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Acinic-cell carcinoma of salivary glands
ORAL PATHOLOGY General .
Section
.
.
.
ACINIC-CELL Report
.
.
.
.
.
CARCINOMA
of Twenty-one
.
.
.
.
OF SALIVARY
.
.
.
.
.
.
.
.
.
.
.
GLANDS
Cases
ISTRODUCTION
T
HE
acirlic-Cdl
CUTiIlOIm,
a rCht,ivdJ*
I'iWC!
tumor
of
gIiLll(I
salivary
Origh
hs
already been described in the literatnrc.‘-9 A detailed discussion of this tumor, 1~owever, was given by Foote and E’razell’j and by Godwin, Foote, and ElrazelL7 These authors reported a total of twcntysevcn cases, and their findings may be snmmarizcd as folloms : 1. 3. 3. 4.
The tumor’ is limited to the parotid gland. Most patients arc in the fourth and sixth decades oI’ life. Frmalcs arc affcctcd nlore frequently than males (l’i of Yi cases). Clinicall.v, tho lesion milt& the miscd tumors of salivary gland origin. 5. Grossly, it is Cll~~~l~XjLlli~tCY~, solid or cystic , grayish white in color, and lacks the nnxoid appcarancc of the mixed tumors. 6. Microscopicall!-, it consists of cells which resemble the acinar cells of the parotid gland. These arc arranged in solid sheets of crude acini. Some wlls appear wntclr clear. Occasionally, lesions have q-stic alIt1 papillary vystic Ccatures. The tumor cells do not stain with nnwic*arminc or fat stains. ‘7. The tumor arisw from the ;leirlic cells. 8. Rccnrrcnccs owners in about 50 per cent of the cases. 9. The tumor is capable of mct,astases, and these occur more often to the distant organs than to the regional nodes. 10. The tumor is lmt treated surgicallp. Gorlin and ~‘ha~~cllir~ findings were in essential Research,
*Chief.
Departmrnt Walter Reed
rrportctl agreement
of I>ental and Oral Army Medical Center,
scwntecn cases of this tumor, and their with those. listed above. They did, however, Pathology, Washington, 62
T’nited D.
States C.
Army
Institute
of Dental
\‘ol II me Number
ACINIC-CELL
I ‘7
I
CARCIROMA
OF
SALIVARY
GLANDS
63
describe one case in which the tumor occurred in the sublingual gland and one in which the tongue was the site of tumor growth. In a group of twenty-four cases, Beahrs and associates9 found five lesions which were associated with facial pain and four in which there was evidence of weakness of facial musculature. T:he purpose of the present study is to give the clinical and microscopic featurmes, natural history, histogencsis, and treatment results of twenty-one cases of acinic-cell carcinoma. METHODS
AXD
MATERIAL
The present study is based on twenty-one cases of acinic-cell carcinoma on file at the Armed Forces Institute of Pathology since 1955. Selected specimens were stained with mucicarmine. Follow-up data were obtained in sixteen of the twenty-one cases. FINDINGS
Clinical Features.-In the present series of twenty-one cases there wcrc twelve male and nine female patients (Table I), ranging in age from 11 to 75 years. The largest number of cases (seven) occurred in the t.hird decade of life. Fourteen patients were white, two were Negro, and in five instances race was not recorded. Twenty cases involved the parotid gland, and one tumor occurred in a cervical node. At the time of treatment the tumors had been present for 10 days to 10 years, with an average duration of a little over 3 years. In most inTABLE
Age
I.
A~INIC-CELL
CARCINOMA
Incidence Age
(years)
Nnmber 0
11-20 21-30 31-40 41-50 51-60 61-70 71-80
3 7 3 3 ; 1
Sex lktribution Males --12 Females---S
site Parotid Cervical
Eace Distribution White ----------------14 Nepo --_______------Unknown --------------5
2
Size 1.1 hy 0.5 cm. to 5 cm.; &bra&n 10 days
to 10 years
Resdts of Treatment Recurrences----2 Metastases ----3
of
l-10
cases cases
one case 15 by 20 cm.
gland node
----------20 -----------A
cases
O.P. I’)64
.ces the tumor was well circumscrilxxl, sometimes freely movable, and of s,lOW with. In a single cast the Icsion was tliffnsc and fiscd to the surrounding tis1. In one patient, w1~0sc Imnor hat1 lwen present Ear 5 years, a rapid gru wt11
Fig.
1.
Fig.
2.
indic
\‘olume
I’7
Number
1
ACINIC-CELL
CARCINOMA
OF
SALIVARY
65
G-LANDS
of t1he lesion occurred in association wjth pregnancy. At examination, this lesiion pree ;ented as a large, confluent, fluid-filled mass. It occupied the upper n eck and extended from the lower pole of the parotid gland to the mid-cervical a,rea and attained a size of 15 by 20 cm.
Fig.
Fig.
4.1The
undifferentiated
3.-Clear
cells
cells
(arrow).
the
of
the
acinic-cell
The dark cells serous type.
carcinoma
seen
in
this
photomicrograph
are
of
Fig.
Fig.
Pig. Fig.
i.-Sec‘retury B.-Secretory
material material
in the duct of a normal parotid gland in an acinic-cell carcinoma (arrow).
(arrow).
