Cellular Mixed Tumors of the Salivary Glands Robert E.
Ryan, Jr, MD; Lawrence
W.
DeSanto, MD; Louis H. Weiland, MD; Kenneth D. Devine, MD; Oliver H. Beahrs, MD
\s=b\Mixed tumors are unusual in that they possess both epithelial and mesenchymal elements. The proportions of the two elements vary greatly; the lesions with a pronounced preponderance of epithelial tissue have been called cellular mixed tumors. This increase in epithelial cellularity often results in misdiagnosis or in concern that the tumor may be more aggressive than the ordinary mixed tumor\p=m-\possiblyeven malignant. We have reviewed 1,095 consecutive parotid tumors that were removed at the Mayo Clinic, Rochester, Minn, from 1950 through 1970. Ninety-three of the lesions were diagnosed initially as cellular mixed tumors, and slides were available for review. Of these 93, 43 fulfilled our criteria of having greater than 80% of each tumor composed of the packed epithelial cells. All tumors had a corresponding reduction in the mesenchymal portion. The records of the 43 patients were studied to determine the clinical behavior of these neoplasms, particularly with regard to recurrence, metastasis, and malignant transformation. Our findings confirmed our clinical suspicions that some of these cellular mixed tumors, notably those that showed histopathologic evidence of an increased rate of mitotic activity, can and do act in a more aggressive manner.
(Arch Otolaryngol 104:451-453, 1978)
Mixed
tumors
are
the most
com¬
neoplasms of the major salivary glands. Although mixed tu¬ mors are benign, when they are surgi¬ cally enucleated, recurrences are com¬ mon. Microscopically, the tumors are composed of an epithelial and a mesenchymal component. Qualitative and quantitative variations in these components can be striking, and these mon
variations have been more
descriptive
of the for these adenoma." a source
name
tumors, "pleomorphic Mixed tumors
are simple to diag¬ histologically when there is a mesenchymal portion that consists of myxoid tissue or cartilage. However,
nose
when the epithelial component domi¬ nates to the exclusion of the mesen¬ chymal tissue, the histologie diagnosis may not be so easy. Such tumors have been designated "cellular mixed tu¬ mors." Their histologie diagnosis not only is more difficult, but their pronounced cellularity and cytologie monotony may cause concern about their malignant potential. Several investigators have attempted to clas-
Accepted for publication Feb 27, 1978. From the Mayo Clinic and Mayo Foundation, Rochester, Minn. Read before the meeting of American Society for Head and Neck Surgery, Boston, May 10-12, 1977.
Reprint requests to Section of Publications, Mayo Clinic, 220 First St SW, Rochester, MN 55901 (Dr Ryan).
Downloaded From: http://archotol.jamanetwork.com/ by a University of Iowa User on 06/11/2015
sify the mixed tumor into subtypes on the basis of the histologie patterns,
but
a
clinical correlation has been
lacking. The purpose of this study was to determine if our clinical impression of a more aggressive behavior for the so-called cellular mixed tumors verifiable.
was
CLINICAL MATERIAL Records of all patients with a salivary tumor that was removed during the years 1950 to 1970 were reviewed. There were 1,095 such patients. From this group, 93 patients with a histologie diagnosis of an atypical or cellular mixed tumor were selected for further study. The lesions of these 93 patients were reviewed clinically and restudied histologically, and the num¬ ber was reduced further. To be included in the final group that was designated as cellular mixed tumors, the lesion must have had the following microscopic characteris¬ tics on the first tissue specimen: (1) very cellular features, with the epithelial compo¬ nent comprising at least 80% of the tumor bulk and (2) cytologie features that were identical to those of the epithelial cells in "ordinary" mixed tumors. The microscopic review concentrated on the features of cellularity, mitotic activity, and cytologie anaplasia. These were determined from multiple samples that represented all areas of the specimen. The lesions of 43 patients satisfied these criteria. The clinical records of these patients were then reviewed to compare the clinical behavior of these patients with the histologie features of their tumors.
