Papillary Cystadenoma Lymphomatosum (Warthin's Tumor) in Patients in a General Hospital over a 24-year Period

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1 Papillary Cystadenoma Lymphomatosum (Warthin's Tumor) in Patients in a General Hospital over a 24-year Period SCOTT E. DIETERT, M.D. Eli Lilly and Company, Greenfield Laboratories, Toxicology Division, Box 708, Greenfield, Indiana ABSTRACT Dietert, Scott E.: Papillary cystadenoma lymphomatosum (Warthin's tumor) in patients in a general hospital over a 24-year period. Am J Clin Pathol 63: , One hundred thirty-seven Warthin's tumors from 120 patients seen during a 23 V2 year period were studied as two groups. The first group consisted of 32 tumors removed by the otolaryngology department. Material from these cases was re-examined microscopically for evidence of tumor occurrence within lymph nodes located inside and outside the parotid gland. This group of 32 tumors was also studied as part of the second group, 105 additional lesions removed by the surgery department. Data on patient age, sex, and race, as well as tumor multiplicity, location, and size, were incorporated into a single statistical analysis. Seventy-two per cent of the tumors in the first group were intranodal in location. Second primary Warthin's tumors occurred in 13 (11%) of the patients. Eight occult tumors were identified, and their importance is discussed. A single Negro, a man, was found among 118 patients. The observed frequency of the tumor was twentyfold less than expected among the Negro population. (Key words: Papillary cystadenoma lymphomatosum; Warthin's tumor; Salivary gland; Lymph node.) ALTHOUGH SEVERAL WORKERS, including Thompson and Bryant, 11 Bernier and Bhaskar, 4 and more recently Azzopardi and Hou, 2 have emphasized that papillary cystadenoma lymphomatosum (Warthin's tumor 12 ) is a heterotopic salivary gland lesion arising in a lymph node, this tumor has continued to receive attention as a Received September 26, 1974; accepted for publication November 22, This study was undertaken while the author was an American Cancer Society Fellow in Surgical Pathology at Washington University School of Medicine, St. Louis, Missouri ( ). Address reprint requests to Dr. Dietert. primary lesion of the parotid gland. The World Health Organization's International Histological Classification of Tumours has designated this tumor an adenolymphoma and has classified it as a subtype of the salivary gland monomorphic adenoma. 10 The Laboratory of Surgical Pathology received, from the Otolaryngology Department at Barnes Hospital, an encapsulated nodule excised from the soft tissues in the right parotid gland region. Microscopic examination demonstrated an enlarged lymph node, adjacent to the capsule of the parotid gland, which contained 866

2 June 1975 PAPILLARY CYSTADENOMA LYMPHOMATOSUM 867 an epithelium-lined, multicystic lesion histologically identical to a classic papillary cystadenoma lymphomatosum. 5 This case stimulated a review of the 32 Warthin's tumors removed by the Otolaryngology Department from 1964 through June Data from 105 additional Warthin's tumors, contributed by the Surgery Department since 1950, were included to make portions of this report more valid statistically. A series of 106 cases reported in was obtained from the files of the Armed Forces Institute of Pathology. It was felt that the experience with this tumor of a large civilian referral hospital might provide additional information. Materials and Methods The tumors analyzed in this study were obtained from the organ-lesion file of the Division of Surgical Pathology, Department of Pathology, Washington University School of Medicine, and Barnes Hospital in St. Louis, Missouri. Two tumor groups were utilized. The first consisted of 32 tumors removed from 30 patients by the Department of Otolaryngology between 1964 and June 30, The microscopic slides and surgical pathology reports for each of these specimens were reviewed. Specific attention was focused on the precise histologic location of each tumor, i.e., (1) within a lymph node situated inside a salivary gland; (2) within a lymph node, in an extraglandular