Volume Kumber
17 1
ACTNTC-CELL
CARClSOMd
OF
SM,T\-ARB
GI,.1NDS
67
oval, centrally or eccentrically located, vesicular nucleus (Fig. 1). The cells are large enough that sections often go through their cytoplasm without rcvealing the nucleus. They lie in solid sheets, or they may be arranged in tubes, acini, or small clusters. Their cytoplasm is basophilic, contains fine to coarse granules, and when stained with hematoxylin and eosin has a light to very dark purple or bluish color (Fig. 1). If sections include part of the surrounding parotid gland, the similarity between the acinie cells of the tumor and those of the serous gland is striking (Fig. 2). In addition to the acinic cells, the so-called tcnter-clenr cells form varying amounts of the tumor parcnchyma. They resemble the acinic c.ells except that
Fig.
7.-Acinic-ccl1
carcinoma
showing
ductal
arrangement.
their cytoplasm appears empty and dots not stain for fat or mucin (Fig. 3). These cells are similar to the clear cells seen in mucoepidermoid tumors of salivar;y glands. The third cellular component of the acinic-cell carcinoma is an l&ndifferentiated e@theZiat c&Z which is much smaller than the other two cell types. As compared to the amount of its cytoplasm, it has a prominent nucleus (Fig. 4).
These cells vary in shape from small cuboidal to columnar or l)olyhedral and are similar to those seen in the intra- and interlobular ducts of the salivary glands. Transitions from these cells to the water-clear wlls, as ~11 as the acinic cells. can be demonstrated. The three cell types of the acinic-cell carcinoma usuall>- occur together and which are interspersed by corm ICC form almost solid sheets or “lobules”
Fig.
mgs.
8.
8 and
S.-Low-
and
high-power which
arose
photomicrographs in a cervical
of lymph
an acinic-cell node.
carcinoma
(:LI.L.o\v)
Volume 17 Number 1
ACINIC-CELL
CARCINOMA
OF
SALIVARY
GLANDS
69
tissue septa. In most, if not all, tumors numerous intercellular vacuoles can be seen, and some of these vacuoles contain a homogenous or granular, shrunken, stringy, basophilic material which is similar to that seen in some of the ducts of the adjoining normal parotid tissue (Figs. 5 and 6). In one case, microscopic foci of calcification were seen in the secretory material. Morphologically, these calcifications resemble the salivary stones. In some areas of acinic-cell carcinoma the tumor cells form small and large ductlike structures which are either empty or coni.ain the secretory basophilic material described above (Fig. 7). Areas of sclerosis in two cases and foci of calcification in one case were seen in the tumor sltroma. In the present series, the two cases that follow are of particular interest. CASE L-A white boy, 17 years of age, presented with a slowly enlarging cervical nodule of 3 years’ duration. A clinical diagnosis of branchial cleft cyst was made. Although a mixed tumor of the parotid gland was considered in the differential diagnosis, the lesion’s location low in the neck excluded this interpretation. At exploration it was found that the (‘node ” rvas not attached to any salivary gland, and the thyroid and parathyroids, as well as the salivary glands, were normal. The lesion was excised and the gross specimen was described as a lymph node. Hi,stologic sections revealed a typical acinic-cell carcinoma which had almost completely replaced a lymph node (Fig. 8). On the periphery of the tumor, portions of the lymph node architecture could be identified (Fig. 9). This tumor apparently arose as a primary lesion in the cervical node. CASE 2.-A 41.year-old white woman noticed a swelling on the right side of her neck, in the parotid area, in 1953. The lesion was biopsied in 1954 and diagnosed as a “mixed tumor. ” In 1956 a second biopsy specimenn was taken and reported as “inflammation of the parotid gland. ” Later in the same year another biopsy led to a diagnosis of a “mixed tumor. ” (None of these biopsy or surgical specimens were available for study.) About July, 1957, the patient became pregnant, and from about this time on she noted a rapid swelling and a red-purple discoloration of the skin in the right cervical region. Examination 6 months later revealed “large confluent, cystic, nodular masses which were tensely filled with fluid and which occupied the entire upper neck. They were continuous with the lower pole of the parotid and extended to the mid-cervical region. The involved area was at least 15-20 cm. in size and some of the cystic masses were as large as a tennis ball.” In March, 1958, 16 days postpartum, a total parotidectomy and right radical neck dissection was performed. The gross specimen weighed 310 grams. On sectioning, it was revealed that there were three large tumor nodules composed of “ lobulated yellow-gray tissue with cystic center. ’ ’ The largest tumor nodule was 5 cm. in diameter. Microscopic examination showed a typical acinic-cell carcinoma, the extensive size of vvhich was due to the presence of a few large cysts (Figs. 10 and 11). These were lined with flattened or cuboidal epithelium and granulation tissue and extended up to the overlying skin. Whereas the contents of the large cystic cavities had been lost during tissue preparation, the smaller ones contained homogenous secretory material. The apparent rapid growth of this tumor during pregnancy is of interest and will be discussed later.
Results of Treatment.-With the exception of one case which was treated by excision followed by radiation (5,056 r), all acinic-cell carcinomas in this study were treated surgically. The surgical treatment consisted of subtotal parotidNectomy (thirteen cases), total parotidectomy (two cases), or radical neck dissection (four cases). The single case of extraparotid tumor (Case 1) was treated by local excision.
Fig.
IO.
Fig.
11.
Figs.
10 and
Il.-Acinic-cell of this
carcinoma which rapidly grwvth was due tc secretory
enlarged activity
during pregnancy. of the tumor.
Major
part
ACINIC-CELL
ChRCISOMd
OF
SALIVARY
GLANDS
71
In most cases included in this study the follow-up period has been too short to be significant. Follow-up information, however, was obtained in all cases i.n which at least 1 year had elapsed since treatment. All twelve patients in this group are living and well. Five patients have been free of disease for more than 1 year, three for 2 years, two for 3 y-cars, and two for about 41/a years. DISCUSSION
The present series of twenty-one cases of acinic-cell carcinoma substantiates in many respects the observations made earlier by Godwin, Foote, and Frazel17 and by Foote and Frazell.G The following discussion, therefore, will emphasize those characteristics of this tumor which have not been reported in the literature.
