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ADENOCYSTIC BASAL CELL CARCINOMA OF THE TRACHEA
ADENOCYSTIC BASAL CELL CARCINOMA OF THE TRACHEA S. F. Market, M.D., and M. R. Abell, M.D., Ph.D., Ann Arbor,
Mich.
A
DENOCYSTic (pseudoadenomatous) basal cell carcinoma is an uncommon but distinctive neoplasm that is found in a variety of locations in the body. Eeferences to this neoplasm in the trachea have consisted of reports of indi vidual cases and several small series. Because of a general lack of detailed survival studies and because this neoplasm is often grouped with similar lesions in the bronchus and elsewhere, it has been difficult to appraise its natural history and prognosis. We have seen only five examples of adenocystic carcinoma that arose in the trachea. The long-term survival information that is available on these, however, provides us with data that permit a fair appraisal of the natural history of this rather rare neoplasm and justifies this report. MATERIAL· AND METHOD
The tissues of all lesions of trachea that were seen at The University of Michigan Medical Center from November, 1934, through June, 1962, and coded as trachéal adenoma, adenocystic, or pseudoadenomatous basal cell carcinoma, adenocarcinoma, bronchial adenoma, medullary carcinoma, and unclassified neoplasm were reviewed. Five adenocystic basal cell carcinomas arising in the trachea were found. Four cases have been referred to briefly by Smout and French. 1 There were no examples of earcinoid or mucoepidermoid tumors. Clinical information including survival to the time of this writing was available for all cases. Tissue sections were stained routinely with hematoxylin and eosin. Selected sections were also stained with mucicarmine and alcian green. CLINICAL OBSERVATIONS
All five patients were Caucasian females, 21, 42, 44, 46, and 63 years of age, respectively, at the time of diagnosis (Table I ) . Symptoms attributable to the neoplasm were present in every case and, in order of frequency, consisted of wheezing, dyspnea, cough, fatigue, and hemoptysis. One patient had had re current pneumonitis. The duration of symptoms prior to diagnosis varied from 1 month to li/£ years. No roentgenographic abnormalities of the trachea were noted initially in From the Department of Pathology, The University of Michigan, Ann Arbor, Mich. Received for publication Feb. 5, 1964.
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AGE (YEARS)
P R E S E N T I N G S Y M P T O M S AND DURATION
1 (Fig. 1)
21
Recurrent pneumonitis—1% yr.
Distal trachea
2 (Figs. 2, 3)
42
Dyspnea, wheezing, cough, fatigue, hemoptysis—8 mo.
Upper trachea
46
Wheezing—?
Upper trachea
63
Cough, fatigue—1 yr.
Distal trachea
44
Dyspnea, wheezing—1 mo.
Distal trachea
CASE N O .
(Figs. 4-7)
(Figs. 8-12) 5 (Figs. 13, 14) •Trachea! obstructive
symptoms
recurred
LOCATION
1 month before death. Death was attributed to
any case, but recurrences following irradiation treatment were frequently ac companied by evidence of narrowing and/or distortion of the^ trachea. Eoentgenographically evident pulmonary métastases were present in one ease. These were noted 11 years after initial treatment of the primary trachéal neoplasm and followed several recurrences. This was the only instance of clini cal or pathological evidence of métastases. PATHOLOGICAL· OBSERVATIONS
The primary tumors were visualized and described at tracheoscopy ; no thoracotomies or mediastinotomies were performed. Three tumors arose in the distal trachea and two originated in the proximal trachea just below the larynx. They were pink to gray-white, bosselated, smooth masses, varying from 1 to 3 cm. in diameter. They extended externally and also into the lumen with consequent narrowing thereof. Recurrent tumors appeared more friable as well as infiltrative. They were associated with scarring and distortion incident to previous treatment. The distinctive features of adenocystic carcinoma were represented pri marily by the classic and tubular patterns of growth (Figs. 1, 2, 4, 5, 8, 9, and 13). The basic cells were small with dark, uniform nuclei and, generally, little cytoplasm. They were cuboidal or polygonal in shape and arranged in anastomos ing cords, tubular structures, and medullary masses in which there were acinar and microcystic formations. A variety of other less commonly appreciated pat terns of growth were encountered in every neoplasm and by themselves they might cause considerable difficulty in diagnosis; however, each neoplasm also
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DATE ΟΓ INITIAL TREATMENT
DATE OF FIRST HISTOLOGICALLY CONFIRMED RECURRENCE
9/44
10/55
-
2/46
8/51
3/53 11/53 12/53 2/54 3/54
3/54 (8 yr.)
Î/47
2/49
4/51 12/51 11/53 2/54 1/58 2/58 (lung metast.) 5/59 8/60
11/60 (13 yr.)
1/55
2/56
-
12/63 (8 yr.)
-
2/57
-
-
12/63 (6.8 yr.)
-
pulmonary
hemorrhage.
DATE OF SUBSEQUENT HISTOLOGICALLY CONFIRMED RECURRENCES
No necropsy was
SURVIVAL ALIVE
-
|
DEAD 2/57* (12.6 yr.)
performed.
had areas of typical adenocystic carcinoma so that the diagnosis could be made with complete assurance (Figs. 1, 2, 4, 5, 8, 9, and 13). One neoplasm had islands in which ductal structures were formed by cuboidal cells with a moderate amount of eosinophilic cytoplasm. Around these were areas of loosely arranged, small cells with scant wispy cytoplasm and hyperehromatic nuclei, lying in a myxomatous stroma which stained well with alcian green (Figs. 4 and 6). The arrangement suggested that the neoplastic cells arose from the subcolumnar reserve cells and differentiated into ductal structures. A recurrence of this neoplasm had, in addition to classical adenocystic carcinoma, areas of medullary growth composed of cuboidal and polygonal cells with eosinophilic and amphophilic cytoplasm and centrally placed vesicular nuclei (Fig. 7). These features resembled those of earcinoid tumors. Another neoplasm possessed areas of small polygonal cells with little cyto plasm and irregularly-shaped hyperehromatic nuclei, arranged in a cribriform pattern—the result of inspissated secretion distending pseudoacini (Fig. 3). A third neoplasm had areas in which cords of polygonal cells similar to those described above rested in a myxomatous stroma which stained well with alcian green (Fig. 14). These areas resembled a mixed tumor of salivary gland and may account for the confusion between these neoplasms in the earlier litera ture. Recurrent neoplasm, from a fourth patient seen 3 months after irradiation treatment of the primary growth, was composed of large, polygonal, squamoid cells with abundant cytoplasm, distinct cell boundaries, and hyperehromatic nuclei arranged into pseudoacini (Fig. 12).
