. ( ?)

Mass

29 Nostril floor 30 Lacrimal gland 31 Lacrimal gland 32 Lacrimal duct 33 Lacrimal gland 34 Up. lip 35 Up. lip 36 Posterior pharynx (?)

37 Base tongue 38 Floor mouth

w

Mt

w

W

W

F W F

w

w

38 CASES O F ADENOID CYSTIC CARCINOMA Proced. Tot. Follow&/or durat. up aft. treat. tum. treat. Metast. OutcomeLOC.excis., 13. yr. 2. yr. ... Liv. without tumor loc. excis., & rad. excis. Liv. wii h ... 4. yr. Loc. excis. 2. yr. tumor & r?d. excis. Died ? 4. yr. LOC.excis. 8. yr. tumor 12. yr. Pneumonect., bronchoscopy, & X ray 2. yr. RronchosCOPY

? RronchosCOPY & X ray 2. yr. 6. yr. X ray & chemother. Radon (4 19. yr. 3. yr. times), (mu1t.) X ray (5 times), & radium 5. yr., Loc. excis. 14. yr. 3. yr., & (2 times), 1. yr. X ray, & rad. excis. 3.5 yr. ... Radium & X ray (3 times) Rad. surg., 9. yr. 3. yr. re-excis., & X ray 6. yr. ... X ray

...

?

Orbital exent. & X ray Loc. excis.

Lung & esophagus

Died tumor

1.5 yr.

?

?

?

Died “coronary occlusion” Lost to follow-up

4. yr.

Lung

19. yr.

Lung

12. yr.

Liv. with tumor Died tumor

6. yr.

...

Liv. without tumor

3. yr.

?

Died tumor

6. yr.

Lungs

Liv. with tumor

...

...

Liv. with tunlor

4. mo.

...

...

Liv. without tumor

?

?

?

2. yr.

...

3. yr.

?

Lost to follow-up Died endometrial carc. Died tumor

1.0~.excis., 5. yr. re-excis., & iridium 192 ther. Craniotomy, 7. yr. X ray, & craniotomy

(?I

Radiation

1.5 yr.

1. yr.

...

Liv. with tumor( ?)

Excis. & radiat. (3 times)

6. yr.

5. yr.

Lungs

(?I

(?I

Liv. with tumor

-

tMongolian.

versity of Pennsylvania complaining of excessive lacrimation, decrease in visual acuity of the left eye, and pain of the left side of the face. He was admitted to the hospital in January, 1959, with a swelling of the left cheek and orbit. Biopsy of the left maxilla revealed

recurrent tumor. A roentgenogram showed neoplastic involvement of the left maxillary sinus region, the ethmoid region, and questionable extension to the sphenoid region. External radiotherapy was started, and the patient received 5,500 rads to the left maxillary

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CANCER November-December 1961