Fig.
lZ.-Photomicrograph
of
a gland which cells (arrow)
showed from
sialadenitis. ductal cells.
Note
differentiation
of
acinic
HTistogenesis.-It has been suggested that the acinic-cell carcinoma arises from the acini of the parotid gland. 6, 7 This assumption is based mainly upon the morphologic similarity between the predominant tumor cell and the acinar cells of the parotid gland. It is known, however, that the parotid, as well as the other saliva-ry glands, arises in the embryo as a system of ducts, and it is only later that the ductal cells different,iate into the acinar cells and the acini. Furthermore, in cxpcrimental obstructive adenit,is, the acini of a salivary gland rapidly atrophy and only the duct system remains. lo If , in such a gland, the obstruction is eliminated the gland begins to show some regeneration of acini.ll This acinar regeneration begins in the ductal cells. Finally, in human obstructive adenitis of the parotid gland, one can sometimes see the differentiation of the ductal cells into acinar cells (Fig. 12). It is apparent, therefore, that the embryologic and
".J i-
1:11.\51i.\11
i~,b.s~\I .l.,uJ.iry
biti. l(‘l,i
experimental findings, as well as olx3ervat iolrs on I~uniari inat~~rii~ I! indical c t hai the primary source of the acinar cc~lls is the pluripofCnt ductal c~~~ii~lirlium. II is most, likely that the acinic-ccl1 car(*illolnzl arks from tht,se r;ltht>r than I’ronr the acinnr cells. ~Vf?lWOh/giC *rynZptoW.T.-111 prilliar~~ ilc*i~liWTll r;bwinwias of the pilt’Otit1 gland, facial nerve involvc~mcnt, has IKVW r~c~~wrtrtl 0111v oriw previousl,v.!’ Tn on0 of tlic present series “signs of facial wc~aknc~ss” were also obscr~ed. The: patient, a X-year-old white man, hat1 a IKY-shapc~l ~loclnle in the parotid gland l’or 10 >-ca 1’s. Six months prior* lo ildltliSSiol1 11~ rioted :I rapid increase in size and it signs of facial weakness. ” It is apparent that,. on occasion. a l)rimary acinic-cell carcinoma may be associated wit,h I’acial ncryc inrolvcment. Rites of Origin.--ller,clof’orc, an cst raglaiid~dar acinic-cell carcinoma has ncvcl’ been reported. In the present gronp, twenty tumors arose in the parotid gland while one arose wi-it.ltin a ccrvic~al lymph node. Both on histologic stud? and at exploration, it was apparent that this lesion was not, related to the parotid or an!: other salivary gland. It has bun shown tllilt drn?ng cmbryogenesis the cervical lymph nodes and the parotid gland devclol, in the same arca of the neck and that t,hc parotid epithclium bc~~m~cs inclr~d(ltl within the cervical nodes.‘“~ I3 From this epithclium a group of lesions, ranging front IVari bin’s tumor to the branchial cysts, have been shown to original(~.‘“~ ‘3 It is not surprising, thercforc, that on rare occasions the cpithelium wit,hin the ctxrvical nodes gives rise to an acinic-cdl carcinoma. Sinct>, in the last all:llysis, this cpithelium is derived from the parotitl gland, it ma>- be nrgncd that this rase represents an acinic-cell carcinoma ol’ misplaced parotid tissue, in much the same way that a thyroid tumor may 1)~ found in the dorsum of the tongue. Nonetheless, it should be borne in mint1 that a primary acinic-cc311 tumor (or other salivary gland tumor) may arise in a cervical node and be ensil>, mistaken for a metastasis. When a node containing a salivary gland turnor is discdovered, thcr~~fore, but a primary lesion cannot bc clinically demonstratetl in the rcpional saliraq 1 glands, the patient should not he subjcctc4 lo unncccssa 1.y 14;ldicilI SllJ'giCill proccldurc>s or csploratory operations. Secrdoqj Activity--I like the inu(~o~piclermoici t clmor, the acinic-ccl1 carcinoma is a functioning tInnor. That is, its component cells secrete a material which, microscopically at least, rc3cmbles the sccrrt~ion of the normal parot,id gland. This secretory activitp of the tumor cells is trident as (1) large pools and cysts of the sfxrctory material seen in some t,imiors and (2) numcrons intcrccllnlar vacuoles, many of’ wltich contain the homogcinous basophilic secretion. The sccrctory activit)- of the acinic-cell carcinoma is well demonstrated in Case 2. in which the nrassivc~ iltcarc;rsc it) sixcl of tha tumor Tvils apparently due to the acc~nmnlat,ion of :I prcaf tl~l oi’ sc~cr(~tion. This cast is of further irttcrest in that 111r rapid incrc:lsc> in both sixck and secret ion was associated with prignancy. One might speculaiv t,llilt the sutldcn increase in size of this t,umor, which for 5 previous years had shown comparatively little activity, was a result of pregnancy. This speculation finds some basis in the following observations :
Volume Number
17 il
ACINIC-CELL
CARCISOMA
OF
SALIVARP
GLASDS
73