site; or (3) within a salivary gland. Statistical parameters consisting of patient age, sex, and race (Negro or non-negro), as well as gross tumor location, size, and multiplicity in a single patient, were recorded. To enhance the statistical validity of these six parameters, a second tumor group was included. This group consisted of 105 additional Warthin's tumors removed from 90 patients by the Surgery Department (Plastic and General Surgery Divisions) between 1950 and June 30, The data on the six parameters contained in the surgical pathology reports of these cases were added to that obtained from the first group. Review of the microscopic slides from this second group was deferred in many instances since the histopathologic diagnosis of Warthin's tumor is one of the simple pattern recognition and the frequent occurrence of tumors within lymph nodes had been substantiated already in the first group of 32 lesions. Results Report of a Case A 49-year-old Caucasian woman had a painless mass in the right side of the neck, which had enlarged slowly over the previous three months. She denied facial weakness, weight loss, dysphagia, and hoarseness. Physical examination revealed a 2-cm., firm, nontender, mobile mass at the angle of the right jaw. The facial nerve was intact. A clinical diagnosis of probable parotid gland tumor was made. At operation a 2-cm., circumscribed mass overlying the digastric muscle was identified in the right side of the neck and easily dissected free. The mass was adjacent to, but not within, the right parotid gland. Pathologic Examination. The specimen consisted of a single, 2 X 1.3 X 1 cm., sharply-circumscribed, apparently-encapsulated, ovoid, bosselated, black-brown nodule. Sections displayed a honeycombed pattern of multiple, thin-walled cysts, some of which were as large as 0.2 cm. in diameter and contained watery, transparent, tan-brown fluid. Microscopic examination demonstrated an enlarged lymph node with parenchymal distortion by a multiloculated microcystic lesion (Fig. 1). The delimiting capsule was intact, and residual nodal parenchyma was present along one margin of the specimen (Fig. 1). At high magnification, subcapsular and penetrating cortical sinuses charac-

3 868 DIETERT AJ.C.P. Vol. 63 /-. V**b J> \ ^ tr^ \ FIG. 1. Lymph node, right parotid gland region. Approximately two-thirds of the parenchyma is distorted by a multiloculated microcystic lesion. The delimiting capsule (arrows) remains intact. A portion of normal residual lymph node is identifiable at the left margin (LN). The cysts contained watery, brown-tan, transparent fluid. Hematoxylin and eosin. xll. teristic of a lymph node were identified (Fig. 2). The multicystic lesion was identical in all aspects to a classic papillary cystadenoma lymphomatosum, 5 and is not described in detail. The numerous cyst walls were lined by a well-differentiated, psuedostratified, columnar, acidophilic, epithelium with an underlying normalappearing lymphoid parenchyma containing scattered germinal centers (Fig. 3). A single microscopic fragment of normal parotid gland was adherent to the outer surface of the lymph node capsule. Thus, the nodule excised from the neck was an FIG. 2 (upper). Lymph node, right parotid gland region. A high-magnification view of the delimiting capsule (C) from the residual normal lymph node identified in Figure 1. Note the readily-discernible subcapsular sinus (S), the contiguous penetrating cortical sinus (arrow) and the adjacent lymphoid parenchyma (P). Erythrocytes and lymphocytes are present in the pericapsular connective tissue. This latter finding is interpreted as surgical artifact. Hematoxylin and eosin. x350. FIG. 3 (lower). Lymph node, right parotid gland region. A representative high-magnification view of one of the cyst walls. Note the two components of a classic papillary cystadenoma lymphomatosum: (1) the pseudostratified, columnar, well-differentiated, epithelial lining cells (arrows); (2) the underlying lymphoid tissue consisting of lymphocytes (L) and occasional germinal centers (G). The cyst lumen is empty except for rare detached cell fragments. Hematoxylin and eosin. x350.