Vol. 14

region; this was followed by satisfactory re- cystic carcinoma. The recurrent tumor was sponse. inoperable at this time. I n October, 1947, a I n March, 1959, the patient began to com- subtotal resection of the left sensory root of plain of pain of the sixth right rib and lumbo- the facial nerve was performed; this was folsacral region radiating into the abdomen. A lowed by relief of pain for about 3 years. He roentgenogram revealed hilar densities and a was seen in January, 1950, with pain of the lesion of the sixth rib. A thoracotomy was per- left cheek. The pain became progressively formed in March, 1960, and biopsy of the lung more severe and in April, 1950, he was reand rib lesions revealed metastatic adenoid admitted to this hospital and resection of cystic carcinoma. No further treatment was the left glossopharyngeal area, C-2, and C-3, undertaken. was performed. He died 7 days after operation. Autopsy revealed extensive tumor of the Case 11. An 83-year-old Negro man was first seen at the Hospital of the University of Penn- left submaxillary region, which extended to sylvania with a hard mass in the left sub- the posterior pharynx. Tumor was found in maxillary region of 6 months’ duration. In a section of the pituitary gland. Death was February, 1955, excision of the left side of the the result of bilateral lobar pneumonia. floor of the mouth and an upper neck disCase 28. A 44-year-old white woman was adsection were performed. The mass was not mitted to the Hospital of the University of attached to the mandible, but extensive neo- Pennsylvania in April, 1925, with a history of plastic involvement of the lingual nerve was a lump of the tongue of 10 days’ duration. Exnoted (Fig. 9), along with metastasis to 1 re- amination under anesthesia revealed “an algional lymph node. The patient was free of mond size hard mass at the extreme base of tumor until February, 1959, at which time a the tongue on the right side.” T h e lesion was mass was noted in the floor of the mouth. considered inoperable; biopsy was performed Radiotherapy has been advised, but the pa- and a diagnosis of “malignant tumor” was tient has refused further treatment. He con- made. The patient received 4 series of extinues to live and is in fair condition with ternal radiation treatments, after which the recurrent tumor. lesion disappeared; it recurred within 3 years. Case 12. A 41-year-old Negro man was first In September, 1928, the mass was treated admitted to the Hospital of the University of with external radiotherapy plus interstitial radon. This same sequence was repeated in Pennsylvania in April, 1947, with a “walnutsized mass” of the right submaxillary gland. 1929. In April, 1930, after interstitial radon The gland was removed in August, 1949, and therapy of 950 r, the tumor again disappeared a diagnosis of adenocystic carcinoma was only to recur within 2 years. In August, 1932, made. In May, 1948, a nodule was noted in the patient again received a dose of external the operative area. During the next 7 years, radiotherapy (amount undetermined) plus this mass increased in size. On June 29, 1955, radium implantation. She was not seen again the recurrent tumor was resected along with until June, 1937, at which time she had a furthe body of the right mandible, and a com- ther recurrence, extension to the neck, and plete right radical neck dissection was done. metastasis to the right lung. At this time she The patient is free of recurrence, 6 years after received 5,500 r of external irradiation to the area of the recurrence. In July, 1944, she again operation. had a recurrence, and the pulmonary lesion Case 13. A 32-year-old white man noted the had doubled in size. She died in October, 1944, onset of dull pain in the left lower jaw in as a result of local hemorrhage from an ulcer February, 1945. This was gradually followed of the mouth that developed after radium by numbness of the left side of the tongue. By therapy. No autopsy was performed. October, 1946, the pain extended over the disUnfortunately, no measurements of the tribution of the facial nerve, the motion of radiation therapy other than those recorded are the jaw was limited, and the left submaxillary available. It may be surmised that the amount gland was enlarged. In November, 1946, the of radiation in many of the treatments was left submaxillary gland was excised, and a minimal in view of the patient’s ability to pathological diagnosis of “mixed tumor” was tolerate the repeated radiotherapy. Radiation made. Within a few months after this opera- therapy succeeded in achieving palliation of tion, the pain recurred and attempts at tem- this tumor for a period of 19 years. porary nerve block resulted in only limited Review of the original biopsy taken in 1925 relief. I n September, 1947, the patient was first showed this tumor to have been an adenoid seen at the Hospital of the University of Penn- cystic carcinoma. sylvania, still suffering from pain. Review of Case 29. In 1945, a soft nodule of 5 to 6 the histological sections of the submaxillary gland resulted in the diagnosis of adenoid years’ duration was excised from the floor of

No. 6

TABLE 4 CLINICAL ONSET OF SYMPTOMS I N ADENOID CYSTIC CARCINOMA Clin. onset No. pt. -~

Mass, enlargement, or swelling Painful or tender mass Pain alone Dyspnea Ulcer mucosa with bleeding Proptosis Tinnitus Unknown TOTAL