IL has been shown that the removal of the salivary glands in female rats leads to retarded development and atrophy of the reproductive organs.14J I5 Furthermore, injections of salivary gland homogenat,cs are believed to reverse these ch8nges.l” Gonadectomized male and female rats show a decrease in the secretory tubules and granules of the submaxillary gland. Gonadotrophic hormones; produce ovarian tumors in mice. It is well known that in human beings the estrogen-producing tumors show an increased incidence of endometrial carcinoma. Furthermore, it has been demonstrated that castration or estrogen administration will produce regression of some prostatic carcinomas and that breast, carcinomas may regress temporarily following the administration of androgens or estrogens. la, I9 It has been further observed clinically that carcinoma of the breast grows rapidly during pregnancy. All of these isolated facts indicate (1) that some physiologic relationship exists between the salivary gland:3 and the sex glands and (2) that growth of certain tumors in man can bc influenced by sex hormones. It is quite possible, therefore, that the rapid growth of the acinic-cell carcinoma in Case 2 was a result of increased amounts of progesterone. It is conceivable that the acinic-cell carcinoma would respond favorably to estrogens. C’linical Features and Behavior.-The present study confirms previous reports that the acinic-cell carcinoma is capable of metastasis. Although, distant metastases in the present series were not observed, they have been described in the literature. The recurrence rate of this tumor as observed in the present study is lower than that reported previously, but this discrepancy may be due to the fact that our series has a shorter follow-up period. In the present series this tumor was found to be more common in the male than in the female, and the largest number of cases occurred in patients between 21 and 30 years of age. These data are in contrast to those reported in the literature, but this may be explained partly by the fact that the major source of the material in the present series was a military population. SUMMARY
This study concerns the clinical, gross, and microscopic features, natural history, and follow-up data on twenty-one cases of acinic-cell carcinoma. The findings were as follows: 1.. In the present series the tumor was most common in the third decade of life and was seen more frequently in the male than in the female. 2. Clinically, it resembled the mixed tumor and ranged in duration from 10 da.ys to 10 years, with an average duration of 3 years. 3. In one case the primary tumor was associated with “facial nerve weakness. ’ ’ 44. Twenty of the twenty-one cases occurred in the parotid gland. 5. In one case a primary tumor arose from the ectopic glandular epithelium within a cervical lymph node. 6. Histologically, the tumors consisted of the acinic cells, water-clear cells, and an undiferentiated epithelial cell. The latter resembled the ductal cells of the parotid gland.
Gland, Am. .r. l'ath. 2: 1.53.1.57, 19%. C. B.: ~~dt~nom;~. of the Salivary J. I'ath. Sr Had. 58: 699-7 10, 1946. 0. C.: Salivary &lenoms and Adenolymphoma, Adenoma of the Parotid Gland, .\rch. Path. 46: J T., and Calvin, 8. H., Jr.: 1ss39, 1948. of Glandu1a.r Tumors ot Salivary Glands : 1. Bauer, W. II., and Bz~cr, J. I). : Classification Study of 143 Cases, ,\. hl. A. Arch. Path. 55: 328-346, 1953. J. H., and Frcneh, A. J. : Surgical Trwtnwnt of Epitllvli:il 6. Buxton, R. IV., Maxwell, Tumors of tlLe Parotid Gland, Hurg. Gynee. & Obst. 97: 401-416, 19.X. 6. Foote. F. W.. Jr.. and Frazcll. 1:. I,.: Tumors 01 the Major Salivary Glands, Cnnwr 6: 1. Schutz, 2. Lloyd, 3. Godwin
7. 8.
Gilads, J. Oral Surg. ii: 304-306, 19.X. 0. II., ~Voolner, I,. B., Carvctll. S. IV., nncl lliviue, I<. 1). : Surgiwl JIan:tg~~~t~~~r~l of Parotid Lesions, A. M. A. Arch. Surg. 80: 490-904, 1960. Expcrirncutal Olsl ruvtiyc A(lcrli( ic 10. Bhaskar, R. N., Holden, T. F;., and JV\‘cinmann, J. l'.: in the Mouse, ,I. I). Bcs. 35: 85%%?, 19X. 11. Bhaskar, R. N.: Rog,ncration of Salivary Gland in the Rabbit. (In l~wparation. ) J. T,., a.ncl Hhaskar, S. K. : I,~m~~hoc~pithcli:~l T,esions of Salivary Glands ; 1I is12. Bvrnier, tnrwni& and Classiticntion Based on 186 (.“aws. Cancxx 11: 1156-l 179. 19.X 13. Rhaska;, S. N., and Bemicr, .T. I,.: kli,dogenc~sis of Kranehial Cysts: :I Report of 46s ca.ws, hm. ,I. Path. 35: 407-423, 1959. 9. Bcahrs,
14. 16.
keprbductive Suddick, R. P.: mogcnates
IG.
Shafer,
571,
17. 18.
19.
i)rgans of the Female Rat, J. I). Res. 36: Effect of Salivariadencctomy and Administration Upon the Reproductive Organs of the Female
559-565. 1957. . of Salivary Gland Rat, .I. 1). lies. 39:
Ho.ZJ-
1960.
W. CT., and Muhlcr, .T. c’. : F:l’fcc*t of Gonntlcctomv ant1 8(,x I Io~~moncs on tllra Structure of the Rat Ralivarv Glands, .I. T). Rrs. 32: 262-268, 1933. T,i, M. H., and Gardner, XV. TT. : &rther Studies on the fathogvnwin of O\-arinn ‘I’umow in Mice, Cancer Rcs. 9: 3541, 1949. C. I’.: Slu~iiw on l’rosfatic (Ixn(‘tsr. 1. l’lrc JTuggins, C., St~cvens, R,. .I%, .Tr., and Hotlges, Effect of Castration ou Xdv3nccd Carcinoma of the Prostate Gland. Arch. Surg. 43: d009.““3“A) 1941. . Ruggins, C., and Johnson, M. a1. : Cancer of the Rladtler and Prostate,, .T. .\. II. A. 135: 1146-1159, 1947.
