Epithelial Lacrimal Gland Tumors Pathologic Classification and Current Understanding

CLINICAL SCIENCES Epithelial Lacrimal Gland Tumors Pathologic Classification and Current Understanding

Ezekiel Weis, MD, MPH; Jack Rootman, MD; Thomas J. Joly, MD, PhD; Kenneth W. Berean, MD; Hind M. Al-Katan, MD; Sylvia Pasternak, MD; Giulio Bonavolontà, MD; Diego Strianese, MD; Peerooz Saeed, MD; Kenneth A. Feldman, MD; Sumalee Vangveeravong, MD; Jocelyne S. Lapointe, MD; Valerie A. White, MD, MHSc

Objective: To apply the updated epithelial salivary gland mors were found to be unclassifiable with the updated classification scheme to a large cohort of lacrimal gland scheme, with 2 having histologically malignant features. tumors so as to provide an updated lacrimal gland tu- Deficiencies and variations in pathologic assessment were mor classification scheme. noted. Variation in the histologic findings of pleomorphic adenoma and assessment of the extent of invasion of Methods: A retrospective multicenter cohort study of carcinoma ex pleomorphic adenoma were highlighted. 118 cases of epithelial neoplasia was undertaken. Main outcome measures included pathologic analysis, subtyp- Conclusions: The use of the more histologically di- ing, and survival. verse classification of salivary gland tumors can be successfully applied to the epithelial lacrimal gland neo- Results: Of 118 cases, 17 (14%) were reclassified using plasms. This expanded classification system led to the proposed expanded classification scheme based on the reclassifying 14% of cases. Currently, there are no con- current World Health Organization classification of sali- sistent pathologic standards for processing and evaluat- vary gland tumors. The most frequent neoplasms were pleo- ing these lesions. morphic adenoma and adenoid cystic carcinoma, of which we highlight more unusual histologic features. Three tu- Arch Ophthalmol. 2009;127(8):1016-1028

ACRIMAL GLAND LESIONS REP- showed an expanded classification based on resent 5% to 25% of orbital the 1992 WHO classification of salivary tumors, and the proportion in gland tumors. It is also clear that the sali- the literature that are epithe- vary gland classification has filtered into the lial range from 23% to 70% of lacrimal gland literature, which has de- biopsiedL cases.1-6 Despite our current un- scribed many tumors analogous to their sali- derstanding that rational clinical manage- vary gland counterparts, including ductal ment of salivary and lacrimal gland tu- carcinoma,18-23 acinic cell carcinoma,24-27 pri- mors depends on specific histologic tumor mary squamous cell carcinoma,28-31 muco- typing,3-5,7-13 there has been no official up- epidermoid carcinoma,20,32-38 oncocytic car- date of the lacrimal gland tumor classifi- cinoma,39 polymorphous low-grade cation since the World Health Organiza- adenocarcinoma,5,40 myoepithelial carci- tion (WHO) publication of 1980.14 The noma,41-43 lymphoepithelial carcino- Armed Forces Institute of Pathology (AFIP) ma,44,45 epithelial-myoepithelial carcino- monograph on lacrimal gland tumors pub- ma,42 cystadenocarcinoma,46 primary lished in 1994 reviewed 39 cases but did sebaceous adenocarcinoma,5,47-53 basal cell not attempt a comprehensive reclassifica- adenocarcinoma,54 oncocytoma,55,56 cyst- tion.15 Our understanding of lacrimal gland adenoma,57 and myoepithelioma.5,43,58-62 tumors reflects the histologically similar but The purposes of our study are to re- more prevalent salivary gland tumors, the view the standards of histologic analysis classification of which has undergone sev- and propose an updated classification eral iterations since the introduction of the scheme based on a series of 118 cases from AFIP classification in 195316 to include 4 contributing institutions reviewed by a newly recognized tumor types correlating head and neck pathologist (K.W.B.) well Author Affiliations are listed at with biological behavior. In 2006 the AFIP versed in salivary gland tumor pathology the end of this article. monograph on lacrimal gland tumors17 and classification.

