CLINICAL SCIENCES Epithelial Lacrimal Gland Tumors

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 glandclassification scheme to a large cohort of lacrimal glandtumors so as to provide an updated lacrimal gland tu-mor classification scheme.

Methods: A retrospective multicenter cohort study of118 cases of epithelial neoplasia was undertaken. Mainoutcome measures included pathologic analysis, subtyp-ing, and survival.

Results: Of 118 cases, 17 (14%) were reclassified usingthe proposed expanded classification scheme based on thecurrent World Health Organization classification of sali-vary gland tumors. The most frequent neoplasms were pleo-morphic adenoma and adenoid cystic carcinoma, of whichwe highlight more unusual histologic features. Three tu-

mors were found to be unclassifiable with the updatedscheme, with 2 having histologically malignant features.Deficiencies and variations in pathologic assessment werenoted. Variation in the histologic findings of pleomor-phic adenoma and assessment of the extent of invasion ofcarcinoma ex pleomorphic adenoma were highlighted.

Conclusions: The use of the more histologically di-verse classification of salivary gland tumors can be suc-cessfully applied to the epithelial lacrimal gland neo-plasms. This expanded classification system led toreclassifying 14% of cases. Currently, there are no con-sistent pathologic standards for processing and evaluat-ing these lesions.

Arch Ophthalmol. 2009;127(8):1016-1028

L ACRIMAL GLAND LESIONS REP-resent 5% to 25% of orbitaltumors, and the proportion inthe literature that are epithe-lial range from 23% to 70% of

biopsied cases.1-6 Despite our current un-derstanding that rational clinical manage-ment of salivary and lacrimal gland tu-mors depends on specific histologic tumortyping,3-5,7-13 there has been no official up-date of the lacrimal gland tumor classifi-cation since the World Health Organiza-tion (WHO) publication of 1980.14 TheArmed Forces Institute of Pathology (AFIP)monograph on lacrimal gland tumors pub-lished in 1994 reviewed 39 cases but didnot attempt a comprehensive reclassifica-tion.15 Our understanding of lacrimal glandtumors reflects the histologically similar butmore prevalent salivary gland tumors, theclassification of which has undergone sev-eral iterations since the introduction of theAFIP classification in 195316 to includenewly recognized tumor types correlatingwith biological behavior. In 2006 the AFIPmonograph on lacrimal gland tumors17

showed an expanded classification based onthe 1992 WHO classification of salivarygland tumors. It is also clear that the sali-vary gland classification has filtered into thelacrimal gland literature, which has de-scribed many tumors analogous to their sali-vary gland counterparts, including ductalcarcinoma,18-23 acinic cell carcinoma,24-27 pri-mary squamous cell carcinoma,28-31 muco-epidermoid carcinoma,20,32-38 oncocytic car-cinoma,39 polymorphous low-gradeadenocarcinoma,5,40 myoepithelial carci-noma,41-43 lymphoepithelial carcino-ma,44,45 epithelial-myoepithelial carcino-ma,42 cystadenocarcinoma,46 primarysebaceous adenocarcinoma,5,47-53 basal celladenocarcinoma,54 oncocytoma,55,56 cyst-adenoma,57 and myoepithelioma.5,43,58-62

The purposes of our study are to re-view the standards of histologic analysisand propose an updated classificationscheme based on a series of 118 cases from4 contributing institutions reviewed by ahead and neck pathologist (K.W.B.) wellversed in salivary gland tumor pathologyand classification.

Author Affiliations are listed atthe end of this article.

(REPRINTED) ARCH OPHTHALMOL / VOL 127 (NO. 8), AUG 2009 WWW.ARCHOPHTHALMOL.COM1016

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METHODS

Epithelial lacrimal gland neoplasms from 4 contributing insti-tutions were reviewed for clinical profile, pathology, and out-come at the University of British Columbia, Vancouver, Brit-ish Columbia, Canada. Only cases with pathology specimensavailable for examination were included, resulting in a total of118 cases in the combined series.

PATHOLOGIC ANALYSIS

All pathology specimens were evaluated by a single patholo-gist specializing in head and neck pathology (K.W.B.). Speci-mens were classified according to the most recent WHO sali-vary gland tumor classification.63 The amount of materialavailable varied, and initial review was based on hematoxylin-eosin–stained sections. Additional material, analysis with his-tochemical and immunohistochemical stains, and a more com-plete examination of the extent of the tumor were requestedfor any case in which the diagnosis was questionable. Initialreview was performed with the pathologist blinded to the clini-cal history and original diagnosis. All of the cases with rare di-agnoses, with atypical findings, or in which the review diag-nosis differed from the original were submitted to a secondreview by a committee comprising the head and neck patholo-gist (K.W.B.) and 2 ophthalmic pathologists (V.A.W. and J.R.).

STATISTICAL ANALYSIS

Linear and logistic regression was used to compare baseline char-acteristics between different tumor subtypes and histologic find-ings. Clinical outcomes for adenoid cystic carcinoma were ana-lyzed using survival analysis in the form of the log-rank test.Statistical significance was defined as P� .05.