Section
.
.
.
ACINIC-CELL Report
.
.
.
.
.
CARCINOMA
of Twenty-one
.
.
.
.
OF SALIVARY
.
.
.
.
.
.
.
.
.
.
.
GLANDS
Cases
ISTRODUCTION
T
HE
acirlic-Cdl
CUTiIlOIm,
a rCht,ivdJ*
I'iWC!
tumor
of
gIiLll(I
salivary
Origh
hs
already been described in the literatnrc.‘-9 A detailed discussion of this tumor, 1~owever, was given by Foote and E’razell’j and by Godwin, Foote, and ElrazelL7 These authors reported a total of twcntysevcn cases, and their findings may be snmmarizcd as folloms : 1. 3. 3. 4.
The tumor’ is limited to the parotid gland. Most patients arc in the fourth and sixth decades oI’ life. Frmalcs arc affcctcd nlore frequently than males (l’i of Yi cases). Clinicall.v, tho lesion milt& the miscd tumors of salivary gland origin. 5. Grossly, it is Cll~~~l~XjLlli~tCY~, solid or cystic , grayish white in color, and lacks the nnxoid appcarancc of the mixed tumors. 6. Microscopicall!-, it consists of cells which resemble the acinar cells of the parotid gland. These arc arranged in solid sheets of crude acini. Some wlls appear wntclr clear. Occasionally, lesions have q-stic alIt1 papillary vystic Ccatures. The tumor cells do not stain with nnwic*arminc or fat stains. ‘7. The tumor arisw from the ;leirlic cells. 8. Rccnrrcnccs owners in about 50 per cent of the cases. 9. The tumor is capable of mct,astases, and these occur more often to the distant organs than to the regional nodes. 10. The tumor is lmt treated surgicallp. Gorlin and ~‘ha~~cllir~ findings were in essential Research,
*Chief.
Departmrnt Walter Reed
rrportctl agreement
of I>ental and Oral Army Medical Center,
scwntecn cases of this tumor, and their with those. listed above. They did, however, Pathology, Washington, 62
T’nited D.
States C.
Army
Institute
of Dental
\‘ol II me Number
ACINIC-CELL
I ‘7
I
CARCIROMA
OF
SALIVARY
GLANDS
63
describe one case in which the tumor occurred in the sublingual gland and one in which the tongue was the site of tumor growth. In a group of twenty-four cases, Beahrs and associates9 found five lesions which were associated with facial pain and four in which there was evidence of weakness of facial musculature. T:he purpose of the present study is to give the clinical and microscopic featurmes, natural history, histogencsis, and treatment results of twenty-one cases of acinic-cell carcinoma. METHODS
AXD
MATERIAL
The present study is based on twenty-one cases of acinic-cell carcinoma on file at the Armed Forces Institute of Pathology since 1955. Selected specimens were stained with mucicarmine. Follow-up data were obtained in sixteen of the twenty-one cases. FINDINGS
Clinical Features.-In the present series of twenty-one cases there wcrc twelve male and nine female patients (Table I), ranging in age from 11 to 75 years. The largest number of cases (seven) occurred in the t.hird decade of life. Fourteen patients were white, two were Negro, and in five instances race was not recorded. Twenty cases involved the parotid gland, and one tumor occurred in a cervical node. At the time of treatment the tumors had been present for 10 days to 10 years, with an average duration of a little over 3 years. In most inTABLE
Age
I.
A~INIC-CELL
CARCINOMA
Incidence Age
(years)
Nnmber 0
11-20 21-30 31-40 41-50 51-60 61-70 71-80
3 7 3 3 ; 1
Sex lktribution Males --12 Females---S
site Parotid Cervical
Eace Distribution White ----------------14 Nepo --_______------Unknown --------------5
2
Size 1.1 hy 0.5 cm. to 5 cm.; &bra&n 10 days
to 10 years
Resdts of Treatment Recurrences----2 Metastases ----3
of
l-10
cases cases
one case 15 by 20 cm.
gland node
----------20 -----------A
cases
O.P. I’)64
.ces the tumor was well circumscrilxxl, sometimes freely movable, and of s,lOW with. In a single cast the Icsion was tliffnsc and fiscd to the surrounding tis1. In one patient, w1~0sc Imnor hat1 lwen present Ear 5 years, a rapid gru wt11
Fig.
1.
Fig.
2.
indic
\‘olume
I’7
Number
1
ACINIC-CELL
CARCINOMA
OF
SALIVARY
65
G-LANDS
of t1he lesion occurred in association wjth pregnancy. At examination, this lesiion pree ;ented as a large, confluent, fluid-filled mass. It occupied the upper n eck and extended from the lower pole of the parotid gland to the mid-cervical a,rea and attained a size of 15 by 20 cm.
Fig.
Fig.
4.1The
undifferentiated
3.-Clear
cells
cells
(arrow).
the
of
the
acinic-cell
The dark cells serous type.
carcinoma
seen
in
this
photomicrograph
are
of
Fig.
Fig.
Pig. Fig.
i.-Sec‘retury B.-Secretory
material material
in the duct of a normal parotid gland in an acinic-cell carcinoma (arrow).
(arrow).