gland
mixed tumors. Neoplasm shows classic mixture of epithelium and chondromyxoid stroma. Note that epithe¬ lial cells are plump and spindled, similar or identical to those of cellular mixed tumors
Fig 1.—Benign
(hematoxylin-eosin,
Fig 2.—Left, Marked cellularity and absence of stromal elements. Cells are plump, slightly spindled, and show clustering near capsule (at right) (hematoxylin-eosin, 400). Right, Cells show same plumpness and spindling as those in left part (hematoxylin-eosin, X100). ciated in
salivary neoplasms. Initially, patients were treated by superfi¬ cial parotidectomy, three by total parotidectomy, and one by insertion 17
180).
Also studied were the primary sites of the lesions, the types of therapy, and the presence of metastatic disease at any time during the treatment.
FINDINGS Clinical Features
The ages of the 43 patients (26 and 17 men) ranged from 29 to 76 years, with 33 (80%) being in the fourth to the sixth decade of life. women
of radon seeds. Thirteen patients had recurrence after their initial treatment. Of the 13 patients, six were re-treated by surgi¬ cal excision, and all six have remained free of disease. Metastatic lesions subsequently developed in the other seven.
Pathologic
Features
mass was
Gross.-Most of the cellular mixed
the initial complaint of all 43 patients. The mass had been present in these patients from one to 18 months. Nine of the patients had been treated surgi¬ cally before re-treatment at our clinic. Thirty-three of the lesions were located in the parotid gland, three in the submandibular gland, four in the soft palate, and three in the buccal
tumors were encapsulated, homogene¬ ous, tan-gray, and soft. They lacked the "cartilaginous" appearance of ordinary mixed tumors. None of the tumors had evidence of hemorrhage or
A
persistently enlarging
area.
Treatment All but one patient were surgically treated initially. Initially, 22 were treated by localized excision of the lesion. Some of these were treated before 1950, when the hazard of simple enucleation was not well appre-
necrosis, although rent tumors
desmoplastic
were
some
of the
recur¬
accompanied by
a
response. Microscopic—The usual cells were identical to the epithelial cells in ordi¬ nary mixed tumors (Fig 1). Myoepithelial cells could be identified in all lesions. The chondroid, myxoid, or fibrous component that is seen in usual mixed tumors was lacking or minimal in this cellular variant. Some showed grouping or alveolar cluster¬ ing of cells, but a distinctly glandular pattern was unusual. The usually
Downloaded From: http://archotol.jamanetwork.com/ by a University of Iowa User on 06/11/2015
3.—Numerous mitotic figures (arrows) present in cellular tumor. Cells main¬ tain microscopic features of those found in ordinary mixed tumors (hematoxylin-
Fig
are
eosin, x400).
accepted criteria for malignancy, such as nuclear hyperchromatin, pleomorphism, and anaplasia, were lacking in these tumors. A careful and prolonged search revealed only an occasional mitotic figure. However, in the seven
in which metastatic tumors developed, mitotic figures were more frequent and ranged from three to 20 cases
static lesions eventually developed in all seven of these patients. Of these seven patients, two had metastasis to the neck, three to the lungs, and one to the neck and lungs; one had diffuse localized disease that occurred as multiple local nodules. The initial tumor sites in these patients were the parotid gland in two, the palate in three, and the buccal area in two.