RESULTS

The pathology specimens of 118 cases from 4 institu-tions were classified as shown in Table 1. This study wascoordinated by the Orbit Clinic, University of British Co-lumbia. Forty cases from the University of British Colum-bia, 33 from the Department of Ophthalmology, Univer-sity of Naples, Naples, Italy, 33 from the Department ofOphthalmology, University of Amsterdam, Amsterdam, theNetherlands, and 12 from the Department of Ophthal-mology, Kaiser Permanente Medical Center, Harbor City,California, were enrolled. No interinstitution or intra-institution standards for specimen sampling or handlingwere found. The most frequent diagnosis was pleomor-phic adenoma (PA), followed by adenoid cystic carci-noma (ACC) and carcinoma ex pleomorphic adenoma(CEPA). Three tumors were unclassifiable, 2 of which wereconsidered to have histopathologically malignant fea-tures and the third of which was indeterminate. Of the 118cases, 17 were reclassified in this study (Table 2).

BENIGN NEOPLASMS

Pleomorphic Adenoma

According to the AFIP salivary gland tumor classifica-tion, the “essential diagnostic feature” of a PA, or be-nign mixed tumor, is that it is “composed of both epi-

thelial and mesenchymal-like tissues.”63 The epithelialcells form characteristic ductal structures with surround-ing myoepithelial cells, which trail out gradually intomyxomatous mesenchyme (Figure 1A). All but 2 of the57 cases of PA in our series easily fit this description andwere diagnosed as such in the original pathology reports.

Variable features typical of PA were systematically ana-lyzed, including cellularity, presence of myxoid, chon-droid, and hyaline stroma, and cellular characteristics in-cluding squamous metaplasia and presence of plasmacytoidcells. Other rare features were occasionally noted.

Typical and infrequent features are summarized inTable 3 and shown in Figure 1. The mean diameter was24.5 mm, ranging from 10 to 40 mm. Mitotic figures wererarely detected. Tumor capsules varied from a few mi-crometers to a few hundred micrometers in thickness andwere incomplete in some. In 31 cases in which we hadadequate sections to analyze the full extent of the tu-mor, 27 were found to border or invade the capsule and4 (including 3 not originally reported) extended beyond.

The review diagnosis differed from the original diag-nosis in 2 cases. One case, originally diagnosed as nonin-vasive carcinoma in PA, was on review considered a PAwith epithelial atypia and oncocytic metaplasia not war-ranting a diagnosis of carcinoma. The second case, origi-nally diagnosed as acinic cell carcinoma, was considereda variant PA with atypical features.

The3clinicallyrecurrent tumorswerecharacterizedhis-tologicallybymultifocalandmultinodulargrowthpatterns.The recurrences occurred at 23, 25, and 30 years after theinitial resection. In all 3 cases, the tumor formed numer-ous nodules generally composed predominantly of stromawith minor epithelial components. One tumor showed fo-calcalcificationandanothershowedfocalossification.Therewas no evidence of malignant transformation.

Other Benign Tumors

A single case of myoepithelioma was identified.64 It waswell circumscribed and composed of sheets of myoepi-thelial cells with rare ducts. Most of the cells were hya-

Table 1. Updated Diagnoses of 118 EpithelialLacrimal Gland Tumors Using Proposed Salivary GlandClassification Scheme

DiagnosisCases, No. (%)

(N=118)

Pleomorphic adenoma 57 (48)Adenoid cystic carcinoma 38 (32)Carcinoma ex pleomorphic adenoma 9 (8)Adenocarcinoma 3 (3)Mucoepidermoid carcinoma 2 (2)Lacrimal ductal carcinoma 2 (2)Unclassifiable carcinoma 2 (2)Unclassifiable neoplasm 1 (1)Squamous cell carcinoma 1 (1)Myoepithelial carcinoma 1 (1)Myoepithelioma 1 (1)Oncocytoma 1 (1)Total 118 (102)a

aArtifactually greater than 100% owing to rounding to the nearest integer.




line or plasmacytoid myoepithelial cells, but epithelioidand spindle cells were also present in small numbers.There was no specialized stroma present and mitotic fig-ures were undetectable. Myoepithelial prominence notreaching the 90% to 95% required by this definition wasfound in 5 cases of PA in our series. A final tumor origi-nally diagnosed as a Warthin tumor was on review con-sidered an oncocytoma.

MALIGNANT NEOPLASMS

Adenoid Cystic Carcinoma

Our series included 38 cases of ACC (32%), which wasthe most common malignant neoplasm. The mean his-tologic diameter was 27.7 mm, with the diameter rang-ing from 16 to 42 mm and no statistically significant dif-ference when compared with PA (P=.09). Most tumorshad combinations of 2 or 3 histologic patterns (Table4).Comedonecrosis was present in 10 cases, in both crib-riform and solid patterns, but was most prominent in areasof the solid pattern.

Mitotic activity ranged from undetectable to 25 mi-totic figures per 10 high-power fields. In general, thelowest activity was found in tumors with tubular andcribriform patterns (median, 2.9 mitotic figures per 10high-power fields), while tumors with at least somecomponent of solid pattern had higher mitotic activity(median, 10.1 mitotic figures per 10 high-power fields)(P� .001).