17 7 5 3 2 1 1 2

38

the right nostril of a 50-year-old white woman. T h e tumor recurred within the ensuing 5 years. I n 1950, it was re-excised, only to recur within the next 3 years. In 1953, the patient received external radiotherapy, consisting of 3,500 r in air to the right nostril; after this the tumor regressed, only to recur again. She was first seen at the Hospital of the University of Pennsylvania with a mass just inside the right nares on the floor of the right nasal cavity. Histological sections in the previous excisions were diagnosed as adenoid cystic carcinoma. I n December, 1954, a radical excision of the floor of the right nostril and nasal septum was performed; to date, the patient is free of recurrence (6 years after operation). Case 31. A 26-year-old white woman developed a shooting intermittent pain of the right eye in August, 1951. This pain became progressively worse and was followed by the development of exophthalmus and a questionable mass of the right lacrimal region. She was first admitted to the Hospital of the University of Pennsylvania in March, 1954, when biopsy of the orbital mass showed adenoid cystic carcinoma of the lacrimal gland. An orbital exenteration was performed, along with the removal of the orbital roof. I n February, 1958, a nodule on the floor of the right TABLE 5 DURATIOIV O F SYMPTOMS AT T I M E OF DIAGNOSIS I N ADENOID CYSTIC CARCINOMA Durat. sympt. 0-6 mo. 7-12 mo. 1 yr. 2 yr. 3 yr. 4 yr. 5 yr. 6 yr. 10 yr. Unknown

TOTAL

1245

ADENOID CYSTICCARCINOMA Moran et al.

No. pt. 10 3 3 4 2 4 4

1 1

6

38

orbit was diagnosed as recurrent tumor. An extensive surgical exploration a t this time, along with partial resection, revealed extension of tumor to the zygomatic bone, ethmoid region, and optic foramen. I n April, 1959, she noted the onset of headaches and paresthaias of the face. A nodule of the right temporal area was noted in December, 1959, and resected. T h e recurrent tumor of the orbital region continued to enlarge and was treated with 4,600 rads of external irradiation. A good response of the tumor to the radiotherapy was noted. T h e patient is living with recurrent tumor. I n September, 1960, evidence of pulmonary metastasis was noted on a roentgenogram. CLINICAL FINDINGS T h e most frequent clinical indication of the onset of adenoid cystic carcinoma was the TABLE 6 TOTAL DURATION OF ADENOID CYSTIC CARCINOMA* Tot. durat.t 0-5 yr. 6-10 vr.

11-is &.

16-20 yr. Unknown

No. pt. 10 16 4 2

3

-

*The total duration was measured from the first clinical manifestation to the most recent appearance. The range was from 4 months to 19 years. tThe average duration was 7.2 years.

presence of a mass, enlargement, or swelling. This was noted in 17 of 38 cases (Table 4). Eleven of 15 cases of adenoid cystic carcinoma arising in the submaxillary gland reported by Dockerty and Mayo* were found to be associated with pain or tenderness. These findings were attributed to neoplastic involvement of nerve trunks. A high incidence of these findings has been reported by other authors72 12-in a range of 50 to 60% of cases. In 12 of the 38 present cases, pain was 1 of the initial symptoms. I n 5 of these cases, pain alone was the first symptom, while in the other 7 cases it was accompanied by the presence of a mass. T h e relationship of pain to adenoid cystic carcinoma is a very significant feature in the clinical differentiation of this tumor from the benign mixed tumor. During some part of the clinical course, pain was a major factor in 19 of the cases in our series. I n 3 cases in which the tumor arose in either the trachea or the bronchus, dyspnea was the presenting symptom. Mucosal ulceration with