Fig 4.—Malignant mixed tumor. Well-differ¬ entiated adenocarcinoma had origin in benign mixed tumor (latter component not shown) (hematoxylin-eosin,
100).
field (HPF) in the These "mitotically active" mixed tumors differed micro¬ scopically from such malignant mixed
high-power original specimen. per 10
tumors
as
squamous
carcinoma,
and undifferentiated carcinoma. In general, the his¬ topathologic features of the recurrent or the metastatic lesions were not different from those of the original tumor. No tumor showed increased anaplasia or other cytologie presence of malignancy. In individual cases, the mitotic activity was comparable in primary and secondary tumors. In other words, the tumors remained consistent histologically throughout all phases of their natural history.
adenocarcinoma,
Results of Treatment
Of the 43 patients in the series, 30 were treated and had a completely benign course with no recurrence of their disease. The 13 other patients had recurrence after initial therapy. Six of the 13 were re-treated surgical¬ ly, without further problems. The seven other patients had multiple recurrences: four had two recurrent episodes, two had four recurrences, and one had eight recurrences. Meta-
All 43 lesions were available for review, and multiple histologie sec¬ tions were reviewed for evidence of mitotic figures. Any evidence of mito¬ sis, whether it be one mitotic figure or extensive mitosis, was considered to be representative of mitotic activity. Of the 43 specimens, 21 showed mitot¬ ic figures initially. Many of these showed only a rare mitotic figure. After the clinical records were re¬ viewed, microscopic sections were again reviewed. One of us (L.H.W.), who had no prior knowledge of the clinical course of the patients, re¬ viewed the slides to assess the mitotic activity. All 13 recurrent lesions had evidence of mitotic activity at the time of the original diagnosis. At the second review, the degree of mitosis was classified as either rare or severe. All six lesions associated with benign courses had evidence of only rare mitotic activity (one or two mitotic figures per microscopic section (Fig 2). However, the seven lesions that eventually metastasized had marked mitotic activity (one to five mitotic figures per HPF) (Fig 3). COMMENT
This study indicates that diffuse cellular mixed tumors of the salivary glands deserve special consideration. Distinction from the ordinary mixed tumors is not difficult and is based on the predominance of the epithelial component. Foote and Frazell1 have classified mixed tumors according to the following histologie grouping: (1) principally myxoid, (2) equal balance between myxoid and cellular constit¬ uents, (3) predominantly cellular, and (4) extremely cellular. An increased mitotic rate has been previously consisdered to be of little prognostic
Downloaded From: http://archotol.jamanetwork.com/ by a University of Iowa User on 06/11/2015
significance.2 The distinguishing microscopic fea¬ ture
common
to the
seven
lesions that
eventually metastasized or had exten¬
sive local recurrence was an increased mitotic rate. These seven are con¬ trasted to those distinctly malignant mixed tumors that had obvious areas of adenocarcinoma (Fig 4), squamous cell carcinoma, or undifferentiated carcinoma in association with benign mixed tumor. We now believe that cellular mixed tumors with numerous mitotic figures should also be consid¬ ered malignant. CONCLUSIONS
Cellular mixed tumors of the sali¬ gland differ from the more common mixed tumors in the variabil¬ ity of their clinical behavior. Although most of the cellular mixed tumors have a benign course, some metastasize to the cervical lymph node or to the lungs or become locally invasive. Lesions of the minor salivary glands seem to have a more malignant poten¬ tial, although parotid lesions also metastasize. The most reliable determinant of malignancy is an increased mitotic rate, and a careful search for mitotic figures should be made. Any lesion with marked mitoses (greater than one figure per HPF) should be regarded as malignant and treated more aggressively. We recommend that total parotidectomy be done in patients who have lesions that have marked cellularity and significant mitosis. Because of the malignant potential of these tumors, these patients should be followed up carefully. This is not to suggest that the initial surgery should be radical but if lesions with severe mitosis recur, then a more aggressive approach must be undertaken. vary
References 1. Foote FW Jr, Frazell EL: Tumors of the Major Salivary Glands. Atlas of Tumor Pathology, Armed Forces Institute of Pathology, 1954,
section 4, fascicle 11, pp 13-49. 2. Thackray AC: Histological Typing of Salivary Gland Tumours. International Histological Classification of Tumours, Geneva, World Health Organization, 1972, No. 7, pp 20-25.