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©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 METHODS Table 1. Updated Diagnoses of 118 Epithelial Lacrimal Gland Tumors Using Proposed Salivary Gland Epithelial lacrimal gland neoplasms from 4 contributing insti- Classification Scheme tutions were reviewed for clinical profile, pathology, and outcome at the University of British Columbia, Vancouver, Brit- Cases, No. (%) ish Columbia, Canada. Only cases with pathology specimens Diagnosis (N=118) available for examination were included, resulting in a total of Pleomorphic adenoma 57 (48) 118 cases in the combined series. Adenoid cystic carcinoma 38 (32) Carcinoma ex pleomorphic adenoma 9 (8) PATHOLOGIC ANALYSIS Adenocarcinoma 3 (3) Mucoepidermoid carcinoma 2 (2) All pathology specimens were evaluated by a single patholo- Lacrimal ductal carcinoma 2 (2) gist specializing in head and neck pathology (K.W.B.). Speci- Unclassifiable carcinoma 2 (2) mens were classified according to the most recent WHO sali- Unclassifiable neoplasm 1 (1) vary gland tumor classification.63 The amount of material Squamous cell carcinoma 1 (1) Myoepithelial carcinoma 1 (1) available varied, and initial review was based on hematoxylin- Myoepithelioma 1 (1) eosin–stained sections. Additional material, analysis with his- Oncocytoma 1 (1) tochemical and immunohistochemical stains, and a more com- Total 118 (102)a plete examination of the extent of the tumor were requested for any case in which the diagnosis was questionable. Initial a Artifactually greater than 100% owing to rounding to the nearest integer. review was performed with the pathologist blinded to the clinical history and original diagnosis. All of the cases with rare diagnoses, with atypical findings, or in which the review diag- thelial and mesenchymal-like tissues.”63 The epithelial nosis differed from the original were submitted to a second cells form characteristic ductal structures with surround- review by a committee comprising the head and neck patholo- ing myoepithelial cells, which trail out gradually into gist (K.W.B.) and 2 ophthalmic pathologists (V.A.W. and J.R.). myxomatous mesenchyme (Figure 1A). All but 2 of the 57 cases of PA in our series easily fit this description and STATISTICAL ANALYSIS were diagnosed as such in the original pathology reports. Variable features typical of PA were systematically ana- Linear and logistic regression was used to compare baseline char- lyzed, including cellularity, presence of myxoid, chon- acteristics between different tumor subtypes and histologic find- droid, and hyaline stroma, and cellular characteristics in- ings. Clinical outcomes for adenoid cystic carcinoma were ana- cluding squamous metaplasia and presence of plasmacytoid lyzed using survival analysis in the form of the log-rank test. Ͻ cells. Other rare features were occasionally noted. Statistical significance was defined as P .05. Typical and infrequent features are summarized in Table 3 and shown in Figure 1. The mean diameter was RESULTS 24.5 mm, ranging from 10 to 40 mm. Mitotic figures were rarely detected. Tumor capsules varied from a few mi- The pathology specimens of 118 cases from 4 institu- crometers to a few hundred micrometers in thickness and tions were classified as shown in Table 1. This study was were incomplete in some. In 31 cases in which we had coordinated by the Orbit Clinic, University of British Co- adequate sections to analyze the full extent of the tu- lumbia. Forty cases from the University of British Colum- mor, 27 were found to border or invade the capsule and bia, 33 from the Department of Ophthalmology, Univer- 4 (including 3 not originally reported) extended beyond. sity of Naples, Naples, Italy, 33 from the Department of The review diagnosis differed from the original diag- Ophthalmology, University of Amsterdam, Amsterdam, the nosis in 2 cases. One case, originally diagnosed as nonin- Netherlands, and 12 from the Department of Ophthal- vasive carcinoma in PA, was on review considered a PA mology, Kaiser Permanente Medical Center, Harbor City, with epithelial atypia and oncocytic metaplasia not war- California, were enrolled. No interinstitution or intra- ranting a diagnosis of carcinoma. The second case, origi- institution standards for specimen sampling or handling nally diagnosed as acinic cell carcinoma, was considered were found. The most frequent diagnosis was pleomor- a variant PA with atypical features. phic adenoma (PA), followed by adenoid cystic carci- The 3 clinically recurrent tumors were characterized his- noma (ACC) and carcinoma ex pleomorphic adenoma tologically by multifocal and multinodular growth patterns. (CEPA). Three tumors were unclassifiable, 2 of which were The recurrences occurred at 23, 25, and 30 years after the considered to have histopathologically malignant fea- initial resection. In all 3 cases, the tumor formed numer- tures and the third of which was indeterminate. Of the 118 ous nodules generally composed predominantly of stroma cases, 17 were reclassified in this study (Table 2). with minor epithelial components. One tumor showed focal calcification and another showed focal ossification. There BENIGN NEOPLASMS was no evidence of malignant transformation.

Pleomorphic Adenoma Other Benign Tumors

According to the AFIP salivary gland tumor classifica- A single case of myoepithelioma was identified.64 It was tion, the “essential diagnostic feature” of a PA, or be- well circumscribed and composed of sheets of myoepi- nign mixed tumor, is that it is “composed of both epithelial cells with rare ducts. Most of the cells were hya-

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©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 MALIGNANT NEOPLASMS Table 2. Summary of Rediagnosis Based on Pathologic Review Adenoid Cystic Carcinoma