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mmmmm
Fig. 1.—Case 1 Adenocystic basal cell carcinoma. Duct-like and pseudo-acinar structures lie in relatively acellular stroma. (Hematoxylin and eosin, χΙΊΟ ; reduced Ψ;.)
c^t^FrL· 2 T T C amsue c o2 ·s aAdenocystic basal cell carcinoma which communicates with and perhaDS l e th reduced %") P' e»'-' m · This is the initial specimen. (Hematoxylin and iïïsin χ 14ot
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ÙA Fig. 3.—Case 2. Recurrent adenocystic basal cell carcinoma. Small polygonal cells are arranged in a cribriform pattern. The paler areas consist of extracellular pools of secretions which stain well with alcian green. (Hematoxylin, eosin, and saffron, X140 ; reduced ψι.)
Fig. 4.—Case 3. Recurrent adenocystic basal cell carcinoma. The initial tumor and two previous recurrences were treated surgically at another hospital. Two different growth patterns are present. (Hematoxylin, eosin, and saffron, X100 ; reduced ψι.)
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Pig. 5.—Case 3. Higher magnification of neoplasm depicted in Pig. 4. This is the so-called classic, microcystic or pseudoadenomatous pattern of growth. The cells are uniform, hyperchromatic, and there is little cytoplasm. The cystic spaces contain alcian green positive ma terial. (Hematoxylin, eosin, and saffron, X300 ; reduced "¥;. )
Pig. 6.—Case 3. Another area of the neoplasm depicted in Pig. 4. Here the neoplastic cells form medullary islands with duct-like structures surrounded by loosely arranged, small, hyperchromatic cells. There is abundant extracellular alcian green positive material. (Hematoxylin, eosin, and saffron, X300 ; reduced %.)
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■ '■
:
s
-,
*·· "'"y"...
Fig. 7.—Case 3. Recurrent trachéal neoplasm which was biopsied several hours before patient died. There is a medullary pattern of growth. The neoplastic cells are uniform and polygonal with a moderate amount of eosinophilic to amphophilic cytoplasm and centrally placed vesicular nuclei. There is a tendency to form duct-like structures. Note the similarity to carcinoid tumors. (Hematoxylin, eosin, and saffron, X340 ; reduced Vj. )
Pig. 8.—Case 4. Adenocystic basal cell carcinoma. This is the initial tumor. This area of the neoplasm shows the classical pseudoadenomatous or microcystic pattern of growth. (Hema toxylin and eosin, X120; reduced ψτ.)
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F i g . 9.—Case 4. H i g h e r m a g n i f i c a t i o n of t h e a r e a of n e o p l a s m depicted in F i g . 8. Uniform, h y p e r c h r o m a t i c cells w i t h little c y t o p l a s m form p s e u d o g l a n d u l a r s t r u c t u r e s c o n t a i n i n g a l c i a n g r e e n positive m a t e r i a l . ( H e m a t o x y l i n a n d eosin, X340 ; r e d u c e d %.)
P i g . 10.—Case 4. A n o t h e r a r e a of t h e n e o p l a s m depicted in P i g . 8. H e r e t h e r e is a m e d u l l o t r a b e c u l a r p a t t e r n of g r o w t h w i t h n u m e r o u s d u c t - l i k e s t r u c t u r e s . ( H e m a t o x y l i n a n d eosin, X120 ; r e d u c e d %.)
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. M§^; Pig. 11.—Case 4. Higher magnification of the area depicted in Pig. 10. Dense aggregates of duct-like structures. Note that the ducts are surrounded by a double layer of cells. The inner layer is composed of uniform, low columnar cells with a moderate amount of cytoplasm and vesicular nuclei. The outer layer consists of smaller, darker cells with little cytoplasm. These structures simulate ducts of normal salivary gland. (Hematoxylin and eosin, X340 ; reduced ψΐ.)
Fig. 12.—Case 4. Recurrent adenocystic carcinoma 3 months after irradiation treatment. The growth pattern is typical of adenocystic carcinoma but the cytological features are atypical. The neoplastic cells are large with abundant eosinophilic cytoplasm, clear cellular boundaries, and rather uniform vesicular nuclei with prominent nucleoli. These changes probably represent effects of irradiation. (Hematoxylin and eosin, X340 ; reduced ψτ·)
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Fig. 13.—Case 5. Adenocystic basal cell carcinoma, with the typical pattern of growth. (Hematoxylin. eosin, and saffron, X120 ; reduced %. )
Pig. 14.—Case 5. Area of neoplasm adjacent to that depicted in Fig. 13. Here the neoplastic cells form cords in a myxomatous stroma. Note the similarity to areas found in mixed tumors of salivary glands. (Hematoxylin, eosin, and saffron, X120 ; reduced %. )
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None of the neoplasms had the usual cytological atypicalities of frank carci noma. Uniformity of cells was the rule and mitoses were rare. Nevertheless the neoplastic cells were undifferentiated and infiltrative growth was always ap parent. There was usually abundant stroma which was of either myxomatous or dense hyaline character. Perineural lymphatic infiltration was seen in only one neoplasm but this may have been because most of the tissue specimens were small and superficial. Every neoplasm had abundant alcian green positive material intracellularly, in the pseudoglandular lumens, and frequently in the stroma as well. Occasionally the secretions were an eosinophilic hyaline substance that did not give a positive alcian green reaction. Except for one instance, the secretions were not as strongly positive with alcian green stains as were those in the cells of the surrounding normal glands and the trachéal mucosa. The origins of the neoplasms could not be ascertained. In one lesion (Fig. 2), the neoplastic cells communicated with and perhaps arose from the subcolumnar reserve cells of the surface epithelium but in the others no communi cation with the surface was found. TREATMENT, CLINICAL COURSE, AND SURVIVAL
Four patients were initially treated by partial endoscopie resection followed immediately by 3,000 to 6,100 roentgens of x-ray or cobalt-60 radiation. The fifth patient was treated by endoscopie resection only. Every patient has been fol lowed clinically for 6.8 to 13 years and repeat irradiation and/or endoscopie resections have been performed (Table I ) . One patient had a thoracotomy and left lingular wedge resection and superior dorsal segmenteetomy for a pulmonary metastasis which was detected 11 years after endoscopie resection of the pri mary trachéal neoplasm and following multiple local recurrences. Three patients died within the period of study. I n each case death was directly or indirectly attributable to recurrent neoplasm. One patient died 12y2 years after initial treatment. She had clinical evidence of recurrent neoplasm. Death occurred at home at the age of 34 years and was attributed to pulmonary hemorrhage secondary to the intratracheal tumor; no necropsy was performed. A second patient died 8 years after initial treatment. Death was due to trachéal obstruction by recurrent neoplasm which at necropsy was seen to encircle the trachea and practically occlude the lumen; no métastases were found. The third patient died 13 years after initial treatment. Death occurred several hours following a tracheoscopic resection of recurrent neoplasm. At necropsy there was extensive recurrent neoplasm infiltrating the trachea, larynx, and thyroid gland and there were numerous pulmonary métastases. Each of these 3 patients pursued a similar clinical course characterized by slow but inexorable local growth of their neoplasms with local recurrences which defied attempts at eradication. Métastases occurred late in the course of one patient and were confined to the lungs. I t should be noted that the first clinical recurrences of neoplasm in the 3 fatal cases were 11, 5, and 2 years, respectively, after initial treatment.