Ryan, Jr, MD; Lawrence
W.
DeSanto, MD; Louis H. Weiland, MD; Kenneth D. Devine, MD; Oliver H. Beahrs, MD
\s=b\Mixed tumors are unusual in that they possess both epithelial and mesenchymal elements. The proportions of the two elements vary greatly; the lesions with a pronounced preponderance of epithelial tissue have been called cellular mixed tumors. This increase in epithelial cellularity often results in misdiagnosis or in concern that the tumor may be more aggressive than the ordinary mixed tumor\p=m-\possiblyeven malignant. We have reviewed 1,095 consecutive parotid tumors that were removed at the Mayo Clinic, Rochester, Minn, from 1950 through 1970. Ninety-three of the lesions were diagnosed initially as cellular mixed tumors, and slides were available for review. Of these 93, 43 fulfilled our criteria of having greater than 80% of each tumor composed of the packed epithelial cells. All tumors had a corresponding reduction in the mesenchymal portion. The records of the 43 patients were studied to determine the clinical behavior of these neoplasms, particularly with regard to recurrence, metastasis, and malignant transformation. Our findings confirmed our clinical suspicions that some of these cellular mixed tumors, notably those that showed histopathologic evidence of an increased rate of mitotic activity, can and do act in a more aggressive manner.
(Arch Otolaryngol 104:451-453, 1978)
Mixed
tumors
are
the most
com¬
neoplasms of the major salivary glands. Although mixed tu¬ mors are benign, when they are surgi¬ cally enucleated, recurrences are com¬ mon. Microscopically, the tumors are composed of an epithelial and a mesenchymal component. Qualitative and quantitative variations in these components can be striking, and these mon
variations have been more
descriptive
of the for these adenoma." a source
name
tumors, "pleomorphic Mixed tumors
are simple to diag¬ histologically when there is a mesenchymal portion that consists of myxoid tissue or cartilage. However,
nose
when the epithelial component domi¬ nates to the exclusion of the mesen¬ chymal tissue, the histologie diagnosis may not be so easy. Such tumors have been designated "cellular mixed tu¬ mors." Their histologie diagnosis not only is more difficult, but their pronounced cellularity and cytologie monotony may cause concern about their malignant potential. Several investigators have attempted to clas-
Accepted for publication Feb 27, 1978. From the Mayo Clinic and Mayo Foundation, Rochester, Minn. Read before the meeting of American Society for Head and Neck Surgery, Boston, May 10-12, 1977.
Reprint requests to Section of Publications, Mayo Clinic, 220 First St SW, Rochester, MN 55901 (Dr Ryan).
Downloaded From: http://archotol.jamanetwork.com/ by a University of Iowa User on 06/11/2015
sify the mixed tumor into subtypes on the basis of the histologie patterns,
but
a
clinical correlation has been
lacking. The purpose of this study was to determine if our clinical impression of a more aggressive behavior for the so-called cellular mixed tumors verifiable.
was
CLINICAL MATERIAL Records of all patients with a salivary tumor that was removed during the years 1950 to 1970 were reviewed. There were 1,095 such patients. From this group, 93 patients with a histologie diagnosis of an atypical or cellular mixed tumor were selected for further study. The lesions of these 93 patients were reviewed clinically and restudied histologically, and the num¬ ber was reduced further. To be included in the final group that was designated as cellular mixed tumors, the lesion must have had the following microscopic characteris¬ tics on the first tissue specimen: (1) very cellular features, with the epithelial compo¬ nent comprising at least 80% of the tumor bulk and (2) cytologie features that were identical to those of the epithelial cells in "ordinary" mixed tumors. The microscopic review concentrated on the features of cellularity, mitotic activity, and cytologie anaplasia. These were determined from multiple samples that represented all areas of the specimen. The lesions of 43 patients satisfied these criteria. The clinical records of these patients were then reviewed to compare the clinical behavior of these patients with the histologie features of their tumors.