Original Diagnosis Cases, if Different Findings Our series included 38 cases of ACC (32%), which was Diagnosis No. (Cases, No.) on Review the most common malignant neoplasm. The mean histologic diameter was 27.7 mm, with the diameter rang- PA 54 Acinic cell Variant PA with carcinoma (1) atypical features ing from 16 to 42 mm and no statistically significant dif- Noninvasive PA with epithelial ference when compared with PA (P=.09). Most tumors carcinoma in atypia, myoepithelial had combinations of 2 or 3 histologic patterns (Table 4). PA (1) rich with oncocytic Comedonecrosis was present in 10 cases, in both crib- metaplasia riform and solid patterns, but was most prominent in areas PA recurrence 3 NA NA Myoepithelioma 1 NA NA of the solid pattern. Oncocytoma 1 Warthin tumor (1) Oncocytoma with Mitotic activity ranged from undetectable to 25 mi- lymphocytic totic figures per 10 high-power fields. In general, the hyperplasia lowest activity was found in tumors with tubular and ACC 36 Undifferentiated Solid-pattern ACC cribriform patterns (median, 2.9 mitotic figures per 10 carcinoma arising from ACC (1) high-power fields), while tumors with at least some ACC with 2 ACC (1) ACC with focal, poorly component of solid pattern had higher mitotic activity dedifferentiation differentiated (median, 10.1 mitotic figures per 10 high-power fields) carcinoma (PϽ.001). Epidermoid ACC with focal, poorly The ACCs were nonencapsulated with infiltration of carcinoma (1) differentiated ADCA CEPA noninvasive 3 MECA (1) ADCA possibly ex PA surrounding fat, periorbita, and muscle. Invasion into the CEPA minimally 1NANA sclera or optic nerve was not identified in any case. Peri- invasive neural invasion was seen in 13 cases, although caution CEPA invasive 5 ACC ex PA (1) ADCA possibly ex PA, in interpreting this is necessary because of the variable MECA ex PA sectioning patterns by the different institutions. Peri- MECA (1) Circumscribed ADCA ex PA neural invasion did not correlate with mitotic activity MECA in preexisting NA (P=.90), particular histologic pattern noted on analysis pseudotumor (1) (cribriform, P=.50; tubular, PϾ.99; solid, P=.49), or pre- Carcinosarcoma, Biphasic carcinoma, dominant pattern (cribriform, P=.38; tubular, P=.51; malignant mixed carcinosarcomatous solid, PϾ.99). Perineural invasion was described in 9 tumor (1) pattern, ex PA original pathology reports, including 2 cases in which it ADCA 3 ACC (1) NA Mucoepidermoid 2NANA was not found on review. Inconsistent sampling, orien- carcinoma tation, and pathologic preparation of bone samples were Ductal carcinoma 2 ADCA (1) NA noted. Of the 11 cases in which bone was sampled, 7 were Myoepithelial 1 Malignant epithelial Nests of myoepithelial positive and 4 were negative for tumor. The absence of a carcinoma neoplasm, most cells with nuclear cribriform pattern (P=.01) and the presence of a solid consistent with atypia, and no gland ACC (1) formation pattern (P=.02) were significantly associated with death. Squamous cell 1NANA In 2 cases, an area of high-grade carcinoma was found carcinoma within the ACC: a poorly differentiated adenocarci- Unclassifiable 2 ACC (1) Unclassifiable noma in one and undifferentiated carcinoma in the other carcinoma carcinoma (Figure 2). The undifferentiated carcinoma was not men- Mucoepidermoid Biphasic unclassifiable carcinoma (1) carcinoma tioned in the original pathology report. The ACC with Unclassifiable 1 PA with Spindle cell neoplasm adenocarcinoma had originally been diagnosed as epi- neoplasm sarcomatous of uncertain dermoid carcinoma. The adenocarcinoma was too poorly transformation histiogenesis, preserved to determine mitotic activity, while the mi- (1) uncertain malignant totic rate in the undifferentiated carcinoma (6 mitotic fig- potential ures per 10 high-power fields) was clearly higher than Abbreviations: ACC, adenoid cystic carcinoma; ADCA, adenocarcinoma; that in the surrounding ACC (2 mitotic figures per 10 CEPA, carcinoma ex pleomorphic adenoma; MECA, mucoepidermoid high-power fields). A third case had originally been di- carcinoma; NA, not applicable; PA, pleomorphic adenoma. agnosed with ACC with undifferentiated carcinoma but was found on review to be a solid-pattern ACC.

line or plasmacytoid myoepithelial cells, but epithelioid Carcinoma Ex Pleomorphic Adenoma and spindle cells were also present in small numbers. There was no specialized stroma present and mitotic fig- The second most common malignant tumor in our se- ures were undetectable. Myoepithelial prominence not ries and the literature is CEPA, or malignant mixed tu- reaching the 90% to 95% required by this definition was mor, of which we had 9 cases. The malignant compo- found in 5 cases of PA in our series. A final tumor origi- nents included 7 adenocarcinomas, 1 mucoepidermoid nally diagnosed as a Warthin tumor was on review con- carcinoma, and 1 biphasic, carcinosarcomatous tumor. sidered an oncocytoma. In most, the carcinomas were poorly differentiated, with

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C D

Figure 1. Pleomorphic adenoma (hematoxylin-eosin). A, Typical pleomorphic adenoma with a myxoid stroma and cellular myoepithelial area. Focal squamous metaplasia is present (arrows) (original magnification ϫ100). B, Atypical pleomorphic adenoma with focal nuclear enlargement and prominent nucleoli within epithelial cells lining glands (original magnification ϫ200). C, Atypical pleomorphic adenoma with moderate nuclear enlargement and pleomorphism and prominent nucleoli (original magnification ϫ200). D, Focus of marked nuclear pleomorphism within a pleomorphic adenoma. In this tumor, myoepithelial cells, some with plasmacytoid or hyaline morphology, are the cells with pleomorphic nucleoli. Note the absence of mitotic activity or necrosis (original magnification ϫ400).