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Two patients are alive and well 8 and 6.8 years after initial treatment. The former patient had locally recurrent neoplasm demonstrable 2 months after initial treatment. This was only partially resected according to the surgeon but the patient has had no further manifestation of residual neoplasm during the past 7 years. The latter patient has had no evidence of recurrent neoplasm. The prognosis for these 2 surviving patients must remain guarded at this time in view of the courses taken by the 3 fatal cases. DISCUSSION
Adenocystic (pseudoadenomatous) basal cell carcinoma has been recog nized as a distinct histological entity for over 100 years. Neoplasms of this type have been described in the salivary glands, pharynx, nasopharynx, paranasal sinuses, oral cavity, lacrimal glands, bronchus, trachea, esophagus, breast, and vulva.1"12 The most common locations are the oral cavity, salivary glands, and upper respiratory tract. 1 ' 2 3 Of 87 adenocystic basal cell carcinomas seen at this institution during the period of this study, five (4.4 per cent) originated in the trachea and an equal number arose in bronchi. Recently we12 reviewed 61 cases of bronchial neoplasms commonly desig nated as bronchial adenomas. In that group there were 53 carcinoid tumors, five adenocystic carcinomas, and three mucoepidermoid tumors. Our review of trachéal neoplasms failed to reveal any examples of either carcinoid or muco epidermoid tumors. Eufinger28 reported one, and Weisel, Lepley, and Watson 13 reported four carcinoid tumors arising in the trachea. These authors did not include any photomicrographs of their cases. We are not aware of any other documented examples of trachéal carcinoid tumors, and others 25 have questioned the existence of trachéal carcinoids; hence there should be reservations about accepting these cases. Adenocystic carcinomas accounted for five (23 per cent) of 22 primary trachéal carcinomas seen at this institution during the period of this study. Tinney, Moersch, and McDonald4 found it to be the second most common pri mary malignant neoplasm of the trachea, accounting for 8 (30 per cent) of 27 cases. The 5 patients in this series were from 21 to 63 (average 43) years of age at the time of diagnosis. The ages of 26 patients with adenocystic carcinomas of trachea reported by others 2 · 5 " 8 · 33 were from 29 to 64 (average 42) years. The 5 patients in this series were all females. Of 22 cases of similar trachéal tumors reported by others, 2 - 5 " 8 ' 23 only 10 occurred in females. It is interesting that at this hospital four of five adenocystic carcinomas of bronchi 12 and 35 of 60 adenocystic carcinomas originating in other sites,1 excluding breast and vulva, also occurred in females. Female sex predilection has also been noted by Harrison 14 and Russell24 but not by other authors. 2 1 ' 2 3 ' 3 3 The origin of these neoplasms in trachea is unsettled. It has been suggested that they arise from displaced salivary glands, 2 from dystrophic bronchial buds, 29 from mucous glands and/or their ducts, 4 ' 32 from myoepithelial cells of ducts of the mucous glands, 30 and from the basal layer of the pseudostratified
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epithelium. 31 We did not have sufficient tissues from all patients in this study from which to draw definite conclusions about the origin of these neoplasms. In one case, however, neoplastic cells were in continuity with and appeared to arise from the basal cell or subcolumnar reserve cell layer of the surface epithe lium. We are of the opinion that these neoplasms probably arise from subcolum nar reserve cells of the ducts of mucous glands as well as from similar cells associated with the surface epithelium. The studies of Weiss and Ingram 18 and Reid33 support this hypothesis. Adenocystie basal cell carcinoma of the trachea, in common with its counter parts arising elsewhere, is a slowly growing, insidious, and frequently lethal neoplasm with histologieal features that belie its ultimate poor prognosis. This type of neoplasm frequently infiltrates perineural lymphatics, 1 ' 1 5 ' 1 6 ' 2 3 but métastases occur less frequently, late in the course, and usually do not play a prominent role in the clinical picture of the disease. Lampe and Zatzkin17 noted the late occurrence of and remarkably symptom-free, prolonged survival of patients with pulmonary métastases from this type of neoplasm. Three of the 5 patients in this series died directly or indirectly as a result of their neoplasms. Their clinical courses were similarly characterized by pro longed survival punctuated by numerous local recurrences with associated tra chéal obstruction. Only one patient developed métastases which were localized to the lungs and were of little apparent clinical significance. Although 2 pa tients have survived 6.8 and 8 years, respectively, it should be noted that there was survival in the fatal cases of 8, 12.6, and 13 years after initial treatment. Therefore the usual 5- or 10-year survival rates are tenuous indicators of cure for these neoplasms. Our experience with adenocystie carcinoma of the trachea is similar to that of Clark, Clagett, and McDonald.2 They reported a series of 15 patients of whom 10 died, 2 with proved métastases. Reid33 reported 4 additional cases of which 2 patients died with widespread métastases, and another was alive with recurrent neoplasm. Because of the rarity of adenocystie carcinomas of the trachea, no one has had very much experience with their treatment. Studies of adenocystie carcinoma of other sites have led to conflicting views regarding the merits of radiotherapy. Spies,21 Ahlbom,26 and Lampe 17 held that these neoplasms are radiosensitive whereas it was the opinion of Foote and Frazell 15 and Harrison 14 that these tumors did not respond to irradiation. It is apparent from our experience, com bined with that of others, 2 ' 3 3 ' 2 3 that irradiation therapy alone offers little if any hope for cure but it may induce long-term regression. At the present time, wide surgical excision probably offers the best chance for cure of these neoplasms. The development of bronchoplastic and tracheoplastic operative procedures makes extensive trachéal resection pos sible.13' 2 2 ' 2 5 · 2 7 ' 3 4 Two points about the behavior of these neoplasms should be borne in mind by the surgeon and pathologist. First, the full extent of these neoplasms is usually not apparent grossly. Their propensity for infiltrating perineural lymphatics and soft tissues results in widespread, insidious exten sion. Second, experience with similar tumors arising elsewhere indicates that
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regional lymph nodes may contain métastases. 1 ' 12 · " · 1 5 Therefore, we believe that wide surgical excision will be the treatment of choice in the future and that this should include adjacent lymph nodes. Frozen section techniques for determining the adequacy of resection may be of assistance in carrying out such procedures. SUMMARY
Five basal cell carcinomas of the trachea, all in women whose ages ranged from 21 to 63 years at the time of diagnosis, are reported. The variations in patterns of growth that may occur are stressed. The histological findings sug gest that these neoplasms arise from reserve cells of ducts or surface mucosa. Four patients were treated initially by endoscopie resection followed by irra diation; the fifth patient was treated by resection only. The three ultimately fatal neoplasms were characterized by slow progressive growth and local recur rences and there wTas one instance of pulmonary métastases. Three patients died as a result of extensive locally recurrent and infiltrative neoplasm 8, 12i/£>, and 13 years after treatment; 2 patients are alive 6.8 and 8 years after treat ment. The authors are indebted to Dr. Marvin S. Smout, Victoria Hospital, London, Ontario, for information on the necropsy findings in one of the cases reported here. REFERENCES
1. Smout, M. S., and French, A. J . : Prognosis of Pseudoadenomatous Basal-Cell Carcinoma; Cylindroma, Adenocvstie Carcinoma, A. M. A. Arch. P a t h . 72: 107-112, 1961. 2. Clark, P . L., I l l , Clagett, O. T., and McDonald, J . E.: Cylindromas of the Trachea, Proc. Staff Meet. Mayo Clin. 28: 513-519, 1953. 3. Wilkins, E. W., Jr., Darling, R. C , Soutter, L., and Sniff en, E. C : A Continuing Clinical Survey of Adenomas of the Trachea and Bronchus in a General Hospital, J . THORACIC & CARDIOVAS. SURG. 46: 279-291, 1963.