1246 CANCER November-December 1961 Vol. 14 bleeding was the initial finding in 2 cases of TABLE 8 this neoplasm originating in the palate. I n 1 INTERVAL FROM FIRST SYMPTOM TO APPEARANCE O F VISCERAL METASTASIS case in which the tumor arose in the base of I N ADENOID CYSTIC CARCINOMA the tongue, unilateral vocal cord paralysis was Primary Site Interval, present a t the time of the first examination. Of Case site metast. yr. * 3 patients with tumor arising in the lacrimal no. 3 Palate Lung 6. gland, 2 presented with symptoms of a pain4 Palate Lung 2. ful exophthalmus while the third patient had Palate 7 Brain, bone, proptosis. liver, & lung 4.5 Palate 9 Lung & rib 9. A case of adenoid cystic carcinoma arising 13 Submax. gland Pituitary 6. presumably in the posterior pharynx produced 14 Submax. gland Lung 7. Soft palate Lung & brain 9. eustachian tube obstruction resulting in tin- 16 Base tongue 17 Brain 4. nitus. Parotid gland Lung 6. 18 Bronchus Growth Rate. Adenoid cystic carcinoma is 24 Lung 9. Trachea Lung 5. characteristically a slow-growing neoplasm, as 27 Tongue Lung 12. 28 illustrated by the relatively long duration of 29 Palate Lung. 4. Lacrimal gland Lung & brain 10. symptoms at the time of diagnosis (Table 5). 31 Floor mouth Lung & rib 5. This slow growth is further illustrated by the 38 *The average interval was 7.5 years. length of the estimated total duration of the TABLE 7 PERIOD O F T I M E FROM PRIMARY TREATM E N T O F TUMOR TO LOCAL RECURRENCE O F ADENOID CYSTIC CARCINOMA* Per. timet 0-6 mo. 7-12 mo. 1 yr. 2 yr. 3 yr. 4 yr. 5 yr. 6 yr. 7 yr. 8 yr. Unknown

TOTAL

No. pt.

4 3 2 1 1 1

28

*The range in time was from 1 month to 8 years 11 months. tThe average period of time was 3.0 years.

neoplasm, which (in this series) averaged 7.2 years among the 35 patients for whom these data were available (Table 6). This slow growth rate was also noted in the period of time from treatment to recurrence. Most recurrences (among the 28 patients evaluated) appeared 3 or more years after treatment (Table 7). Thus, it may be seen that a lengthy follow-up period is necessary to evaluate any type of therapy. Bone Inmsion. Adenoid cystic carcinoma arising in the palate, pharynx, and lacrimal glands frequently invades adjacent bone. This was noted in 13 of 15 cases arising in these areas (Fig. 12). This high incidence of bone invasion makes i t necessary that the underlying bone is widely resected at time of surgery.

Metastasis. T h e reported incidence129 16, l8 of regional lymph node involvement by adenoid cystic carcinoma ranges from 20. to 30.%. T h e incidence of lymph node metastasis in the present group of cases could not be determined because the regional lymph nodes were available for study in only 6 cases-of which 2 showed metastatic tumor. T h e incidence of distant metastasis from this group of neoplasms was not appreciated for many years; however, Baclesse,3 in 1946, reported finding skeletal and pulmonary metastasis developing 15 to 22 years after the onset of the lesion. I n 1949, Lampe and Zatzkin,20 in follow-up reports on 25 patients with adenoid cystic carcinoma during a 19year period, found that 20.% had developed pulmonary metastasis. HarrisonlGreported visTABLE 9 RESULTS O F RADIOTHERAPY O F ADENOID CYSTIC CARCINOMA

Pt. status Radiation therapy alone Liv. free turn. Died recur. tum. Liv. with recur. tum. Recent case Lost to follow-up Surgical excision followed by radiotherapy Liv. free turn. Died recur. tum. Liv. with recur. tum. Died 0th. cause Recent case Radiotherapy followed by radical excision Liv. free turn.

TOTAL

No. pt. 0

7 1 2 1

0 4 3 1 1 2

22

No. 6

ADENOID CYSTICCARCINOMA * Mo?-an et al.

ceral metastasis in 6 of 46 patients with this type of tumor. I n the present series, distant metastasis occurred in 15 of 36 patients for whom adequate follow-up was available. Pulmonary metastasis occurred in 13 cases, brain involvement in 4 cases, bone metastasis in 3 cases, and liver metastasis in 1 case. T h e relationship of these metastases to the slow growth is shown in Table 8, with a range of from 2. to 12. years between the clinical onset and the observation of the metastatic lesion. T h e average interval was 7.5 years.