the exception of 1 well-differentiated papillary adeno- PA with intact capsules. One of these was mainly a cel- carcinoma and the carcinosarcoma that had distinct, well- lular PA with a prominent myoepithelial component, and differentiated adenocarcinomatous and spindle cell sar- the other had both cellular and stromal areas. We called comatous components (Figure 3). The mucoepidermoid the malignant transformation in these cases noninvasive carcinoma showed high-grade cytologic atypia. The ad- as it was completely contained within the surrounding enocarcinomas displayed high mitotic activity, with a PA. In a third case, the adenocarcinoma composed more mean of 8 mitotic figures per 10 high-power fields and a than half of the tumor but remained within the preex- range from less than 1 to 26 mitotic figures per 10 high- isting PA, and the malignant component appeared to be power fields. The sarcomatous component of the bipha- replacing the ductal epithelium of the adenoma. sic tumor had a mitotic rate of 6 mitotic figures per 10 In a fourth case, considered minimally invasive, the high-power fields, and the adenocarcinomatous compo- malignant component invaded through the capsule of a nent had a mitotic rate of 30 mitotic figures per 10 high- mixed cellular and stromal PA but not more than 0.1 mm power fields. beyond. In a fifth case, the PA comprised a small nodule The extent of the malignant component and its rela- of intermediate cellularity with a prominent myoepithe- tionship to the PA capsule varied between cases. Tu- lial component in a densely hyalinized stroma, com- mors could be classified into 3 main groups: those con- pletely surrounded by an invasive adenocarcinoma ex- fined within PA (noninvasive; 3 cases) (Figure 4), those tending up to 18 mm beyond its border. The sixth case that invaded less than 1.5 mm from the capsule (mini- was similar except that the remnants of the cellular com- mally invasive; 1 case) (Figure 5), and those that had ponents of the PA were almost unrecognizable in the cen- spread more than 1.5 mm beyond the capsule into sur- tral hyaline nodule of the high-grade mucoepidermoid rounding tissue (invasive; 5 cases) (Figure 6). Two ad- carcinoma. enocarcinomas arose as minor components (approxi- Three additional tumors diagnosed as CEPA had no mately 30% and Ͻ50%) completely surrounded by typical recognizable cellular elements of a PA but shared the com-

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©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 mon feature of a circumscribed hyalinized nodule within significant cellular elements at all. The original pathol- a malignant tumor. One nodule had a scattering of cells ogy report of one of these gave a diagnosis of CEPA. Given of benign appearance within it, and the other 2 had no the continuum of changes described for the first 6 cases, we diagnosed these last 3 cases as likely CEPA as well. Other tumors, such as 2 examples of ACC and 1 of mu- Table 3. Histologic Features of 57 Pleomorphic Adenomas coepidermoid carcinoma, had some hyalinization within the stroma but lacked a circumscribed nodule and there- Cases, No. (%) fore were not considered to have arisen in PA. Histologic Feature (n=57) Tumor cellularity OTHER PRIMARY CARCINOMAS Predominantly cellular 41 (72) Predominantly stromal 9 (16) Adenocarcinoma Mixed cellular and stromal 7 (12) Stromal components We had 3 cases of primary adenocarcinoma. One had Myxoid 57 (100) sheets of very high-grade anaplastic cells with promi- Chondroid 25 (44) Hyaline 20 (34) nent gland formation, extensive necrosis, and a very high Squamous metaplasia 30 (53) mitotic rate (85 mitotic figures per 10 high-power fields). Plasmacytoid cells 27 (47) A second had lower-grade pleomorphism, highly differ- Myoepithelial prominence 5 (9) entiated gland formation throughout, and a very low mi- Cellular atypia 5 (9) totic rate of less than 1 mitotic figure per 10 high-power Oncocytic metaplasia 3 (5) fields. The third had variable gland formation com- Osseous metaplasia 2 (4)a Calcification without metaplasia 2 (4)a bined with nests of clear cells and areas resembling solid- Crystalloid inclusions 1 (2) Adipose metaplasia 1 (2) Bordering or extending into pseudocapsule 27 (87)b Extending beyond pseudocapsule 4 (13)b

a One case of primary tumor and 1 case of recurrent tumor. b Only 31 cases had adequate sections to analyze the full extent of the tumor.

Table 4. Histologic Growth Patterns for 38 Cases of Adenoid Cystic Carcinoma

Cases, No. (%) (n=38) Histologic Growth Pattern Pattern Present Pattern Predominant Cribriform 35 (92) 21 (55) Solid 13 (34) 7 (18) Figure 3. Carcinoma (carcinosarcoma) that arose in a pleomorphic Tubular 11 (29) 2 (5) adenoma. Nests of squamoid cells appear on the right and on the upper left, Mixed NA 8 (21) with central necrosis within a cellular stroma with spindled and polygonal cells exhibiting marked nuclear pleomorphism (hematoxylin-eosin, original Abbreviation: NA, not applicable. magnification ϫ200).

A B

Figure 2. Adenoid cystic carcinoma, dedifferentiated (hematoxylin-eosin). A, Cribriform-patterned adenoid cystic carcinoma on the left, and nests of poorly differentiated carcinoma on the right (original magnification ϫ40). B, Nest of anaplastic cells with marked nuclear pleomorphism and central necrosis (original magnification ϫ400).

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Figure 4. Noninvasive carcinoma arising in pleomorphic adenoma (hematoxylin-eosin). A, The upper portion shows the cellular component of the carcinoma, while a portion of the capsule is seen inferiorly (green arrows). Hyalinized residual pleomorphic adenoma is present on the bottom left (black arrow) (original magnification ϫ20). B, High-power view of the carcinoma (original magnification ϫ200).

A B

Figure 5. Minimally invasive carcinoma arising in pleomorphic adenoma (hematoxylin-eosin). A, The tumor in this field is composed predominantly of glandular elements. There is a small focus of the residual capsule of pleomorphic adenoma (green arrows), with tumor bulging out into the adjacent lacrimal gland and adipose tissue (black arrows) (original magnification ϫ40). B, High-power view of invasive focus, showing single-layered glands lined by cells with moderately atypical nuclei, prominent nucleoli, and occasional mitotic figures (arrows) (original magnification ϫ200).