4. Tinney, W. S., Moersch, H. J., and McDonald, J . E.: Tumors of the Trachea, Arch. Otolaryngol. 41: 284-290, 1945. 5. Guttman, M. E. : P r i m a r y Adenocystic Carcinoma or Cylindroma of the Trachea, Ann. Otol. 45: 894-901, 1936. 6. Enterline, H. T., and Schoenberg, H. W.: Carcinoma (Cylindromatous Type) of Trachea and Bronchi and Bronchial Adenoma; A Comparative Study, Cancer 7: 663-670, 1954. 7. Belsey, E. H. E., and Valentine, J . C : Cylindromatous Mucous-Gland Tumours of the Trachea and Bronchi: A Report of Three Cases, J . P a t h . & Bact. 6 3 : 377-387, 1951. 8. Kramer, E., and Som, M. L.: Cylindroma of the Upper Air Passages: A Cylindromatous Type of Mixed Tumor, Arch. Otolaryngol. 29: 356-370, 1939. 9. Abell, M. E. : Adenocystic (Pseudoadenomatous) Basal Cell Carcinoma of Vestibular Glands of Vulva, Am. J . Obst. & Gynec. 82: 470-482, 1963. 10. Gregg, J. B., and Stamler, P . W.: Unusual Neoplasms of the Esophagus: Review of L i t e r a t u r e and Eeport of a Case, Arch. Otolaryngol. 59: 159-169, 1954. 11. Stewart, F . W.: Tumors of the Breast; Atlas of Tumor Pathology, sect. 9, fasc. 34, Washington, D. C , 1950, Armed Forces I n s t i t u t e of Pathology, pp. 1-114. 12. Markel, S. F., Abell, M. E., Haight, C , and French, A. J . : Neoplasms of Bronchus Commonly Designated as Adenomas, Cancer. ( I n press.) 13. Weisel, W., Lepley, D., Jr., and Watson, E. E.: Eespiratory Tract Adenomas: A Ten-Year Survey, Ann. Surg. 154: 898-902, 1961. 14. Harrison, K.: A Study of Ectopie Mixed Salivary Tumours; H u n t e r i a n Lecture, Ann. Eoyal Coll. Surg" 18: 99-122, 1956. 15. Foote, F . W., Jr., and Frazell, E. L.: Tumors of Major Salivary Glands, Cancer 6: 1065-1133, 1953. 16. Bauer, W. H., and Bauer, J. D.: Classification of Glandular Tumors of Salivary Glands; Study of One-Hundred Forty-Three Cases, A. M. A. Arch. P a t h . 55: 328-346, 1953.
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17. Lampe, I., and Zatzkin, H . : Pulmonary Métastases of Pseudoadenomatous Basal-Cell Carcinoma (Mucous and Salivary Gland Tumor), Radiology 5 3 : 379-385, 1949. 18. Weiss, L., and Ingrain, M.: Adenomatoid Bronchial Tumors. A Consideration of t h e Carcinoid Tumors and the Salivary Tumors of the Bronchial Tree, Cancer 14: 161-178, 1961. 19. Goodner, J. T., Berg, J . W., and Watson, W. L.: The Nonbenign N a t u r e of Bronchial Carcinoids and Cylindromas, Cancer 14: 539-546, 1961. 20. Lampe, I.: Pseudo-Adenomatous Basal-Cell Carcinoma of the Tongue (Salivary Gland Tumor), Radiology 39: 54-61, 1942. 21. Spies, J . W.: Adenoid Cystic Carcinoma: Generalized Métastases in Three Cases of Basal Cell Type, Arch. Surg. 2 1 : 365-404, 1930. 22. Clagett, O. T., Moersch, H. J., and Grindlay, J . H.: Intrathoracic Trachéal Tumors: Development of Surgical Technics for Their Removal, Ann. Surg. 136: 520-532, 1952. 23. Moran, J . J., Becker, S. M., Brady, L. W., and Rambo, V. B . : Adenoid Cystic Carci noma; A Clinicopathological Study, Cancer 14: 1235-1250, 1961. 24. Russell, H.: Adenomatous Tumours of the Anterior Foregut Region Showing the Cylindroma P a t t e r n , Brit, J. Surg. 43: 248-254, 1955. 25. Paulson, D. L., Shaw, R. R., and Kee, J . L.: In Diagnosis and Treatment of Tumors of t h e Chest, edited by D. M. Spain, New York, 1960, Grune & Stratton, pp. 127-141. 26. Ahlbom, H. E.: Mucous- and Salivary-Gland Tumours: A Clinical Study W i t h Special Reference to Radiotherapy, Based on 254 Cases Treated at Radiumhemmet, Stockholm, Acta radiol. Suppl. 23: 1-452, 1935. 27. Abbott, O.: I n discussion of Wilkins et al. 3 28. Von Eufinger, H. : Operativ behandeltes onkozytäres Karzinoid der Trachea, Med. Klin. 58: 605-607, 1963. 29. Womack, N . A., and Graham, E. A. : Mixed Tumors of the L u n g : So-Called Bronchial or Pulmonary Adenoma, Arch. P a t h . 26: 165-206, 1938. 30. Bauer, W. H., and Fox, R. A.: Adenomyoepithelioma (Cylindroma) of P a l a t a l Mucous Glands, Arch. P a t h . 39: 96-102, 1945. 31. Dean, L. W., J r . : Adenocarcinoma of the Trachea: A Pathological Classification of Assistance in Treatment and Prognosis, Ann. Otol. 5 3 : 669-678, 1944. 32. Azzopardi, J . G., and Smith, O. D.: Salivary Gland Tumours and Their Mucins, J . P a t h . & Bact. 77: 131-140, 1959. 33. Reid, J . D.: Adenoid Cystic Carcinoma (Cylindroma) of the Bronchial Tree, Cancer 5 : 685-694, 1952. 34. Woods, F . M., Neptune, W. B., and Palatchi, A.: Resection of the Carina and MainStem Bronchi With the Use of Extraeorporeal Circulation, New England J. Med. 264: 492-494, 1961.