4 June 1975 PAPILLARY CYSTADENOMA LYMPHOMATOSUM 869 :- - I

5 870 DIETERT A.J.C.P. Vol.63 example of a Warthin's tumor occurring in an extraglandular cervical lymph node from the right parotid gland region. Microscopic Analysis One hundred microscopic slides representing 32 tumors removed from 30 patients by the Otolaryngology Department were reviewed. A diagnosis of papillary cystadenoma lymphomatosum was confirmed in each case. Histologic identification of the precise organ location of each tumor was attempted from the available slides. For 72% of the cases two to five slides representing different tissue blocks were available. In the remaining cases a single slide was available. Three specific tumor locations were distinguished in the microscopic analysis: (1) within a lymph node residing inside a salivary gland; (2) within a lymph node situated in an extraglandular site; (3) within a major salivary gland. The presence of a definitive subcapsular lymphatic sinus beneath at least some portion of the tumor capsule was employed as the sine qua non for identification of a lymph node as a tumor site (Fig. 2). Sixteen tumors (50%) were found within a lymph node situated inside the parotid gland proper. Two of these intranodal intraglandular tumors were discovered incidentally during the examination of excised parotid glands, which accompanied radical neck dissections for cancer therapy. Seven tumors (22%) occurred in a lymph node located in an extraglandular site. Two of these lesions were considered incidental, as they were discovered during the examination of lymph nodes removed in radical neck dissections. In the remaining five cases, the tumor presented as a clinically demonstrable mass in a paraparotid location, i.e., the angle of the mandible, anterior to the ear, or below the ear. Histologically all of the intranodal extraglandular tumors were similar to the lesion in the case described above. In the final nine cases (28%), the tumors could be identified only as arising within the parotid gland. The major factors that prevented identification of an intraglandular lymph node as the tumor site in these cases were inadequate tissue blocks (in number or in the site chosen for tumor sampling) and compression of the lymphoid parenchyma against the tumor capsule. The latter greatly reduced the opportunity to evaluate the presence of a subcapsular sinus. Warthin's tumors were not encountered within the submandibular and sublingual glands. Minor histopathologic variations were seen in three tumors. Two had focal squamous metaplasia of the epithelium lining the cysts. Anucleate squames and squamous "pearl" formation were not demonstrable, however. One of these tumors also contained scattered foci of mucicarmine-positive cells distributed within the lining epithelium. Typical goblet cells were demonstrable among these mucous elements. Foote and Frazell described and illustrated a lesion similar to this tumor. 5 A single tumor demonstrated focal fibrosis and hyalinization of the lymphoid parenchyma with an overlying atrophic, flattened, epithelium. Rare squamous metaplasia and occasional fibrosis have been described by others. 11 Statistical Analysis One hundred thirty-seven Warthin's tumors were found in the Barnes Hospital organ-lesion file, representing the combined surgical efforts of the Departments of Surgery and Otolaryngology between 1950 and June 30, These tumors were removed from 120 patients. Approximately eight tumors a year have been removed by both departments since 1964.

6 June 1975 PAPILLARY CYSTADENOMA LYMPHOMATOSIS PAPILLARY CYSTADENOMA LYMPHOMATOSIS - BARNES HOSPITAL 1950-JUNE Tumors 137 Patients lie I- 14 u. O l2 * UJ CO 2 10 Z5 Z UL 1-5 i h PATIENT AGE- HALF DECADES FIG. 4. A graph of patient age in half decades (abscissa) plotted against the numbers of Warthin's tumors (ordinate) occurring in each half decade. Thirty-three per cent (45) of the tumors occurred during the sixth decade (51-60 years) and 34% (47) occurred during the seventh decade (61-70 years). Twenty per cent (27) were seen between 36 and 50 years, and another 13% (18) occurred after the age of 70 years. Note the absence of any tumors during the first 35 years of life! Mean age 59.3 years, standard deviation 10.5 years, 95% confidence limits (38.3 to 80.3 years), range 36 to 82 years. Since Barnes Hospital is a major referral center for cancers of the head and neck, where radical dissections are commonplace, the Warthin's tumors were identified as those presenting as a primary lesion for therapy and those found incidentally in a