A B C

Figure 6. Invasive carcinoma arising in pleomorphic adenoma. A, A hyalinized nodule on the left is residual from the pleomorphic adenoma. A high-grade carcinoma infiltrating beyond the capsule of the pleomorphic adenoma on the right is shown (hematoxylin-eosin, original magnification ϫ20). B, Higher-power view. On the lower left is a portion of the hyalinized pleomorphic adenoma. On the right is high-grade carcinoma with squamoid morphology in this field (hematoxylin-eosin, original magnification ϫ200). C, Other fields contain mucinous cells, warranting a diagnosis of mucoepidermoid carcinoma. Mucin is seen within cells (periodic acid–Schiff with diastase, original magnification ϫ200).

pattern ACC but had nuclei more pleomorphic than is prominent. This third tumor had originally been diag- typical of ACC. The mitotic rate of this tumor was 6 mi- nosed as ACC, whereas the first 2 were originally diag- totic figures per 10 high-power fields, and apoptosis was nosed as adenocarcinomas.

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©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 Mucoepidermoid Carcinoma tal carcinoma in situ. Mitotic figures were common, with a rate of 9 mitotic figures per 10 high-power fields. The We had 2 cases of mucoepidermoid carcinoma (Figure 7). second case had similar lobules but comedonecrosis was One was highly cellular with a large proportion of inter- more prominent, and the epithelium had a micropapil- mediate cells (approximately 50%), poorly formed glan- lary architecture (Figure 8). The mitotic rate was less dular elements with intracellular mucin, and a minor epi- than 1 mitotic figure per 10 high-power fields. The origi- dermoid component. The other tumor was composed of nal pathology report diagnosed this as high-grade pap- islands of cystic mucin-filled glands and epidermoid nests illary adenocarcinoma. with few intermediate cells embedded in a dense desmoplastic reaction. Both were grade 3 (high-grade) muco- Myoepithelial and Squamous Cell Carcinoma epidermoid carcinomas.65 We had 1 case each of myoepithelial and squamous cell Ductal Carcinoma carcinoma. The myoepithelial carcinoma had nests of myoepithelial cells with nuclear atypia, a mitotic rate of 1 mi- Ductal carcinoma, defined by its resemblance to mam- totic figure per 10 high-power fields, and no gland for- mary ductal carcinoma, has only recently been reported mation (Figure 9). Immunohistochemical staining results in the lacrimal gland, and to our knowledge 1 of our 2 18 were positive for keratin, irregularly positive for S-100 pro- cases was the first reported in the lacrimal gland. In this tein, and weakly positive for actin. The review diagnosis case, the tumor was arranged in lobules composed largely differed from the original diagnosis, which was “malig- of solid epithelial nests, some of which showed central nant epithelial neoplasm, most consistent with ACC.” The necrosis resembling comedonecrosis of mammary duc- single case of squamous cell carcinoma had areas of moderately well-differentiated epithelial cells with occasional keratin pearls, and other foci of more poorly differentiated carcinoma, embedded in a desmoplastic stroma. No goblet cells or mucin production were seen. There was a high mitotic rate of 15 mitotic figures per 10 high-power fields. The tumor was infiltrative with no capsule. The review diagnosis concurred with that of the original.

Unclassifiable Carcinoma

There were 2 cases of carcinoma that did not clearly match the features of any entity in the recent lacrimal and salivary gland tumor classification schemes. One was a biphasic tumor with a hypercellular area containing cells with pleomorphic nuclei and a high mitotic rate of 12 mitotic figures per 10 high-power fields forming multiple squa- Figure 7. Mucoepidermoid carcinoma, with nests of cells within a reactive mous eddies as well as a hypocellular area with cells ar- stroma. Within the nests, cells are arranged in a “paving stone” configuration ranged in nests within a hyaline stroma. Neither area had admixed with vacuolated cells (hematoxylin-eosin, original magnification ϫ400). Inset, Mucin is noted within some of the vacuolated cells (periodic features to support the original diagnosis of ACC. The sec- acid–Schiff with diastase, original magnification ϫ400). ond was a tumor with sheets of eosinophilic, epithelioid

A B

Figure 8. Lacrimal ductal carcinoma (hematoxylin-eosin, original magnification ϫ200). A, Ductlike nest of cells with high-grade nuclei and central necrosis, resembling mammary comedocarcinoma. B, Ductlike nest of cells lined by cells with high-grade nuclear features arranged in a micropapillary architecture. Necrotic debris is present within the lumen and surrounding this nest.