TREATMENT It is impossible to generalize on the results of therapy in a group of tumors arising in such

1247

plasm was radiosensitive and should be treated primarily with irradiation and only secondarily with surgical procedures. Similar views were expressed by Ahlbom1 and, later, by Baclesse.3 Foote and Frazelll2 and Berdal and Myliusj stated that these neoplasms are radioresistant. I n the present group of patients, conventional X-ray therapy techniques were utilized in most instances (with the factors being 200. kv., 15. ma., 1.0 mm. of aluminum, and 0.5 mm. of copper, with a half value layer of 1.3 mm. of copper and a 50-cm. target skin distance). T h e size of the ports chosen was adequate to cover the areas of tumor. There was a very wide range of dosages employed. One patient was treated with interstitial implantation of

FIG. 12. Case 2. Adenoid cystic carcinoma invading bone of the maxilla. ( ~ 1 5 0 . )

variable sites as those included in this series. Obviously, tumors arising in nonresectable sites have a completely hopeless prognosis. I t is on the remainder of the patients in whom the primary site of the tumor-at least early in the course of the disease-is amenable to surgery that most of the emphasis will be placed in this review. Local Excision. Local excision was the primary treatment in 15 cases. Follow-up is available for 14 cases; all of the patients had recurrences of tumor within a period ranging from immediately after excision to 8 years 11 months. Radiotherapy. Conflicting views are expressed in the literature regarding the effectiveness of radiotherapy in cases of adenoid cystic carcinoma. Spies29 stated that this neo-

radioactive sources, and 4 patients had both external beam therapy with conventional X-ray therapy techniques and interstitial implantation of radioactive sources. A total of 22 patients received radiotherapy of varying types (Table 9). I n this group, 11 patients received only radiotherapy. Of these, 7 have died of tumor, 1 is living with tumor, 2 are too recent for evaluation, and 1 has been lost to follow-up. Thus, it is apparent that radiation treatment alone offers no cure. Nine of this group of 22 were treated by surgical excision followed by radiotherapy. Four died of tumor, 3 are living with tumor, 1 died of another tumor, and 1 is too recent to evaluate. Two patients received radiation therapy that was followed by tumor recurrence that

1248

CANCER November-December 1961

TABLE 10 RESULTS OF RADICAL EXCISION OF ADENOID CYSTIC CARCINOMA No. pt.

Results Liv. free turn. Liv. with recur. turn. Died recur. turn. Lost to follow-up Recent case

6

8 2 1

2 19

TOTAL

was radically excised. Both of these patients are living, free of tumor, at present. Despite lack of evidence of cure by radiotherapy alone, many of the patients showed excellent response and regression of tumor for varying lengths of time. Thus, it is felt that radiotherapy has a definite place in the palliative therapy of adenoid cystic carcinoma. Neurosurgical Procedures. Pain is one of the major problems of patients with this type of tumor. It was necessary to perform nerve resections as a palliative procedure for 3 patients. I n all 3, relief of pain for variable periods of time resulted from the procedure. I n 2 cases, craniotomy was performed because of intracranial tumor extensions-wi th short term palliative results. Radical Excision. T h e term “radical excision” is used to indicate complete removal of the tumor along with a wide margin of uninvolved tissue and adjacent lymph nodes and bone. In 6 cases, a complete radical lymph node dissection was also performed. In the present group, a radical or wide excision of the tumor was performed in 19 cases (Table 10). Of this group, 6 patients are living without evidence of recurrence, 8 are living with recurrent tumor, 2 died of recurrent neoplasm, 2 are recent cases, and 1 was lost to follow-up. The length of survival free of recurrence ranged from 2 to 6 years. Obviously in a neoplasm having such a prolonged life history, none of these survivals can be considered to be cures at this point. Regardless of the ultimate outcome, in all instances the radical excision appears to offer the most satisfactory results of any type of therapy in this study. In the group in which radical excision was followed by recurrence, the palliation of pain appears to justify the procedure. PROGNOSIS T h e prognosis in cases of adenoid cystic carcinoma, when observed for an adequate