dissection specimen removed for the regional treatment of malignant disease. Eight Warthin's tumors, histologically identical in every respect to those presenting as clinically-evident lesions, were classified as incidental. They accounted for 6% of all tumors reported here. Four were removed by the Surgery Department and four by the Otolaryngology Department. The tumors were distributed as follows: (1) intranodal and intraglandular (parotid), two; (2) intranodal (cervical) and extraglandular, three; (3) intraglandular (parotid), two; (4) cervical soft tissue, one. The patients consisted of seven men and one woman. One patient was in the sixth decade of life; four were in the seventh decade; and three were in the eighth decade. The implications of these tumors are considered below. Six parameters received attention in the statistical evaluation of these 137 tumors:

7 872 DIETERT AJ.C.P. Vol. 63 (1) patient age; (2) patient sex; (3) patient race (Negro or non-negro); (4) tumor multiplicity in a single patient; (5) tumor location (gross anatomic site and side of neck); (6) tumor size. Patient Age. Figure 4 is a graph of patient ages (in half decades) plotted against the number of tumors occurring in each half decade. In this study Warthin's tumor was not diagnosed during the first 3'/2 decades of life, i.e., before the age of 36. The tumors showed the highest frequency of occurrence in the sixth and seventh decades, when 92 (67%) of the lesions were diagnosed. Twenty per cent were seen before the age 51 years and 13% after the age of 70 years. The mean patient age was 59.3 years, with a range of 36 to 82 years. Patient Sex. One hundred twenty patients were represented by the 137 tumors analyzed. Eighty-seven (73%) were men and 33 (27%) were women. The malefemale ratio of these patients was 2.6:1. Examination of the 30 patients treated by the Otolaryngology Department revealed a male-female ratio of exactly 2:1. Patient Race. Of the 120 patients, 118 could be identified as either Negro or non-negro. There was only a single Negro patient, a man, among the 118 patients. The remaining patients consisted of 85 non-negro men and 32 non-negro women. Thus,.8% of the Warthin's tumor patients were Negro. The significance of this finding will be discussed below. Tumor Multiplicity. Papillary cystadenoma lymphomatosum is noteworthy among salivary gland lesions in its predilection for multiplicity. 5 During the 23/2-year period represented by this study, 14 patients (12%) developed 31 Warthin's tumors. Eleven patients had two tumors each, distributed as follows: (1) eight patients had bilateral lesions occurring in succession over a period of one to 13 years; (2) one patient had bilateral simultaneous tumors; (3) one patient had unilateral simultaneous lesions occurring in the right parotid gland and in a paraparotid lymph node; (4) one patient had unilateral tumors occurring in succession within a period of a year. In three patients three tumors developed. In every case these_tumors occurred in a bilateral distribution. Two patients had bilateral simultaneous tumors, with a single tumor occurring four years earlier and eight years later, respectively. A single patient developed three successive lesions over a one-year time span. These 31 tumors occurred in 11 men and three women, for a male-female ratio of 3.7:1. All patients were non-negro. A consideration of these multiple tumors as postoperative recurrences of a single tumor or as multiple primary lesions appears in the discussion. Tumor Location. Tumor location was analyzed from two macroscopic aspects: (1) the side of the body, and (2) the gross anatomic site of the tumor. One hundred twenty-seven tumors were identified as to location on the right or left side of the head or neck. Fifty-three per cent (67) occurred on the right side, while 47% (60) were present on the left side. Three tumor sites appeared in the surgical pathology reports of the 137 tumors: (1) salivary glands (parotid and submandibular), 126 tumors; (2) soft tissue of the neck, three tumors; (3) cervical lymph nodes, eight tumors. Two cases had been diagnosed as a Warthin's tumor of the submandibular gland. Microscopic review demonstrated, however, that these two tumors occurred in lymph nodes in the vicinity of the submandibular gland! A bona fide papillary cystadenoma lymphomatosum within the submandibular gland was not substantiated in this series. The reports of Thompson and Bryant 11 and Foote and Frazell 5 support this finding. Tumor Size. Tumor size was the most elusive parameter to evaluate accurately.