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C D

Figure 9. Myoepithelial carcinoma (hematoxylin-eosin). A, Tumor composed of multiple lobules (original magnification ϫ40). B, Most of the lobules, such as those on the lower left, consist of predominantly epithelioid cells arranged in cords within a mucinous stroma. Other nodules, such as the one on the center right, have a solid arrangement of epithelioid cells. Note the absence of true ductal differentiation (original magnification ϫ100). C, A lobule of tumor with greater cellularity at the periphery (green arrows) and mucinous stroma in the center containing cords of epithelioid cells. The stroma shows focal collagenization. Occasional mitotic figures are present (black arrows) (original magnification ϫ400). D, Hypocellular tumor lobules with abundant mucohyaline stroma. Cells in the center of the image have clear cytoplasm (original magnification ϫ400).

cells with pleomorphic nuclei and a high mitotic rate of 6 dated.10,28,66 Since the expanded salivary gland classifi- mitotic figures per 10 high-power fields. There was no gland cations were published,67-69 the use of the salivary gland formation and no intracellular or extracellular mucin de- classification for lacrimal gland tumors has been re- tected by histochemical analysis. A recurrence of the tu- ported.5,18-62 In 2006 the AFIP monograph on lacrimal mor excised 2 years later had sheets of cells with a more gland tumors17 showed an expanded classification based anaplastic appearance. The original diagnosis of muco- on the 1991 WHO classification of salivary gland tu- epidermoid carcinoma was not supported by our review. mors. Our study reviewed 118 cases from 4 institutions, successfully applying the updated salivary gland classi- COMMENT fication scheme to lacrimal gland tumors and resulting in a revision of the diagnosis in 14% of cases. Table 5 lists our proposed histologic classification EXPANDED EPITHELIAL LACRIMAL for lacrimal gland epithelial neoplasia based on our se- GLAND TUMOR CLASSIFICATION ries and recently published series (Table 6) and case reports.* The most significant aspect of this listing is the The WHO’s classification scheme for lacrimal gland epi- increased diversity of diagnoses and the inclusion of 14 has provided the context for our un- thelial neoplasia subtypes within the diagnostic categories that may in- derstanding of them and included 2 broad categories of fluence clinical prognosis. Furthermore, review of the “other adenomas” and “other carcinomas.” An updated pathologic specimens revealed no consistent sampling, pathologic classification is needed to include the recog- orientation, or pathologic preparation of samples within nition of the advances in salivary gland histologic clas- and between the various institutions. In response to these sification and the identification of several new entities. In addition, the behavior of various benign and malignant lacrimal gland tumors has been further eluci- *References 5, 12, 13, 15, 20, 24-26, 28, 44-46, 54, 55, 70.

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©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 tial excision.70,74,77 The salivary gland literature reports up Table 5. Proposed Classification for Epithelial to a 9% incidence of transformation over 15 years.76 In our Lacrimal Gland Tumors series, none of the 3 recurrent tumors had transformed, but patients presenting with CEPA were significantly older than Classification Epithelial Lacrimal Gland Tumor Description those with PA (median age difference, 20 years). Tumor Benign Pleomorphic adenoma hyalinization has been shown to correlate with malignant Pleomorphic adenoma with atypia transformation in the salivary gland.78 Extensive hyalin- Myoepithelioma Oncocytoma ization has been reported previously for lacrimal gland 50,74 Cystadenoma CEPA and was a prominent feature in 5 of the 9 cases Malignant of CEPA in our series. If hyalinization is taken as a sign of Low grade Carcinoma ex pleomorphic adenoma/malignant tumor age, then this histologic marker supports the asso- mixed tumor (where the carcinoma is noninvasive ciation between malignant transformation and patient age. Յ or minimally invasive [ 1.5 mm] as defined by Our series included 5 cases of PA with cellular atypia; the World Health Organization classification) Polymorphous low-grade carcinoma all were predominantly cellular tumors and 3 had promi- Mucoepidermoid, grades 1 and 2 nent myoepithelial components, 1 of which had origi- Epithelial-myoepithelial carcinoma nally been diagnosed as CEPA. High cellularity or myo- Acinic cell carcinoma epithelial prominence was a feature in 3 of the 9 cases of Basal cell carcinoma CEPA in our series. It is unknown whether high cellu- Mucinous adenocarcinoma larity, atypia, and myoepithelial prominence may in- High grade Carcinoma ex pleomorphic adenoma/malignant mixed tumor, which includes adenocarcinoma and crease the likelihood of eventual malignant transforma- adenoid cystic carcinoma arising in a pleomorphic tion, and we thus recommend retaining these descriptions adenoma (where the carcinoma is invasive in examining PA. [Ͼ1.5 mm] as defined by the World Health The extent of invasion of the malignant component of Organization classification) CEPA in the salivary gland has been shown to be strongly Adenoid cystic carcinoma not otherwise specified Adenocarcinoma not otherwise specified correlated with subsequent behavior. A number of studies Mucoepidermoid, grade 3 of salivary gland neoplasms have demonstrated that tu- Ductal adenocarcinoma mors in which the malignant component is confined within Squamous cell carcinoma the capsule or shows minimal invasion (variably defined Sebaceous adenocarcinoma as extension 8 mm,79 5 mm,80 or 1.5 mm81 beyond the PA Myoepithelial carcinoma capsule) are associated with a benign course. There is a single Lymphoepithelial carcinoma Other rare and unclassifiable carcinomas report of cervical lymph node metastases from a parotid Dedifferentiation in any of the above carcinomas gland CEPA that was apparently well sampled and showed Histologic Grade cannot be assessed no capsular invasion.82 Despite this isolated case, we feel grade Well differentiated that there is sufficient evidence to support the contention Moderately differentiated, includes adenoid cystic that the extent of invasion is an important prognostic find- carcinoma without basaloid (solid) pattern ing. We suggest adopting the WHO terminology of non- Poorly differentiated, includes adenoid cystic carcinoma with basaloid (solid) pattern invasive, minimally invasive, and invasive to recognize these Undifferentiated differences in outcome. In our series, 3 patients with noninvasive carcinoma and 1 patient with minimally invasive carcinoma (extension Ͻ1.5 mm beyond the PA capsule) findings, Rootman and White71 have given recommen- had no recurrence, whereas only 1 of 4 patients with in- dations on sampling, orientation, and preparation of patho- vasive carcinoma remained disease-free in follow-up. logic specimens of lacrimal gland tumors. We required frank cytologic and/or architectural evidence of malignancy to render a diagnosis of noninva- PROGNOSTIC SIGNIFICANCE sive CEPA. Cases that exhibited nuclear enlargement and OF TUMOR SUBTYPING pleomorphism without evidence of significantly increased mitotic activity or necrosis were considered atypi- PA and CEPA cal PAs. We adopted a conservative approach to the diagnosis of noninvasive CEPA to prevent overtreatment The 2 major factors determining the prognosis of PA are as noninvasive CEPA has a prognosis similar to that of its likelihood of recurrence and evidence of malignant trans- PA, with possible rare exceptions.82 formation. Recurrence rates as high as 30% have been reported in the older literature and literature from main- Adenoid Cystic Carcinoma land China, increasing with the length of follow-up.5,8,72 In contrast, the chance of recurrence is negligible, if not Several studies have shown that solid-pattern ACC por- eliminated, by proper initial surgical management includ- tends a worse prognosis than the cribriform or tubular ing en bloc excision.6,8,10,12,70,73-75 With a mean (SD) fol- pattern for both salivary83-86 and lacrimal87-89 gland tu- low-up of 4.47 (4.58) years, no recurrences occurred in mors. Our series shows a similar tendency as patients with our series for PA handled in this manner. tumors with a solid component had a lower survival rate. The likelihood of malignant transformation of PA ap- The absence of a cribriform pattern was also associated pears to be related to tumor age,8,76 with reports of trans- with poor survival. We recommend retaining histologic formation in recurrent tumors 40 years or longer after ini- pattern descriptions within the ACC category.