Volume Kumber
17 1
ACTNTC-CELL
CARClSOMd
OF
SM,T\-ARB
GI,.1NDS
67
oval, centrally or eccentrically located, vesicular nucleus (Fig. 1). The cells are large enough that sections often go through their cytoplasm without rcvealing the nucleus. They lie in solid sheets, or they may be arranged in tubes, acini, or small clusters. Their cytoplasm is basophilic, contains fine to coarse granules, and when stained with hematoxylin and eosin has a light to very dark purple or bluish color (Fig. 1). If sections include part of the surrounding parotid gland, the similarity between the acinie cells of the tumor and those of the serous gland is striking (Fig. 2). In addition to the acinic cells, the so-called tcnter-clenr cells form varying amounts of the tumor parcnchyma. They resemble the acinic c.ells except that
Fig.
7.-Acinic-ccl1
carcinoma
showing
ductal
arrangement.
their cytoplasm appears empty and dots not stain for fat or mucin (Fig. 3). These cells are similar to the clear cells seen in mucoepidermoid tumors of salivar;y glands. The third cellular component of the acinic-cell carcinoma is an l&ndifferentiated e@theZiat c&Z which is much smaller than the other two cell types. As compared to the amount of its cytoplasm, it has a prominent nucleus (Fig. 4).
These cells vary in shape from small cuboidal to columnar or l)olyhedral and are similar to those seen in the intra- and interlobular ducts of the salivary glands. Transitions from these cells to the water-clear wlls, as ~11 as the acinic cells. can be demonstrated. The three cell types of the acinic-cell carcinoma usuall>- occur together and which are interspersed by corm ICC form almost solid sheets or “lobules”
Fig.
mgs.
8.
8 and
S.-Low-
and
high-power which
arose
photomicrographs in a cervical
of lymph
an acinic-cell node.
carcinoma
(:LI.L.o\v)
Volume 17 Number 1
ACINIC-CELL
CARCINOMA
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69
tissue septa. In most, if not all, tumors numerous intercellular vacuoles can be seen, and some of these vacuoles contain a homogenous or granular, shrunken, stringy, basophilic material which is similar to that seen in some of the ducts of the adjoining normal parotid tissue (Figs. 5 and 6). In one case, microscopic foci of calcification were seen in the secretory material. Morphologically, these calcifications resemble the salivary stones. In some areas of acinic-cell carcinoma the tumor cells form small and large ductlike structures which are either empty or coni.ain the secretory basophilic material described above (Fig. 7). Areas of sclerosis in two cases and foci of calcification in one case were seen in the tumor sltroma. In the present series, the two cases that follow are of particular interest. CASE L-A white boy, 17 years of age, presented with a slowly enlarging cervical nodule of 3 years’ duration. A clinical diagnosis of branchial cleft cyst was made. Although a mixed tumor of the parotid gland was considered in the differential diagnosis, the lesion’s location low in the neck excluded this interpretation. At exploration it was found that the (‘node ” rvas not attached to any salivary gland, and the thyroid and parathyroids, as well as the salivary glands, were normal. The lesion was excised and the gross specimen was described as a lymph node. Hi,stologic sections revealed a typical acinic-cell carcinoma which had almost completely replaced a lymph node (Fig. 8). On the periphery of the tumor, portions of the lymph node architecture could be identified (Fig. 9). This tumor apparently arose as a primary lesion in the cervical node. CASE 2.-A 41.year-old white woman noticed a swelling on the right side of her neck, in the parotid area, in 1953. The lesion was biopsied in 1954 and diagnosed as a “mixed tumor. ” In 1956 a second biopsy specimenn was taken and reported as “inflammation of the parotid gland. ” Later in the same year another biopsy led to a diagnosis of a “mixed tumor. ” (None of these biopsy or surgical specimens were available for study.) About July, 1957, the patient became pregnant, and from about this time on she noted a rapid swelling and a red-purple discoloration of the skin in the right cervical region. Examination 6 months later revealed “large confluent, cystic, nodular masses which were tensely filled with fluid and which occupied the entire upper neck. They were continuous with the lower pole of the parotid and extended to the mid-cervical region. The involved area was at least 15-20 cm. in size and some of the cystic masses were as large as a tennis ball.” In March, 1958, 16 days postpartum, a total parotidectomy and right radical neck dissection was performed. The gross specimen weighed 310 grams. On sectioning, it was revealed that there were three large tumor nodules composed of “ lobulated yellow-gray tissue with cystic center. ’ ’ The largest tumor nodule was 5 cm. in diameter. Microscopic examination showed a typical acinic-cell carcinoma, the extensive size of vvhich was due to the presence of a few large cysts (Figs. 10 and 11). These were lined with flattened or cuboidal epithelium and granulation tissue and extended up to the overlying skin. Whereas the contents of the large cystic cavities had been lost during tissue preparation, the smaller ones contained homogenous secretory material. The apparent rapid growth of this tumor during pregnancy is of interest and will be discussed later.
Results of Treatment.-With the exception of one case which was treated by excision followed by radiation (5,056 r), all acinic-cell carcinomas in this study were treated surgically. The surgical treatment consisted of subtotal parotidNectomy (thirteen cases), total parotidectomy (two cases), or radical neck dissection (four cases). The single case of extraparotid tumor (Case 1) was treated by local excision.
Fig.
IO.
Fig.
11.
Figs.
10 and
Il.-Acinic-cell of this
carcinoma which rapidly grwvth was due tc secretory
enlarged activity
during pregnancy. of the tumor.
Major
part
ACINIC-CELL
ChRCISOMd
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GLANDS
71
In most cases included in this study the follow-up period has been too short to be significant. Follow-up information, however, was obtained in all cases i.n which at least 1 year had elapsed since treatment. All twelve patients in this group are living and well. Five patients have been free of disease for more than 1 year, three for 2 years, two for 3 y-cars, and two for about 41/a years. DISCUSSION
The present series of twenty-one cases of acinic-cell carcinoma substantiates in many respects the observations made earlier by Godwin, Foote, and Frazel17 and by Foote and Frazell.G The following discussion, therefore, will emphasize those characteristics of this tumor which have not been reported in the literature.