Mich.
A
DENOCYSTic (pseudoadenomatous) basal cell carcinoma is an uncommon but distinctive neoplasm that is found in a variety of locations in the body. Eeferences to this neoplasm in the trachea have consisted of reports of indi vidual cases and several small series. Because of a general lack of detailed survival studies and because this neoplasm is often grouped with similar lesions in the bronchus and elsewhere, it has been difficult to appraise its natural history and prognosis. We have seen only five examples of adenocystic carcinoma that arose in the trachea. The long-term survival information that is available on these, however, provides us with data that permit a fair appraisal of the natural history of this rather rare neoplasm and justifies this report. MATERIAL· AND METHOD
The tissues of all lesions of trachea that were seen at The University of Michigan Medical Center from November, 1934, through June, 1962, and coded as trachéal adenoma, adenocystic, or pseudoadenomatous basal cell carcinoma, adenocarcinoma, bronchial adenoma, medullary carcinoma, and unclassified neoplasm were reviewed. Five adenocystic basal cell carcinomas arising in the trachea were found. Four cases have been referred to briefly by Smout and French. 1 There were no examples of earcinoid or mucoepidermoid tumors. Clinical information including survival to the time of this writing was available for all cases. Tissue sections were stained routinely with hematoxylin and eosin. Selected sections were also stained with mucicarmine and alcian green. CLINICAL OBSERVATIONS
All five patients were Caucasian females, 21, 42, 44, 46, and 63 years of age, respectively, at the time of diagnosis (Table I ) . Symptoms attributable to the neoplasm were present in every case and, in order of frequency, consisted of wheezing, dyspnea, cough, fatigue, and hemoptysis. One patient had had re current pneumonitis. The duration of symptoms prior to diagnosis varied from 1 month to li/£ years. No roentgenographic abnormalities of the trachea were noted initially in From the Department of Pathology, The University of Michigan, Ann Arbor, Mich. Received for publication Feb. 5, 1964.
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AGE (YEARS)
P R E S E N T I N G S Y M P T O M S AND DURATION
1 (Fig. 1)
21
Recurrent pneumonitis—1% yr.
Distal trachea
2 (Figs. 2, 3)
42
Dyspnea, wheezing, cough, fatigue, hemoptysis—8 mo.
Upper trachea
46
Wheezing—?
Upper trachea
63
Cough, fatigue—1 yr.
Distal trachea
44
Dyspnea, wheezing—1 mo.
Distal trachea
CASE N O .
(Figs. 4-7)
(Figs. 8-12) 5 (Figs. 13, 14) •Trachea! obstructive
symptoms
recurred
LOCATION
1 month before death. Death was attributed to
any case, but recurrences following irradiation treatment were frequently ac companied by evidence of narrowing and/or distortion of the^ trachea. Eoentgenographically evident pulmonary métastases were present in one ease. These were noted 11 years after initial treatment of the primary trachéal neoplasm and followed several recurrences. This was the only instance of clini cal or pathological evidence of métastases. PATHOLOGICAL· OBSERVATIONS
The primary tumors were visualized and described at tracheoscopy ; no thoracotomies or mediastinotomies were performed. Three tumors arose in the distal trachea and two originated in the proximal trachea just below the larynx. They were pink to gray-white, bosselated, smooth masses, varying from 1 to 3 cm. in diameter. They extended externally and also into the lumen with consequent narrowing thereof. Recurrent tumors appeared more friable as well as infiltrative. They were associated with scarring and distortion incident to previous treatment. The distinctive features of adenocystic carcinoma were represented pri marily by the classic and tubular patterns of growth (Figs. 1, 2, 4, 5, 8, 9, and 13). The basic cells were small with dark, uniform nuclei and, generally, little cytoplasm. They were cuboidal or polygonal in shape and arranged in anastomos ing cords, tubular structures, and medullary masses in which there were acinar and microcystic formations. A variety of other less commonly appreciated pat terns of growth were encountered in every neoplasm and by themselves they might cause considerable difficulty in diagnosis; however, each neoplasm also
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DATE ΟΓ INITIAL TREATMENT
DATE OF FIRST HISTOLOGICALLY CONFIRMED RECURRENCE
9/44
10/55
-
2/46
8/51
3/53 11/53 12/53 2/54 3/54
3/54 (8 yr.)
Î/47
2/49
4/51 12/51 11/53 2/54 1/58 2/58 (lung metast.) 5/59 8/60
11/60 (13 yr.)
1/55
2/56
-
12/63 (8 yr.)
-
2/57
-
-
12/63 (6.8 yr.)
-
pulmonary
hemorrhage.
DATE OF SUBSEQUENT HISTOLOGICALLY CONFIRMED RECURRENCES
No necropsy was
SURVIVAL ALIVE
-
|
DEAD 2/57* (12.6 yr.)
performed.
had areas of typical adenocystic carcinoma so that the diagnosis could be made with complete assurance (Figs. 1, 2, 4, 5, 8, 9, and 13). One neoplasm had islands in which ductal structures were formed by cuboidal cells with a moderate amount of eosinophilic cytoplasm. Around these were areas of loosely arranged, small cells with scant wispy cytoplasm and hyperehromatic nuclei, lying in a myxomatous stroma which stained well with alcian green (Figs. 4 and 6). The arrangement suggested that the neoplastic cells arose from the subcolumnar reserve cells and differentiated into ductal structures. A recurrence of this neoplasm had, in addition to classical adenocystic carcinoma, areas of medullary growth composed of cuboidal and polygonal cells with eosinophilic and amphophilic cytoplasm and centrally placed vesicular nuclei (Fig. 7). These features resembled those of earcinoid tumors. Another neoplasm possessed areas of small polygonal cells with little cyto plasm and irregularly-shaped hyperehromatic nuclei, arranged in a cribriform pattern—the result of inspissated secretion distending pseudoacini (Fig. 3). A third neoplasm had areas in which cords of polygonal cells similar to those described above rested in a myxomatous stroma which stained well with alcian green (Fig. 14). These areas resembled a mixed tumor of salivary gland and may account for the confusion between these neoplasms in the earlier litera ture. Recurrent neoplasm, from a fourth patient seen 3 months after irradiation treatment of the primary growth, was composed of large, polygonal, squamoid cells with abundant cytoplasm, distinct cell boundaries, and hyperehromatic nuclei arranged into pseudoacini (Fig. 12).
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mmmmm
Fig. 1.—Case 1 Adenocystic basal cell carcinoma. Duct-like and pseudo-acinar structures lie in relatively acellular stroma. (Hematoxylin and eosin, χΙΊΟ ; reduced Ψ;.)
c^t^FrL· 2 T T C amsue c o2 ·s aAdenocystic basal cell carcinoma which communicates with and perhaDS l e th reduced %") P' e»'-' m · This is the initial specimen. (Hematoxylin and iïïsin χ 14ot
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ÙA Fig. 3.—Case 2. Recurrent adenocystic basal cell carcinoma. Small polygonal cells are arranged in a cribriform pattern. The paler areas consist of extracellular pools of secretions which stain well with alcian green. (Hematoxylin, eosin, and saffron, X140 ; reduced ψι.)