Vol. 14

period of time, has been shown by many observers to be poor. I n 1956, Harrison16 reported that local recurrence appeared in twothirds of a group of 46 patients followed for as long as 12 years after excision. Half of the patients in his series were dead within 8 years after treatment. Only 8 remained alive and free of tumor for more than 4 years. In a group of 18 cases, Wawro and McAdams30 recorded that 10 patients had local recurrences, and 2 died of disseminated tumor. Quattlebaum, Dockerty, and Mayo25 reported 10 deaths in a group of 21 patients with cylindromas of the parotid gland and only 5 patients who were living free of tumor. In the present series, recurrences took place in 26 of the 36 patients for whom adequate follow-up data were available. Fourteen of the 36 patients died of recurrent tumor, and 2 died of other causes. Ten are living with recurrent tumor, and 6 are living free of tumor (Table 11). Four patients were treated too recently to evaluate the results of treatment. DISCUSSION It is obvious from the results of other observers and from this current series that the outlook for cases of adenoid cystic carcinoma is highly unfavorable. T h e questions now are whether the results of therapy can be improved, and, if so, how this can be done. Adenoid cystic carcinoma arising in a relatively inaccessable region may be difficult or impossible to detect until it is quite far advanced. For these cases invariably there is no hope of cure at present. Most commonly these tumors are manifest as a slow-growing mass or swelling. The insidious development of the neoplasm may be responsible for patient delay; however, it must be pointed out that this slow development may also delude the physician into assuming that the lesion is benign. T h e correction of TABLE 11 PROGNOSIS I N ADENOID CYSTIC CARCINOMA Prognosis Lost to follow-up Died turn. Died 0th. cause Recent case Liv. free turn. Liv. with recur. turn.

No. pt. 2 14

2 4

6 10 ~

TOTAL

38

No. 6

ADENOID CYSTIC CARCINOMA

this error lies only in a histological diagnosis at the earliest possible time. T h e finding of pain in relationship to a mass should prompt the clinician to consider the probability that he is dealing with a malignant neoplasm. This is of particular value in differentiating tumors arising in salivary glands from benign mixed tumors that are rarely painful. T h e other problem that interferes with early diagnosis is the ability of the pathologist to diagnose tumors correctly. Some of the difficulty can be attributed to the fact that adenoid cystic carcinoma is an infrequent tumor in most hospitals. Unfortunately, a frequent source of difficulty seems to be the tendency of some pathologists to classify salivary gland tumors into vague categories that are not based upon a knowledge of the behavior of the neoplasm. This, in turn, may result in a failure to adequately inform the clinician as to the general category of tumor and its expected behavior. A final difficulty lies in the failure of some pathologists to examine an adequate amount of tissue. Difficulties in distinguishing benign mixed tumors from adenoid cystic carcinoma can usually be resolved if enough tissue is examined. T h e question of the extent of the primary surgery is a difficult one, since radical excision would not be justified without a previous histological diagnosis. A rapid frozen section of the tumor at the time of surgery will often offer the solution to this problem. When the diagnosis of adenoid cystic carcinoma is made after limited excision only, the question of the adequacy of the excision is most important. I n most instances the problem can be solved by making serial tissue blocks around the entire margins of the excised specimen and taking other sections through the tumor to determine the depth of the invasion. T h e use of India ink for marking margins for orientation is often very helpful. If this is done, almost invariably any local excision will be found to be inadequate. At this point, it is of the greatest importance that a radical re-excision be performed, without waiting for recurrence. Again, during the reexcision, the question of the adequacy of the excision may arise-particularly in view of the deceptive gross appearance. However, the use of rapid frozen sections during surgery can usually solve this problem. T h e advisability of a complete radical

Moran et al.