Fig.
lZ.-Photomicrograph
of
a gland which cells (arrow)
showed from
sialadenitis. ductal cells.
Note
differentiation
of
acinic
HTistogenesis.-It has been suggested that the acinic-cell carcinoma arises from the acini of the parotid gland. 6, 7 This assumption is based mainly upon the morphologic similarity between the predominant tumor cell and the acinar cells of the parotid gland. It is known, however, that the parotid, as well as the other saliva-ry glands, arises in the embryo as a system of ducts, and it is only later that the ductal cells different,iate into the acinar cells and the acini. Furthermore, in cxpcrimental obstructive adenit,is, the acini of a salivary gland rapidly atrophy and only the duct system remains. lo If , in such a gland, the obstruction is eliminated the gland begins to show some regeneration of acini.ll This acinar regeneration begins in the ductal cells. Finally, in human obstructive adenitis of the parotid gland, one can sometimes see the differentiation of the ductal cells into acinar cells (Fig. 12). It is apparent, therefore, that the embryologic and
".J i-
1:11.\51i.\11
i~,b.s~\I .l.,uJ.iry
biti. l(‘l,i
experimental findings, as well as olx3ervat iolrs on I~uniari inat~~rii~ I! indical c t hai the primary source of the acinar cc~lls is the pluripofCnt ductal c~~~ii~lirlium. II is most, likely that the acinic-ccl1 car(*illolnzl arks from tht,se r;ltht>r than I’ronr the acinnr cells. ~Vf?lWOh/giC *rynZptoW.T.-111 prilliar~~ ilc*i~liWTll r;bwinwias of the pilt’Otit1 gland, facial nerve involvc~mcnt, has IKVW r~c~~wrtrtl 0111v oriw previousl,v.!’ Tn on0 of tlic present series “signs of facial wc~aknc~ss” were also obscr~ed. The: patient, a X-year-old white man, hat1 a IKY-shapc~l ~loclnle in the parotid gland l’or 10 >-ca 1’s. Six months prior* lo ildltliSSiol1 11~ rioted :I rapid increase in size and it signs of facial weakness. ” It is apparent that,. on occasion. a l)rimary acinic-cell carcinoma may be associated wit,h I’acial ncryc inrolvcment. Rites of Origin.--ller,clof’orc, an cst raglaiid~dar acinic-cell carcinoma has ncvcl’ been reported. In the present gronp, twenty tumors arose in the parotid gland while one arose wi-it.ltin a ccrvic~al lymph node. Both on histologic stud? and at exploration, it was apparent that this lesion was not, related to the parotid or an!: other salivary gland. It has bun shown tllilt drn?ng cmbryogenesis the cervical lymph nodes and the parotid gland devclol, in the same arca of the neck and that t,hc parotid epithclium bc~~m~cs inclr~d(ltl within the cervical nodes.‘“~ I3 From this epithclium a group of lesions, ranging front IVari bin’s tumor to the branchial cysts, have been shown to original(~.‘“~ ‘3 It is not surprising, thercforc, that on rare occasions the cpithelium wit,hin the ctxrvical nodes gives rise to an acinic-cdl carcinoma. Sinct>, in the last all:llysis, this cpithelium is derived from the parotitl gland, it ma>- be nrgncd that this rase represents an acinic-cell carcinoma ol’ misplaced parotid tissue, in much the same way that a thyroid tumor may 1)~ found in the dorsum of the tongue. Nonetheless, it should be borne in mint1 that a primary acinic-cc311 tumor (or other salivary gland tumor) may arise in a cervical node and be ensil>, mistaken for a metastasis. When a node containing a salivary gland turnor is discdovered, thcr~~fore, but a primary lesion cannot bc clinically demonstratetl in the rcpional saliraq 1 glands, the patient should not he subjcctc4 lo unncccssa 1.y 14;ldicilI SllJ'giCill proccldurc>s or csploratory operations. Secrdoqj Activity--I like the inu(~o~piclermoici t clmor, the acinic-ccl1 carcinoma is a functioning tInnor. That is, its component cells secrete a material which, microscopically at least, rc3cmbles the sccrrt~ion of the normal parot,id gland. This secretory activitp of the tumor cells is trident as (1) large pools and cysts of the sfxrctory material seen in some t,imiors and (2) numcrons intcrccllnlar vacuoles, many of’ wltich contain the homogcinous basophilic secretion. The sccrctory activit)- of the acinic-cell carcinoma is well demonstrated in Case 2. in which the nrassivc~ iltcarc;rsc it) sixcl of tha tumor Tvils apparently due to the acc~nmnlat,ion of :I prcaf tl~l oi’ sc~cr(~tion. This cast is of further irttcrest in that 111r rapid incrc:lsc> in both sixck and secret ion was associated with prignancy. One might speculaiv t,llilt the sutldcn increase in size of this t,umor, which for 5 previous years had shown comparatively little activity, was a result of pregnancy. This speculation finds some basis in the following observations :
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ACINIC-CELL
CARCISOMA
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GLASDS
73