8 June 1975 PAPILLARY CYSTADENOMA LYMPHOMATOSUM 873 Often only a single tumor dimension was present. Occasionally the size of the superficial parotid lobe was recorded, but the specific tumor dimensions were not included. As a compromise, the largest recorded dimension, when specified as being a tumor measurement, was utilized. Employing these criteria the tumors ranged from 1 to 10 cm. in size, with the majority measuring 2 to 4 cm. These dimensions compared closely to those of Foote and Frazell. 5 Discussion The demonstration of tumor multiplicity in 14 (12%) of the 120 patients with papillary cystadenoma lymphomatosum was not unexpected. Foote and Frazell 5 reported six recurrences among the 49 tumors in their 44 patients. Six patients were described as having bilateral lesions. 5 The distribution of the 31 tumors in our 14 patients is described in detail (see Results) to evaluate postoperative recurrence as one explanation of multiple lesions. It was obvious that postsurgical recurrences could not explain bilateral tumors or simultaneously-occurring unilateral tumors. Four Warthin's tumors developed after an earlier lesion had been excised from the same side and area of the body. The possibility of a tumor recurrence could not be excluded in these instances. The 31 tumors were catagorized as follows: (1) 14 tumors represented the initial primary lesion; (2) four tumors were possible recurrences; (3) the 13 remaining lesions (since metastatic spread was not a consideration) had to be considered second primary tumors. The 13 patients represented by this third catagory reflected an 11% incidence of second primary Warthin's tumors. This value was compared with the data of Moertel on the incidence of multicentric carcinomas in bilaterally-paired organs, i.e., breast, 4%; testis, 2%. 7 While Moertel's carcinoma figures are not truly comparable, a threeto sixfold higher incidence of Warthin's tumor multicentricity may reflect their suspected origin from ectopic portions of salivary gland. Microscopic analysis of the 32 tumors from the 30 Otolaryngology patients revealed that 72% of Warthin's tumors were intra-lymph-nodal in location: 50% were intranodal and intraglandular, while 22% were intranodal and extraglandular. The occurrence of almost three-fourths of the tumors within histologically-documented lymph nodes strongly supported the current theory of Warthin's tumor histogenesis from heterotopic salivary gland epithelium within lymph nodes. 1,2,4,n The tumor-bearing lymph nodes external to the parotid gland inevitably occurred in a paraparotid location. This finding was understandable in light of Thompson and Bryant's observations of the intimate association of lymph nodes and the parotid gland during development. 11 These workers found no such temporal or spatial association of lymph nodes with the developing submandibular gland. 11 Analysis of the entire group of Warthin's tumors revealed two noteworthy findings. The first was the presence of eight incidental (occult) tumors, which were identified during the examination of radical-neck-dissection specimens removed for the regional control of cancer. These lesions comprised 6% of all tumors and 13% (four) of the tumors removed by the Otolaryngology Department. The occurrence of these occult lesions in an anatomic location, sex ratio, and age group similar to the clinically-significant lesions suggested that these "silent" tumors were part of a continuum resulting ultimately in grossly detectable disease. Their presence emphasized the slow evolution of Warthin's tumors and the likelihood of an incidence higher than that indicated by clinical studies. The second finding was the rarity of Warthin's tumors in the Negro population. Only

9 874 DIETERT A.J.C.P. Vol. 63 eight-tenths of one percent of the tumor patients were Negro (a single man). At Barnes Hospital during 1972, 18.6% of all hospitalized patients, 17.1% of hospitalized surgical service patients, and 19.2% of patients with the diagnosis of parotid gland tumor were Negro. The similarity of these Negro percentages is striking. If papillary cystadenoma lymphomatosum occurred with equal frequency in Negro and non-negro people, we would have expected approximately 18% (or 21) of the 118 race-identified patients to be Negro. The single Negro man identified in this report represented a twenty-fold reduction in expected tumor frequency among the Negro population. It would be interesting to extend Thompson and Bryant's study of parotid gland development 11 to Negro fetuses. Significant differences might be found in the association of lymph nodes with parotid gland histogenesis, which might explain the rarity of these tumors among Negro people. The histogram of numbers of Warthin's tumors plotted against patient age (see Fig. 4) showed that 67% of the lesions occurred in the sixth (51 to 60 years) and seventh (61 to 70 years) decades of life. No