1249

lymph node dissection is still open to question. Certainly metastases from adenoid cystic carcinoma to regional lymph nodes d o occur, but they are infrequent. When they do occur the metastases usually involve only the lymph nodes immediately adjacent to the neoplasm. Thus, it seems important to include in the radical excision the adjacent lymph nodes, but whether complete regional lymph node dissection is justified is open to question. I n cases in which it is impossible to decide prior to operation whether a tumor is resectable, it appears reasonable to attempt as wide an excision of the tumor as is technically possible. While this may offer no hope of cure, it has resulted in worthwhile palliation in our experience. No deaths were attributable to radical operative procedures in our series of cases. It is not believed that any of the 6 patients having no recurrence after radical excision represent cures at this point, since the maximum follow-up period for them is only 6 years. It is believed, however, that these patients represent the ones with the best results obtained in the present series, and, therefore, radical excision is currently the treatment of choice. If surgical excision is impossible, consideration should be given to the use of radiotherapy. While it has been shown that this mode of treatment offers no hope of cure, temporary regression almost always followed such treatment. Since regression was demonstrated in some cases after relatively small amounts of radiation, no definite statement can be made concerning the optimum dose of radiation in the treatment of this type of tumor. SUMMARY 1. I n a group of 38 cases of adenoid cystic carcinoma, the most common site of origin was the hard palate; the next most common site was the major salivary glands. No race or sex predilection was demonstrated in this series. 2. Although the microscopic appearance of this tumor is quite characteristic, it has been confused with the benign mixed tumor, mucoepidermoid carcinoma, and basal cell carcinoma. 3. T h e most common clinical manifestations of this tumor were the appearance of a mass and the presence of pain. 4. T h e slow growth rate of this neoplasm is

1250

CANCER Nouember-December 1961 Vol. 14 apparent from the lengthy periods between 7. Local excision was invariably followed the appearance of the first symptom and the by recurrence. Twenty-two patients in this diagnosis, the long total life history, and the present group received radiotherapy. No eviprolonged latent period between initial treat- dence of cure after radiation was noted, alment and recurrence. though temporary regression of the tumor was 5. Neoplastic invasion of adjacent bone was common. noted in 13 of 15 of these tumors arising in 8. T h e only successful results were in a the palate, pharynx, or lacrimal glands. group of 19 patients who had radical surgical 6. Distant metastasis occurred in 15 of 36 excisions. Of this group, 6 have lived, free of cases in which adequate follow-up data were tumor, for periods ranging from 2 to 6 years available. after treatment. REFERENCES 1. AHLBOM, H. E.: Mucous- and salivary-gland tumours; clinical study with special reference to radiotherapy, based on 254 cases treated at Radiumhemmet, Stockholm. Acta radiol. suppl. 23: 1-452, 1935. 2. AZZOPARDI, J. G., and SMITH,0. D.: Salivary gland tumours and their mucins. J. Path. 6.R u t . 77: 131-140, 1959. F.: Les metastases et la radio-sensibilite 3. BACLESSE,

des cylindromes et des tumeurs mixtes des glandes salivaires. Rev. stomatol. 47: 469-474, 1946. 4. BAUER, W. H., and Fox, R. A.: Adenomyoepithelioma (cylindroma) of palatal mucous glands. Arch. Path. 39: 96-102, 1945; [corr. 4 0 80, 19451. 5. BERDAL, P., and MYLIUS,E.: Cylindromas of respiratory tract, upper part of digestive tract and adjoining organs. Acta oto-laryng. suppl. 118: 32-44, 1954. 6. BILLROTH. T.: Beobachtunpen iiber Geschwiilste der Speicheldriisen. Virchows 2rch. path. Anat. 17: 357-375, 1859.

7. BUXTON,R. W.: Cylindromatous salivary gland tumors. Maryland M. J . 7: 357-362, 1958. 8. DOCKERTY, M. B., and MAYO,C. W.: Primary tumors of submaxillary gland with special reference to mixed tumors. Surg. Gynec. Q Obst. 74: 1033-1045, 1942.