gland
mixed tumors. Neoplasm shows classic mixture of epithelium and chondromyxoid stroma. Note that epithe¬ lial cells are plump and spindled, similar or identical to those of cellular mixed tumors
Fig 1.—Benign
(hematoxylin-eosin,
Fig 2.—Left, Marked cellularity and absence of stromal elements. Cells are plump, slightly spindled, and show clustering near capsule (at right) (hematoxylin-eosin, 400). Right, Cells show same plumpness and spindling as those in left part (hematoxylin-eosin, X100). ciated in
salivary neoplasms. Initially, patients were treated by superfi¬ cial parotidectomy, three by total parotidectomy, and one by insertion 17
180).
Also studied were the primary sites of the lesions, the types of therapy, and the presence of metastatic disease at any time during the treatment.
FINDINGS Clinical Features
The ages of the 43 patients (26 and 17 men) ranged from 29 to 76 years, with 33 (80%) being in the fourth to the sixth decade of life. women
of radon seeds. Thirteen patients had recurrence after their initial treatment. Of the 13 patients, six were re-treated by surgi¬ cal excision, and all six have remained free of disease. Metastatic lesions subsequently developed in the other seven.
Pathologic
Features
mass was
Gross.-Most of the cellular mixed
the initial complaint of all 43 patients. The mass had been present in these patients from one to 18 months. Nine of the patients had been treated surgi¬ cally before re-treatment at our clinic. Thirty-three of the lesions were located in the parotid gland, three in the submandibular gland, four in the soft palate, and three in the buccal
tumors were encapsulated, homogene¬ ous, tan-gray, and soft. They lacked the "cartilaginous" appearance of ordinary mixed tumors. None of the tumors had evidence of hemorrhage or
A
persistently enlarging
area.
Treatment All but one patient were surgically treated initially. Initially, 22 were treated by localized excision of the lesion. Some of these were treated before 1950, when the hazard of simple enucleation was not well appre-
necrosis, although rent tumors
desmoplastic
were
some
of the
recur¬
accompanied by
a
response. Microscopic—The usual cells were identical to the epithelial cells in ordi¬ nary mixed tumors (Fig 1). Myoepithelial cells could be identified in all lesions. The chondroid, myxoid, or fibrous component that is seen in usual mixed tumors was lacking or minimal in this cellular variant. Some showed grouping or alveolar cluster¬ ing of cells, but a distinctly glandular pattern was unusual. The usually
Downloaded From: http://archotol.jamanetwork.com/ by a University of Iowa User on 06/11/2015
3.—Numerous mitotic figures (arrows) present in cellular tumor. Cells main¬ tain microscopic features of those found in ordinary mixed tumors (hematoxylin-
Fig
are
eosin, x400).
accepted criteria for malignancy, such as nuclear hyperchromatin, pleomorphism, and anaplasia, were lacking in these tumors. A careful and prolonged search revealed only an occasional mitotic figure. However, in the seven
in which metastatic tumors developed, mitotic figures were more frequent and ranged from three to 20 cases
static lesions eventually developed in all seven of these patients. Of these seven patients, two had metastasis to the neck, three to the lungs, and one to the neck and lungs; one had diffuse localized disease that occurred as multiple local nodules. The initial tumor sites in these patients were the parotid gland in two, the palate in three, and the buccal area in two.