patient was less than 36 years old when the tumor was discovered. Clearly, papillary cystadenoma lymphomatosum is a disease of the latter half of life, as 80% of the tumors in this series occurred in patients more than 50 years old. Foote and Frazell 5 reported the fifth and sixth decades as most commonly involved by Warthin's tumor. The age distribution in the present study was very similar to the findings of Thompson and Bryant, 11 who reported 50% of 180 tumors in the sixth and seventh decades, and those of Bernier and Bhaskar, 4 who found 71% of 106 tumors in these two decades. An intriguing problem posed by these "late-life" tumors is their presumptive paradoxical origin during embryogenesis. The heterotopic epithelial elements appear to remain dormant for approximately VA decades, only to reveal their presence with the advance of age. The significance of the eosinophilic transformation of epithelial cells into oxyphils (parathyroid gland), oncocytes (salivary gland), and Hiirthle cells (thyroid gland) remains obscure. 8 These altered cells have at least one major similarity: the presence of numerous, frequently-enlarged, cytoplasmic mitochondria. 3,6,9 The relationship of biologic aging and the nature of the intracellular stimulus to this alteration in the mitochondrial population must await further investigation. The male-to-female patient ratio in this study was approximately 3:1 (2.6:1) among 120 patients. A preponderance of males among Warthin's tumor patients was not surprising. Previous reports have shown the following male-female ratios: (1) Thompson and Bryant, 11 7:1 (160 patients); (2) Bernier and Bhaskar, 4 9:1 (106 patients); (3) Foote and Frazell, 5 10:1 (44 patients). The Barnes Hospital figures represent the lowest sex ratio reported to date. It is apparent that comparatively small changes in the numbers of males to females in a restricted population can change significantly the sex ratio. For example, among 200 individuals, the successive reduction of the number of females by ten, starting with a 3:1 malefemale ratio (150 male, 50 female) produces sex ratios of 4:1, 6:1, and 9:1 (180 male, 20 female). Since the earlier reports in the literature dated from 1950 to 1958, it was decided to divide the 120 patients into two groups: (1) those diagnosed between 1950 and 1959, and (2) those diagnosed between 1960 and June 30, The former group ( ) contained 30 male and 6 female patients, for a 5:1 sex ratio. The latter group ( ) contained 57 male and 27 female patients, for a 2:1 sex ratio. It is interesting to speculate about a "true"

10 June 1975 PAPILLARY CYSTADENOMA LYMPHOMATOSUM 875 decrease in the Warthin's tumor sex ratio since If the current theory of tumor histogenesis is correct, it would not predict a significant change in the incidence of salivary epithelial inclusions in lymph nodes of males and females. One wonders whether, if the Thompson and Bryant 11 studies allowed comparison of males and females, a difference in lymph nodeparotid gland association during development would be identified. In conclusion, the range of reported sex ratios is almost certainly the result of random statistical variation. All investigators have concurred with a male preponderance. The present study has demonstrated that this sex difference may not be as great as reported previously. References 1. Albrecht H, Arzt L: Beitrage zur frage der gewebsverirrung. Papillare cystadenome in lymphdriisen. Frankfurt Z Pathol 4:47-69, Azzopardi JG, Hou LT: The genesis of adenolymphoma. J Pathol Bacteriol 88: , Balogh K Jr, Roth SI: Histochemical and electron microscopic studies of eosinophilic granular cells (oncocytes) in tumors of the parotid gland. Lab Invest 14: , Bernier JL, Bhaskar SN: Lymphoepithelial lesions of salivary glands. Histogenesis and classification based on 186 cases. Cancer 11: , Foote FW Jr, Frazeli EL: Tumors of the major salivary glands, Atlas of Tumor Pathology. Section IV, Fascicle 11. Washington, D.C., Armed Forces Institute of Pathology, 1954, pp McGavran MH: The ultrastructure of papillary cystadenoma lymphomatosum of the parotid gland. Virchows Arch [Pathol Anat] 338: , Moertel CG: Multiple primary malignant neoplasms. Recent Results Cancer Res 7:63-108, Roth SI, Olen E, Hansen LS: The eosinophilic cells of the parathyroid (oxyphil cells), salivary (oncocytes), and thyroid (Hiirthle cells) glands. Lab Invest 11: , Tandler B, Shipkey FH: Ultrastructure of Warthin's tumor. I. Mitochondria. J Ultrastruct Res 11: , Thackray AC: Histological Typing of Salivary Gland Tumours. International Histological Classification of Tumours, Number 7. Geneva, World Health Organization, 1972, pp Thompson AS, Bryant HC Jr: Histogenesis of papillary cystadenoma lymphomatosum (Warthin's tumor) of the parotid salivary gland. Am J Pathol 26: , Warthin AS: Papillary cystadenoma lymphomatosum. A rare teratoid of the parotid region. J Cancer Res 13: , 1929