Fig. 4.—Case 3. Recurrent adenocystic basal cell carcinoma. The initial tumor and two previous recurrences were treated surgically at another hospital. Two different growth patterns are present. (Hematoxylin, eosin, and saffron, X100 ; reduced ψι.)
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Pig. 5.—Case 3. Higher magnification of neoplasm depicted in Pig. 4. This is the so-called classic, microcystic or pseudoadenomatous pattern of growth. The cells are uniform, hyperchromatic, and there is little cytoplasm. The cystic spaces contain alcian green positive ma terial. (Hematoxylin, eosin, and saffron, X300 ; reduced "¥;. )
Pig. 6.—Case 3. Another area of the neoplasm depicted in Pig. 4. Here the neoplastic cells form medullary islands with duct-like structures surrounded by loosely arranged, small, hyperchromatic cells. There is abundant extracellular alcian green positive material. (Hematoxylin, eosin, and saffron, X300 ; reduced %.)
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■ '■
:
s
-,
*·· "'"y"...
Fig. 7.—Case 3. Recurrent trachéal neoplasm which was biopsied several hours before patient died. There is a medullary pattern of growth. The neoplastic cells are uniform and polygonal with a moderate amount of eosinophilic to amphophilic cytoplasm and centrally placed vesicular nuclei. There is a tendency to form duct-like structures. Note the similarity to carcinoid tumors. (Hematoxylin, eosin, and saffron, X340 ; reduced Vj. )
Pig. 8.—Case 4. Adenocystic basal cell carcinoma. This is the initial tumor. This area of the neoplasm shows the classical pseudoadenomatous or microcystic pattern of growth. (Hema toxylin and eosin, X120; reduced ψτ.)
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F i g . 9.—Case 4. H i g h e r m a g n i f i c a t i o n of t h e a r e a of n e o p l a s m depicted in F i g . 8. Uniform, h y p e r c h r o m a t i c cells w i t h little c y t o p l a s m form p s e u d o g l a n d u l a r s t r u c t u r e s c o n t a i n i n g a l c i a n g r e e n positive m a t e r i a l . ( H e m a t o x y l i n a n d eosin, X340 ; r e d u c e d %.)
P i g . 10.—Case 4. A n o t h e r a r e a of t h e n e o p l a s m depicted in P i g . 8. H e r e t h e r e is a m e d u l l o t r a b e c u l a r p a t t e r n of g r o w t h w i t h n u m e r o u s d u c t - l i k e s t r u c t u r e s . ( H e m a t o x y l i n a n d eosin, X120 ; r e d u c e d %.)
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. M§^; Pig. 11.—Case 4. Higher magnification of the area depicted in Pig. 10. Dense aggregates of duct-like structures. Note that the ducts are surrounded by a double layer of cells. The inner layer is composed of uniform, low columnar cells with a moderate amount of cytoplasm and vesicular nuclei. The outer layer consists of smaller, darker cells with little cytoplasm. These structures simulate ducts of normal salivary gland. (Hematoxylin and eosin, X340 ; reduced ψΐ.)
Fig. 12.—Case 4. Recurrent adenocystic carcinoma 3 months after irradiation treatment. The growth pattern is typical of adenocystic carcinoma but the cytological features are atypical. The neoplastic cells are large with abundant eosinophilic cytoplasm, clear cellular boundaries, and rather uniform vesicular nuclei with prominent nucleoli. These changes probably represent effects of irradiation. (Hematoxylin and eosin, X340 ; reduced ψτ·)
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Fig. 13.—Case 5. Adenocystic basal cell carcinoma, with the typical pattern of growth. (Hematoxylin. eosin, and saffron, X120 ; reduced %. )
Pig. 14.—Case 5. Area of neoplasm adjacent to that depicted in Fig. 13. Here the neoplastic cells form cords in a myxomatous stroma. Note the similarity to areas found in mixed tumors of salivary glands. (Hematoxylin, eosin, and saffron, X120 ; reduced %. )
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None of the neoplasms had the usual cytological atypicalities of frank carci noma. Uniformity of cells was the rule and mitoses were rare. Nevertheless the neoplastic cells were undifferentiated and infiltrative growth was always ap parent. There was usually abundant stroma which was of either myxomatous or dense hyaline character. Perineural lymphatic infiltration was seen in only one neoplasm but this may have been because most of the tissue specimens were small and superficial. Every neoplasm had abundant alcian green positive material intracellularly, in the pseudoglandular lumens, and frequently in the stroma as well. Occasionally the secretions were an eosinophilic hyaline substance that did not give a positive alcian green reaction. Except for one instance, the secretions were not as strongly positive with alcian green stains as were those in the cells of the surrounding normal glands and the trachéal mucosa. The origins of the neoplasms could not be ascertained. In one lesion (Fig. 2), the neoplastic cells communicated with and perhaps arose from the subcolumnar reserve cells of the surface epithelium but in the others no communi cation with the surface was found. TREATMENT, CLINICAL COURSE, AND SURVIVAL
Four patients were initially treated by partial endoscopie resection followed immediately by 3,000 to 6,100 roentgens of x-ray or cobalt-60 radiation. The fifth patient was treated by endoscopie resection only. Every patient has been fol lowed clinically for 6.8 to 13 years and repeat irradiation and/or endoscopie resections have been performed (Table I ) . One patient had a thoracotomy and left lingular wedge resection and superior dorsal segmenteetomy for a pulmonary metastasis which was detected 11 years after endoscopie resection of the pri mary trachéal neoplasm and following multiple local recurrences. Three patients died within the period of study. I n each case death was directly or indirectly attributable to recurrent neoplasm. One patient died 12y2 years after initial treatment. She had clinical evidence of recurrent neoplasm. Death occurred at home at the age of 34 years and was attributed to pulmonary hemorrhage secondary to the intratracheal tumor; no necropsy was performed. A second patient died 8 years after initial treatment. Death was due to trachéal obstruction by recurrent neoplasm which at necropsy was seen to encircle the trachea and practically occlude the lumen; no métastases were found. The third patient died 13 years after initial treatment. Death occurred several hours following a tracheoscopic resection of recurrent neoplasm. At necropsy there was extensive recurrent neoplasm infiltrating the trachea, larynx, and thyroid gland and there were numerous pulmonary métastases. Each of these 3 patients pursued a similar clinical course characterized by slow but inexorable local growth of their neoplasms with local recurrences which defied attempts at eradication. Métastases occurred late in the course of one patient and were confined to the lungs. I t should be noted that the first clinical recurrences of neoplasm in the 3 fatal cases were 11, 5, and 2 years, respectively, after initial treatment.