9. DOCKERTY, M. B., and MAYO,C. W.: “Cylindroma” (adenocarcinoma, cylindroma type); report of 2 cases with metastasis. Surgery 13: 416-422, 1943. 10. ENTERLINE, H. T., and SCHOENBERG, H. W.: Carcinoma (cylindromatous type) of trachea and bronchi and bronchial adenoma; comparative study. Cancer 7: 663-670, 1954. 11. FINE,G.; MARSHALL, R. B., and HORN,R. C., JR.: Tumors of minor salivary glands. Cancer 13: 653-669, 1960. E. L.: Tumors of 12. FOOTE,F. W., JR., and FRAZELL,

the Major Salivary Glands; Atlas of Tumor Pathology, sect. 4, fasc. 11. Washington, D.C. Armed Forces Institute of Pathology. 1954. 13. FRY, R. M.: Structure and origin of “mixed” tumours of salivary glands. Brit. J. Surg. 15: 291-306, 1927-1928. C. L., and KONZELMANN, F. W.: Bron14. JACKSON,

choscopic aspects of bronchial tumors, with special reference to so-called bronchial adenoma; reports of 12 cases. J. Thoracic Surg. 6: 312-329, 1937. H.: Uber gutartige Bronchialtumoren 15. HAMPERL, (Cylindrome und Carcinoide). Virchows Arch. path.

Anat. 300: 46-88, 1937. 16. HARRISON, K.: Study of ectopic mixed salivary tumours; Hunterian lecture. Ann. Roy. Coll. Surgeons England 18: 99-122, 1956. 17. HESCHL,R.: Ueber ein Cylindrom der Lunge. Wien. med. Wchnschr. 27: 385-390, 1877. J. W.; MCDONALD, J. R.; HARRINGTON, 18. KIRKLIN, S. W., and NEW,G. B.: Parotid tumors; histopathology, clinical behavior, and end results. Surg. Gynec. d. Obst. 92: 721-733, 1951.

19. KROMPECHER,E.: Zur Histoeenese und Morphologie der Mischgeschwiilste der“ Haut sowie der Speichel- und Schleimdriisen. Beitr. path. Anat. 44: 51-87, 1908. 20. LAMPE,I., and ZATZKIN, H.: Pulmonary metasta-

ses of pseudo-adenomatous basal-cell carcinoma (mucous and salivary gland tumor). Radiology 53: 379-385, 1949.

21. MCDONALD, J. R., and HAVENS, F. Z.: Study of malignant tumors of glandular nature found in nose, throat and mouth. S. Clin. North America 28: 10871106, 1948. 22. MCFARLAND, J.: Tumors of parotid region; studies of 135 cases. Surg. Gynec. Q Obst. 57: 104-114, 1933. 23. MCFARLAND, J.: Three hundred mixed tumors of salivary glands, of which 69 recurred. Surg. Gynec. 6 Obst. 63: 457-468, 1936. W. S.; ELLIS,F. H., JR.; WOOLNER, L. B., 24. PAYNE, and MOERSCH, H. J.: Surgical treatment of cylindroma (adenoid cystic carcinoma) and muco-epidermoid tumors of bronchus. J. Thoracic Surg. 38: 709-726, 1959. 25. QUATTLEBAUM, F. W.; DOCKERTY, M. B., and MAYO,C. W.: Adenocarcinoma, cylindroma type, of parotid gland; dinical and pathologic study of 21 cases. Surg. Gynec. Q Obst. 82: 342-347, 1946. 26. RIBBERT,[M. W. H.]: Uber das Zylindrom. Deutsche med. Wchnschr. 33: 126, 1907. 27. RUSSELL, H.: Adenomatous tumours of anterior foregut region showing cylindroma pattern. Brit. J . Surg. 43: 248-254, 1955. W. H.: So-called mixed tumors of 28. SHELDON, salivary glands. Arch. Path. 35: 1-20, 1943. 29. SPIES,J. W.: Adenoid cystic carcinoma; generalizqd metastam in 3 cases of basal cell type. Arch. Surg. 21: 365-404, 1930. 30. WAWRO, N. W., and MCADAMS, G.: Cylindromata

of major and minor salivary gland origin. A. M . A. Arch. Surg. 68: 252-261, 1954.