Fig 4.—Malignant mixed tumor. Well-differ¬ entiated adenocarcinoma had origin in benign mixed tumor (latter component not shown) (hematoxylin-eosin,
100).
field (HPF) in the These "mitotically active" mixed tumors differed micro¬ scopically from such malignant mixed
high-power original specimen. per 10
tumors
as
squamous
carcinoma,
and undifferentiated carcinoma. In general, the his¬ topathologic features of the recurrent or the metastatic lesions were not different from those of the original tumor. No tumor showed increased anaplasia or other cytologie presence of malignancy. In individual cases, the mitotic activity was comparable in primary and secondary tumors. In other words, the tumors remained consistent histologically throughout all phases of their natural history.
adenocarcinoma,
Results of Treatment
Of the 43 patients in the series, 30 were treated and had a completely benign course with no recurrence of their disease. The 13 other patients had recurrence after initial therapy. Six of the 13 were re-treated surgical¬ ly, without further problems. The seven other patients had multiple recurrences: four had two recurrent episodes, two had four recurrences, and one had eight recurrences. Meta-
All 43 lesions were available for review, and multiple histologie sec¬ tions were reviewed for evidence of mitotic figures. Any evidence of mito¬ sis, whether it be one mitotic figure or extensive mitosis, was considered to be representative of mitotic activity. Of the 43 specimens, 21 showed mitot¬ ic figures initially. Many of these showed only a rare mitotic figure. After the clinical records were re¬ viewed, microscopic sections were again reviewed. One of us (L.H.W.), who had no prior knowledge of the clinical course of the patients, re¬ viewed the slides to assess the mitotic activity. All 13 recurrent lesions had evidence of mitotic activity at the time of the original diagnosis. At the second review, the degree of mitosis was classified as either rare or severe. All six lesions associated with benign courses had evidence of only rare mitotic activity (one or two mitotic figures per microscopic section (Fig 2). However, the seven lesions that eventually metastasized had marked mitotic activity (one to five mitotic figures per HPF) (Fig 3). COMMENT
This study indicates that diffuse cellular mixed tumors of the salivary glands deserve special consideration. Distinction from the ordinary mixed tumors is not difficult and is based on the predominance of the epithelial component. Foote and Frazell1 have classified mixed tumors according to the following histologie grouping: (1) principally myxoid, (2) equal balance between myxoid and cellular constit¬ uents, (3) predominantly cellular, and (4) extremely cellular. An increased mitotic rate has been previously consisdered to be of little prognostic
Downloaded From: http://archotol.jamanetwork.com/ by a University of Iowa User on 06/11/2015
significance.2 The distinguishing microscopic fea¬ ture
common
to the
seven
lesions that
eventually metastasized or had exten¬
sive local recurrence was an increased mitotic rate. These seven are con¬ trasted to those distinctly malignant mixed tumors that had obvious areas of adenocarcinoma (Fig 4), squamous cell carcinoma, or undifferentiated carcinoma in association with benign mixed tumor. We now believe that cellular mixed tumors with numerous mitotic figures should also be consid¬ ered malignant. CONCLUSIONS
Cellular mixed tumors of the sali¬ gland differ from the more common mixed tumors in the variabil¬ ity of their clinical behavior. Although most of the cellular mixed tumors have a benign course, some metastasize to the cervical lymph node or to the lungs or become locally invasive. Lesions of the minor salivary glands seem to have a more malignant poten¬ tial, although parotid lesions also metastasize. The most reliable determinant of malignancy is an increased mitotic rate, and a careful search for mitotic figures should be made. Any lesion with marked mitoses (greater than one figure per HPF) should be regarded as malignant and treated more aggressively. We recommend that total parotidectomy be done in patients who have lesions that have marked cellularity and significant mitosis. Because of the malignant potential of these tumors, these patients should be followed up carefully. This is not to suggest that the initial surgery should be radical but if lesions with severe mitosis recur, then a more aggressive approach must be undertaken. vary
References 1. Foote FW Jr, Frazell EL: Tumors of the Major Salivary Glands. Atlas of Tumor Pathology, Armed Forces Institute of Pathology, 1954,
section 4, fascicle 11, pp 13-49. 2. Thackray AC: Histological Typing of Salivary Gland Tumours. International Histological Classification of Tumours, Geneva, World Health Organization, 1972, No. 7, pp 20-25.