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Source

Current Ni et al,5 Riedel Paulino and Wright Henderson McLean Shields Epithelial Lacrimal Study 1992 et al,55 1990 Huvos,20 1999 et al,28 1992 et al,12 1994 et al,15 1994 et al,13 2004 Totalb Gland Tumor (n=118) (n=235) (n=29) (n=14) (n=125) (n=58) (n=38) (n=30) (N=647) Benign epithelial neoplasms Pleomorphic adenoma 57 (48) 140 (60) 12 (41) 3 (21) 78 (62) 25 (43) 19 (50) 11 (37) 345 Pleomorphic adenoma 5c with atypia Myoepithelioma 1 (1) 2 (1) 8 Oncocytoma 1 (1) 2 (7) 5 Cystadenomad 1 Malignant epithelial neoplasms Adenoid cystic carcinoma 38 (32) 68 (29) 9 (31) 9 (64) 38 (30) 22 (38) 13 (34) 14 (47) 211 Dedifferentiated 2c Carcinoma ex pleomorphic 9 (8) 25 (11) 3 (10) 2 (14) 6 (5) 10 (17) 5 (13) 4 (13) 64 adenoma Circumscribed 3c Noncircumscribed 6c Mucoepidermoid carcinoma 2 (2) 2 (1) 3 (21) 1 (1) 2 (3) 1 (3) 14 Adenocarcinoma 3 (3) 5 (2) 2 (7) 2 (14) 4 (3) 5 (9) 2 (5) 23 Undifferentiated carcinoma 20 (9) 20 Primary sebaceous 2 (1) 8 adenocarcinoma Myoepithelial carcinoma 1 (1) 1 (Ͻ1) 1 (7) 6 Lacrimal duct carcinoma 2 (2) 1 (7) 5 Polymorphous low-grade 3 (1) 5 adenocarcinoma Primary squamous cell 1 (1) 1 (1) 1 (2) 4 carcinoma Oncocytic carcinoma 1 (3) 1 (7) 3 Acinic cell carcinomad 3 Lymphoepithelial carcinomad 2 Carcinosarcoma 1 (Ͻ1) 2 Basal cell adenocarcinomad 1 Cystadenocarcinomad 1 Epithelial-myoepithelial 1 carcinomad

aValues are expressed as number (percentage) or as number. bIncluding case reports (case reports of pleomorphic adenoma, adenoid cystic carcinoma, and carcinoma ex pleomorphic adenoma are not included). cSubtype of the above category. dNot listed in any recent case series; found in case reports only.