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Two patients are alive and well 8 and 6.8 years after initial treatment. The former patient had locally recurrent neoplasm demonstrable 2 months after initial treatment. This was only partially resected according to the surgeon but the patient has had no further manifestation of residual neoplasm during the past 7 years. The latter patient has had no evidence of recurrent neoplasm. The prognosis for these 2 surviving patients must remain guarded at this time in view of the courses taken by the 3 fatal cases. DISCUSSION
Adenocystic (pseudoadenomatous) basal cell carcinoma has been recog nized as a distinct histological entity for over 100 years. Neoplasms of this type have been described in the salivary glands, pharynx, nasopharynx, paranasal sinuses, oral cavity, lacrimal glands, bronchus, trachea, esophagus, breast, and vulva.1"12 The most common locations are the oral cavity, salivary glands, and upper respiratory tract. 1 ' 2 3 Of 87 adenocystic basal cell carcinomas seen at this institution during the period of this study, five (4.4 per cent) originated in the trachea and an equal number arose in bronchi. Recently we12 reviewed 61 cases of bronchial neoplasms commonly desig nated as bronchial adenomas. In that group there were 53 carcinoid tumors, five adenocystic carcinomas, and three mucoepidermoid tumors. Our review of trachéal neoplasms failed to reveal any examples of either carcinoid or muco epidermoid tumors. Eufinger28 reported one, and Weisel, Lepley, and Watson 13 reported four carcinoid tumors arising in the trachea. These authors did not include any photomicrographs of their cases. We are not aware of any other documented examples of trachéal carcinoid tumors, and others 25 have questioned the existence of trachéal carcinoids; hence there should be reservations about accepting these cases. Adenocystic carcinomas accounted for five (23 per cent) of 22 primary trachéal carcinomas seen at this institution during the period of this study. Tinney, Moersch, and McDonald4 found it to be the second most common pri mary malignant neoplasm of the trachea, accounting for 8 (30 per cent) of 27 cases. The 5 patients in this series were from 21 to 63 (average 43) years of age at the time of diagnosis. The ages of 26 patients with adenocystic carcinomas of trachea reported by others 2 · 5 " 8 · 33 were from 29 to 64 (average 42) years. The 5 patients in this series were all females. Of 22 cases of similar trachéal tumors reported by others, 2 - 5 " 8 ' 23 only 10 occurred in females. It is interesting that at this hospital four of five adenocystic carcinomas of bronchi 12 and 35 of 60 adenocystic carcinomas originating in other sites,1 excluding breast and vulva, also occurred in females. Female sex predilection has also been noted by Harrison 14 and Russell24 but not by other authors. 2 1 ' 2 3 ' 3 3 The origin of these neoplasms in trachea is unsettled. It has been suggested that they arise from displaced salivary glands, 2 from dystrophic bronchial buds, 29 from mucous glands and/or their ducts, 4 ' 32 from myoepithelial cells of ducts of the mucous glands, 30 and from the basal layer of the pseudostratified
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epithelium. 31 We did not have sufficient tissues from all patients in this study from which to draw definite conclusions about the origin of these neoplasms. In one case, however, neoplastic cells were in continuity with and appeared to arise from the basal cell or subcolumnar reserve cell layer of the surface epithe lium. We are of the opinion that these neoplasms probably arise from subcolum nar reserve cells of the ducts of mucous glands as well as from similar cells associated with the surface epithelium. The studies of Weiss and Ingram 18 and Reid33 support this hypothesis. Adenocystie basal cell carcinoma of the trachea, in common with its counter parts arising elsewhere, is a slowly growing, insidious, and frequently lethal neoplasm with histologieal features that belie its ultimate poor prognosis. This type of neoplasm frequently infiltrates perineural lymphatics, 1 ' 1 5 ' 1 6 ' 2 3 but métastases occur less frequently, late in the course, and usually do not play a prominent role in the clinical picture of the disease. Lampe and Zatzkin17 noted the late occurrence of and remarkably symptom-free, prolonged survival of patients with pulmonary métastases from this type of neoplasm. Three of the 5 patients in this series died directly or indirectly as a result of their neoplasms. Their clinical courses were similarly characterized by pro longed survival punctuated by numerous local recurrences with associated tra chéal obstruction. Only one patient developed métastases which were localized to the lungs and were of little apparent clinical significance. Although 2 pa tients have survived 6.8 and 8 years, respectively, it should be noted that there was survival in the fatal cases of 8, 12.6, and 13 years after initial treatment. Therefore the usual 5- or 10-year survival rates are tenuous indicators of cure for these neoplasms. Our experience with adenocystie carcinoma of the trachea is similar to that of Clark, Clagett, and McDonald.2 They reported a series of 15 patients of whom 10 died, 2 with proved métastases. Reid33 reported 4 additional cases of which 2 patients died with widespread métastases, and another was alive with recurrent neoplasm. Because of the rarity of adenocystie carcinomas of the trachea, no one has had very much experience with their treatment. Studies of adenocystie carcinoma of other sites have led to conflicting views regarding the merits of radiotherapy. Spies,21 Ahlbom,26 and Lampe 17 held that these neoplasms are radiosensitive whereas it was the opinion of Foote and Frazell 15 and Harrison 14 that these tumors did not respond to irradiation. It is apparent from our experience, com bined with that of others, 2 ' 3 3 ' 2 3 that irradiation therapy alone offers little if any hope for cure but it may induce long-term regression. At the present time, wide surgical excision probably offers the best chance for cure of these neoplasms. The development of bronchoplastic and tracheoplastic operative procedures makes extensive trachéal resection pos sible.13' 2 2 ' 2 5 · 2 7 ' 3 4 Two points about the behavior of these neoplasms should be borne in mind by the surgeon and pathologist. First, the full extent of these neoplasms is usually not apparent grossly. Their propensity for infiltrating perineural lymphatics and soft tissues results in widespread, insidious exten sion. Second, experience with similar tumors arising elsewhere indicates that
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regional lymph nodes may contain métastases. 1 ' 12 · " · 1 5 Therefore, we believe that wide surgical excision will be the treatment of choice in the future and that this should include adjacent lymph nodes. Frozen section techniques for determining the adequacy of resection may be of assistance in carrying out such procedures. SUMMARY
Five basal cell carcinomas of the trachea, all in women whose ages ranged from 21 to 63 years at the time of diagnosis, are reported. The variations in patterns of growth that may occur are stressed. The histological findings sug gest that these neoplasms arise from reserve cells of ducts or surface mucosa. Four patients were treated initially by endoscopie resection followed by irra diation; the fifth patient was treated by resection only. The three ultimately fatal neoplasms were characterized by slow progressive growth and local recur rences and there wTas one instance of pulmonary métastases. Three patients died as a result of extensive locally recurrent and infiltrative neoplasm 8, 12i/£>, and 13 years after treatment; 2 patients are alive 6.8 and 8 years after treat ment. The authors are indebted to Dr. Marvin S. Smout, Victoria Hospital, London, Ontario, for information on the necropsy findings in one of the cases reported here. REFERENCES
1. Smout, M. S., and French, A. J . : Prognosis of Pseudoadenomatous Basal-Cell Carcinoma; Cylindroma, Adenocvstie Carcinoma, A. M. A. Arch. P a t h . 72: 107-112, 1961. 2. Clark, P . L., I l l , Clagett, O. T., and McDonald, J . E.: Cylindromas of the Trachea, Proc. Staff Meet. Mayo Clin. 28: 513-519, 1953. 3. Wilkins, E. W., Jr., Darling, R. C , Soutter, L., and Sniff en, E. C : A Continuing Clinical Survey of Adenomas of the Trachea and Bronchus in a General Hospital, J . THORACIC & CARDIOVAS. SURG. 46: 279-291, 1963.