IL has been shown that the removal of the salivary glands in female rats leads to retarded development and atrophy of the reproductive organs.14J I5 Furthermore, injections of salivary gland homogenat,cs are believed to reverse these ch8nges.l” Gonadectomized male and female rats show a decrease in the secretory tubules and granules of the submaxillary gland. Gonadotrophic hormones; produce ovarian tumors in mice. It is well known that in human beings the estrogen-producing tumors show an increased incidence of endometrial carcinoma. Furthermore, it has been demonstrated that castration or estrogen administration will produce regression of some prostatic carcinomas and that breast, carcinomas may regress temporarily following the administration of androgens or estrogens. la, I9 It has been further observed clinically that carcinoma of the breast grows rapidly during pregnancy. All of these isolated facts indicate (1) that some physiologic relationship exists between the salivary gland:3 and the sex glands and (2) that growth of certain tumors in man can bc influenced by sex hormones. It is quite possible, therefore, that the rapid growth of the acinic-cell carcinoma in Case 2 was a result of increased amounts of progesterone. It is conceivable that the acinic-cell carcinoma would respond favorably to estrogens. C’linical Features and Behavior.-The present study confirms previous reports that the acinic-cell carcinoma is capable of metastasis. Although, distant metastases in the present series were not observed, they have been described in the literature. The recurrence rate of this tumor as observed in the present study is lower than that reported previously, but this discrepancy may be due to the fact that our series has a shorter follow-up period. In the present series this tumor was found to be more common in the male than in the female, and the largest number of cases occurred in patients between 21 and 30 years of age. These data are in contrast to those reported in the literature, but this may be explained partly by the fact that the major source of the material in the present series was a military population. SUMMARY
This study concerns the clinical, gross, and microscopic features, natural history, and follow-up data on twenty-one cases of acinic-cell carcinoma. The findings were as follows: 1.. In the present series the tumor was most common in the third decade of life and was seen more frequently in the male than in the female. 2. Clinically, it resembled the mixed tumor and ranged in duration from 10 da.ys to 10 years, with an average duration of 3 years. 3. In one case the primary tumor was associated with “facial nerve weakness. ’ ’ 44. Twenty of the twenty-one cases occurred in the parotid gland. 5. In one case a primary tumor arose from the ectopic glandular epithelium within a cervical lymph node. 6. Histologically, the tumors consisted of the acinic cells, water-clear cells, and an undiferentiated epithelial cell. The latter resembled the ductal cells of the parotid gland.
Gland, Am. .r. l'ath. 2: 1.53.1.57, 19%. C. B.: ~~dt~nom;~. of the Salivary J. I'ath. Sr Had. 58: 699-7 10, 1946. 0. C.: Salivary &lenoms and Adenolymphoma, Adenoma of the Parotid Gland, .\rch. Path. 46: J T., and Calvin, 8. H., Jr.: 1ss39, 1948. of Glandu1a.r Tumors ot Salivary Glands : 1. Bauer, W. II., and Bz~cr, J. I). : Classification Study of 143 Cases, ,\. hl. A. Arch. Path. 55: 328-346, 1953. J. H., and Frcneh, A. J. : Surgical Trwtnwnt of Epitllvli:il 6. Buxton, R. IV., Maxwell, Tumors of tlLe Parotid Gland, Hurg. Gynee. & Obst. 97: 401-416, 19.X. 6. Foote. F. W.. Jr.. and Frazcll. 1:. I,.: Tumors 01 the Major Salivary Glands, Cnnwr 6: 1. Schutz, 2. Lloyd, 3. Godwin
7. 8.
Gilads, J. Oral Surg. ii: 304-306, 19.X. 0. II., ~Voolner, I,. B., Carvctll. S. IV., nncl lliviue, I<. 1). : Surgiwl JIan:tg~~~t~~~r~l of Parotid Lesions, A. M. A. Arch. Surg. 80: 490-904, 1960. Expcrirncutal Olsl ruvtiyc A(lcrli( ic 10. Bhaskar, R. N., Holden, T. F;., and JV\‘cinmann, J. l'.: in the Mouse, ,I. I). Bcs. 35: 85%%?, 19X. 11. Bhaskar, R. N.: Rog,ncration of Salivary Gland in the Rabbit. (In l~wparation. ) J. T,., a.ncl Hhaskar, S. K. : I,~m~~hoc~pithcli:~l T,esions of Salivary Glands ; 1I is12. Bvrnier, tnrwni& and Classiticntion Based on 186 (.“aws. Cancxx 11: 1156-l 179. 19.X 13. Rhaska;, S. N., and Bemicr, .T. I,.: kli,dogenc~sis of Kranehial Cysts: :I Report of 46s ca.ws, hm. ,I. Path. 35: 407-423, 1959. 9. Bcahrs,
14. 16.
keprbductive Suddick, R. P.: mogcnates
IG.
Shafer,
571,
17. 18.
19.
i)rgans of the Female Rat, J. I). Res. 36: Effect of Salivariadencctomy and Administration Upon the Reproductive Organs of the Female
559-565. 1957. . of Salivary Gland Rat, .I. 1). lies. 39:
Ho.ZJ-
1960.
W. CT., and Muhlcr, .T. c’. : F:l’fcc*t of Gonntlcctomv ant1 8(,x I Io~~moncs on tllra Structure of the Rat Ralivarv Glands, .I. T). Rrs. 32: 262-268, 1933. T,i, M. H., and Gardner, XV. TT. : &rther Studies on the fathogvnwin of O\-arinn ‘I’umow in Mice, Cancer Rcs. 9: 3541, 1949. C. I’.: Slu~iiw on l’rosfatic (Ixn(‘tsr. 1. l’lrc JTuggins, C., St~cvens, R,. .I%, .Tr., and Hotlges, Effect of Castration ou Xdv3nccd Carcinoma of the Prostate Gland. Arch. Surg. 43: d009.““3“A) 1941. . Ruggins, C., and Johnson, M. a1. : Cancer of the Rladtler and Prostate,, .T. .\. II. A. 135: 1146-1159, 1947.