The phenomenon of dedifferentiation in ACC is a re- PROGNOSTIC SIGNIFICANCE cently described rare event in tumors of minor and ma- OF RARE DIAGNOSES jor salivary glands.90-94 Most commonly, the malignant neoplasm arising within ACC is a high-grade adenocar- Benign Epithelial Neoplasia cinoma. A small number of undifferentiated carcinomas have been described. In 1 case, the malignant compo- Myoepithelioma. Lacrimal gland myoepithelioma has nent was a sarcomatoid neoplasm with focal myoepithe- been reported rarely,5,43,58-62 but it is well described in the lial features.90 In 2 of 3 dedifferentiated ACCs, molecu- salivary gland literature and is widely held to represent lar analysis demonstrated mutation of the p53 gene in one end of the spectrum of benign tumors showing epi- only the dedifferentiated component, suggesting a role thelial and myoepithelial differentiation. Although some for this oncogene in the pathogenesis.91,93 In most of the studies suggest it may be aggressive,1,95 others have in- reported cases, the finding of dedifferentiation has been dicated an excellent outcome.96,97 We include it as a sepa- associated with poor outcome.90,93,94 rate entity because of its unusual microscopic appear- Two cases of dedifferentiated ACC, to our knowledge ance that may make diagnosis difficult. the only known cases of dedifferentiated lacrimal gland ACC, were seen in our series. In one case, the patient has Oncocytoma. The few cases of oncocytoma reported in remained disease-free for more than 10 years of follow- the lacrimal gland literature, including 1 case in our se- up; in the other, the patient died of lung metastases 7.3 ries, have shown no evidence of recurrence throughout years after exenteration. Our classification includes this follow-up.55,56 Our case was initially reported as a War- subtype of ACC as its prognostic significance may be- thin tumor; thus, with this review, Warthin tumor in the come evident as additional cases are reported. lacrimal gland remains an unreported entity.98 Al-

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©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 though the tumor had a prominent lymphocytic infil- ma,42 and cystadenocarcinoma,46 all of which appear to be trate suggestive of a Warthin tumor, the oncocytes them- low grade, as well as primary sebaceous adenocarci- selves were not found in the highly ordered bilayered noma5,47-53 and lymphoepithelial carcinoma,44,45 both of arrangement typical of Warthin tumors.68 which are considered high grade. Since completing this review, we have seen a single case each of epithelial- Malignant Epithelial Neoplasia myoepithelial carcinoma, acinic cell carcinoma, and myoepithelial carcinoma in the Orbit Clinic, University of Brit- Adenocarcinoma. Adenocarcinoma was the third most ish Columbia. common lacrimal gland malignant neoplasm, account- ing for 5% of carcinomas in our series and 4% to 13% in CONCLUSIONS other recent series.5,12,15,20,28,55 Generally, lacrimal gland adenocarcinoma carries a dismal prognosis (fatality rang- This study and review of the literature evokes 3 impor- 8,12,28 and an average survival of 1.5 ing from 50%-80%) tant conclusions. First, the use of a more diverse classi- years.12 It is therefore important to distinguish adeno- fication can be successfully applied to epithelial lacri- carcinoma from low-grade polymorphous adenocarci- mal gland neoplasms. Second, the expanded classification noma or mucoepidermoid carcinoma (grades 1 and 2), system led to reclassifying 14% of cases in our review. both of which carry a better prognosis. Finally, there are currently no pathologic standards for processing and evaluating these lesions. Mucoepidermoid Carcinoma. The prognosis of mucoepidermoid carcinoma varies with tumor grade, with almost no recurrence for grades 1 and 2 tumors and greater Submitted for Publication: January 30, 2009; final re- than 50% mortality from grade 2 tumors.35 vision received April 2, 2009; accepted April 6, 2009. Author Affiliations: Department of Ophthalmology, Uni- Ductal Carcinoma. This series includes the first reported versity of Alberta, Edmonton, Alberta, Canada (Dr Weis); case of lacrimal ductal carcinoma to our knowledge18 and Departments of Ophthalmology and Visual Science a second, originally unrecognized case diagnosed as ad- (Drs Weis, Rootman, Joly, and White), Pathology and enocarcinoma. Both of these cases were disease-free after Laboratory Medicine (Drs Rootman, Berean, and White), excision and radiotherapy. Of the 5 other cases reported and Radiology (Dr Lapointe), Vancouver General Hospi- in the literature, 3 fared well after a single operation and tal and the University of British Columbia, Vancouver, adjunct radiation.18-23 A fourth patient has had local re- British Columbia, Canada; Department of Ophthalmol- currences with surgery alone,19 and the fifth had lym- ogy, Security Forces Hospital, Riyadh, Saudi Arabia phatic metastasis detected prior to scheduled radiotherapy.23 (Dr Al-Katan); Department of Pathology, Dalhousie Uni- versity, Halifax, Nova Scotia, Canada (Dr Pasternak); Myoepithelial Carcinoma. Our case of myoepithelial car- Department of Ophthalmology, University of Naples, cinoma was initially misdiagnosed and is one of few re- Naples, Italy (Drs Bonavolontà and Strianese); Depart- ported cases.41,43 With so few cases, it is impossible to draw ment of Ophthalmology, University of Amsterdam, conclusions regarding clinical behavior. Our patient died Amsterdam, the Netherlands (Dr Saeed); Department of within months of diagnosis without definitive treat- Ophthalmology, Kaiser Permanente Medical Center, ment. In the salivary glands, there is a reported recur- Harbor City, California (Dr Feldman); and Department rence rate greater than 50%.99,100 of Ophthalmology, Siriraj Hospital, Bangkok, Thailand (Dr Vangveeravong). Squamous Cell Carcinoma. Including our single case, Correspondence: Jack Rootman, MD, 2550 Willow St, there are 8 cases of squamous cell carcinoma of the lac- Vancouver, BC V5Z 3N9, Canada (jrootman@interchange rimal gland reported in the literature.28-31 No clinical his- .ubc.ca). tory is available for our case, and no recurrences were Financial Disclosure: None reported. noted in the other published reports. REFERENCES Carcinosarcoma. Carcinosarcoma, a biphasic tumor composed of both carcinoma and sarcoma, is a rare tumor of 1. Reese AB. 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