4. Tinney, W. S., Moersch, H. J., and McDonald, J . E.: Tumors of the Trachea, Arch. Otolaryngol. 41: 284-290, 1945. 5. Guttman, M. E. : P r i m a r y Adenocystic Carcinoma or Cylindroma of the Trachea, Ann. Otol. 45: 894-901, 1936. 6. Enterline, H. T., and Schoenberg, H. W.: Carcinoma (Cylindromatous Type) of Trachea and Bronchi and Bronchial Adenoma; A Comparative Study, Cancer 7: 663-670, 1954. 7. Belsey, E. H. E., and Valentine, J . C : Cylindromatous Mucous-Gland Tumours of the Trachea and Bronchi: A Report of Three Cases, J . P a t h . & Bact. 6 3 : 377-387, 1951. 8. Kramer, E., and Som, M. L.: Cylindroma of the Upper Air Passages: A Cylindromatous Type of Mixed Tumor, Arch. Otolaryngol. 29: 356-370, 1939. 9. Abell, M. E. : Adenocystic (Pseudoadenomatous) Basal Cell Carcinoma of Vestibular Glands of Vulva, Am. J . Obst. & Gynec. 82: 470-482, 1963. 10. Gregg, J. B., and Stamler, P . W.: Unusual Neoplasms of the Esophagus: Review of L i t e r a t u r e and Eeport of a Case, Arch. Otolaryngol. 59: 159-169, 1954. 11. Stewart, F . W.: Tumors of the Breast; Atlas of Tumor Pathology, sect. 9, fasc. 34, Washington, D. C , 1950, Armed Forces I n s t i t u t e of Pathology, pp. 1-114. 12. Markel, S. F., Abell, M. E., Haight, C , and French, A. J . : Neoplasms of Bronchus Commonly Designated as Adenomas, Cancer. ( I n press.) 13. Weisel, W., Lepley, D., Jr., and Watson, E. E.: Eespiratory Tract Adenomas: A Ten-Year Survey, Ann. Surg. 154: 898-902, 1961. 14. Harrison, K.: A Study of Ectopie Mixed Salivary Tumours; H u n t e r i a n Lecture, Ann. Eoyal Coll. Surg" 18: 99-122, 1956. 15. Foote, F . W., Jr., and Frazell, E. L.: Tumors of Major Salivary Glands, Cancer 6: 1065-1133, 1953. 16. Bauer, W. H., and Bauer, J. D.: Classification of Glandular Tumors of Salivary Glands; Study of One-Hundred Forty-Three Cases, A. M. A. Arch. P a t h . 55: 328-346, 1953.
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17. Lampe, I., and Zatzkin, H . : Pulmonary Métastases of Pseudoadenomatous Basal-Cell Carcinoma (Mucous and Salivary Gland Tumor), Radiology 5 3 : 379-385, 1949. 18. Weiss, L., and Ingrain, M.: Adenomatoid Bronchial Tumors. A Consideration of t h e Carcinoid Tumors and the Salivary Tumors of the Bronchial Tree, Cancer 14: 161-178, 1961. 19. Goodner, J. T., Berg, J . W., and Watson, W. L.: The Nonbenign N a t u r e of Bronchial Carcinoids and Cylindromas, Cancer 14: 539-546, 1961. 20. Lampe, I.: Pseudo-Adenomatous Basal-Cell Carcinoma of the Tongue (Salivary Gland Tumor), Radiology 39: 54-61, 1942. 21. Spies, J . W.: Adenoid Cystic Carcinoma: Generalized Métastases in Three Cases of Basal Cell Type, Arch. Surg. 2 1 : 365-404, 1930. 22. Clagett, O. T., Moersch, H. J., and Grindlay, J . H.: Intrathoracic Trachéal Tumors: Development of Surgical Technics for Their Removal, Ann. Surg. 136: 520-532, 1952. 23. Moran, J . J., Becker, S. M., Brady, L. W., and Rambo, V. B . : Adenoid Cystic Carci noma; A Clinicopathological Study, Cancer 14: 1235-1250, 1961. 24. Russell, H.: Adenomatous Tumours of the Anterior Foregut Region Showing the Cylindroma P a t t e r n , Brit, J. Surg. 43: 248-254, 1955. 25. Paulson, D. L., Shaw, R. R., and Kee, J . L.: In Diagnosis and Treatment of Tumors of t h e Chest, edited by D. M. Spain, New York, 1960, Grune & Stratton, pp. 127-141. 26. Ahlbom, H. E.: Mucous- and Salivary-Gland Tumours: A Clinical Study W i t h Special Reference to Radiotherapy, Based on 254 Cases Treated at Radiumhemmet, Stockholm, Acta radiol. Suppl. 23: 1-452, 1935. 27. Abbott, O.: I n discussion of Wilkins et al. 3 28. Von Eufinger, H. : Operativ behandeltes onkozytäres Karzinoid der Trachea, Med. Klin. 58: 605-607, 1963. 29. Womack, N . A., and Graham, E. A. : Mixed Tumors of the L u n g : So-Called Bronchial or Pulmonary Adenoma, Arch. P a t h . 26: 165-206, 1938. 30. Bauer, W. H., and Fox, R. A.: Adenomyoepithelioma (Cylindroma) of P a l a t a l Mucous Glands, Arch. P a t h . 39: 96-102, 1945. 31. Dean, L. W., J r . : Adenocarcinoma of the Trachea: A Pathological Classification of Assistance in Treatment and Prognosis, Ann. Otol. 5 3 : 669-678, 1944. 32. Azzopardi, J . G., and Smith, O. D.: Salivary Gland Tumours and Their Mucins, J . P a t h . & Bact. 77: 131-140, 1959. 33. Reid, J . D.: Adenoid Cystic Carcinoma (Cylindroma) of the Bronchial Tree, Cancer 5 : 685-694, 1952. 34. Woods, F . M., Neptune, W. B., and Palatchi, A.: Resection of the Carina and MainStem Bronchi With the Use of Extraeorporeal Circulation, New England J. Med. 264: 492-494, 1961.