The ACCs were nonencapsulated with infiltration ofsurrounding fat, periorbita, and muscle. Invasion into thesclera or optic nerve was not identified in any case. Peri-neural invasion was seen in 13 cases, although cautionin interpreting this is necessary because of the variablesectioning patterns by the different institutions. Peri-neural invasion did not correlate with mitotic activity(P=.90), particular histologic pattern noted on analysis(cribriform, P=.50; tubular, P� .99; solid, P=.49), or pre-dominant pattern (cribriform, P=.38; tubular, P=.51;solid, P� .99). Perineural invasion was described in 9original pathology reports, including 2 cases in which itwas not found on review. Inconsistent sampling, orien-tation, and pathologic preparation of bone samples werenoted. Of the 11 cases in which bone was sampled, 7 werepositive and 4 were negative for tumor. The absence of acribriform pattern (P=.01) and the presence of a solidpattern (P=.02) were significantly associated with death.

In 2 cases, an area of high-grade carcinoma was foundwithin the ACC: a poorly differentiated adenocarci-noma in one and undifferentiated carcinoma in the other(Figure2). The undifferentiated carcinoma was not men-tioned in the original pathology report. The ACC withadenocarcinoma had originally been diagnosed as epi-dermoid carcinoma. The adenocarcinoma was too poorlypreserved to determine mitotic activity, while the mi-totic rate in the undifferentiated carcinoma (6 mitotic fig-ures per 10 high-power fields) was clearly higher thanthat in the surrounding ACC (2 mitotic figures per 10high-power fields). A third case had originally been di-agnosed with ACC with undifferentiated carcinoma butwas found on review to be a solid-pattern ACC.

Carcinoma Ex Pleomorphic Adenoma

The second most common malignant tumor in our se-ries and the literature is CEPA, or malignant mixed tu-mor, of which we had 9 cases. The malignant compo-nents included 7 adenocarcinomas, 1 mucoepidermoidcarcinoma, and 1 biphasic, carcinosarcomatous tumor.In most, the carcinomas were poorly differentiated, with

Table 2. Summary of RediagnosisBased on Pathologic Review

DiagnosisCases,

No.

Original Diagnosisif Different

(Cases, No.)Findings

on Review

PA 54 Acinic cellcarcinoma (1)

Variant PA withatypical features

Noninvasivecarcinoma inPA (1)

PA with epithelialatypia, myoepithelialrich with oncocyticmetaplasia

PA recurrence 3 NA NAMyoepithelioma 1 NA NAOncocytoma 1 Warthin tumor (1) Oncocytoma with

lymphocytichyperplasia

ACC 36 Undifferentiatedcarcinoma arisingfrom ACC (1)

Solid-pattern ACC

ACC withdedifferentiation

2 ACC (1) ACC with focal, poorlydifferentiatedcarcinoma

Epidermoidcarcinoma (1)

ACC with focal, poorlydifferentiated ADCA

CEPA noninvasive 3 MECA (1) ADCA possibly ex PACEPA minimally

invasive1 NA NA

CEPA invasive 5 ACC ex PA (1) ADCA possibly ex PA,MECA ex PA

MECA (1) Circumscribed ADCAex PA

MECA in preexistingpseudotumor (1)

NA

Carcinosarcoma,malignant mixedtumor (1)

Biphasic carcinoma,carcinosarcomatouspattern, ex PA

ADCA 3 ACC (1) NAMucoepidermoid

carcinoma2 NA NA

Ductal carcinoma 2 ADCA (1) NAMyoepithelial

carcinoma1 Malignant epithelial

neoplasm, mostconsistent withACC (1)

Nests of myoepithelialcells with nuclearatypia, and no glandformation

Squamous cellcarcinoma

1 NA NA

Unclassifiablecarcinoma

2 ACC (1) Unclassifiablecarcinoma

Mucoepidermoidcarcinoma (1)

Biphasic unclassifiablecarcinoma

Unclassifiableneoplasm

1 PA withsarcomatoustransformation(1)

Spindle cell neoplasmof uncertainhistiogenesis,uncertain malignantpotential

Abbreviations: ACC, adenoid cystic carcinoma; ADCA, adenocarcinoma;CEPA, carcinoma ex pleomorphic adenoma; MECA, mucoepidermoidcarcinoma; NA, not applicable; PA, pleomorphic adenoma.




the exception of 1 well-differentiated papillary adeno-carcinoma and the carcinosarcoma that had distinct, well-differentiated adenocarcinomatous and spindle cell sar-comatous components (Figure3). The mucoepidermoidcarcinoma showed high-grade cytologic atypia. The ad-enocarcinomas displayed high mitotic activity, with amean of 8 mitotic figures per 10 high-power fields and arange from less than 1 to 26 mitotic figures per 10 high-power fields. The sarcomatous component of the bipha-sic tumor had a mitotic rate of 6 mitotic figures per 10high-power fields, and the adenocarcinomatous compo-nent had a mitotic rate of 30 mitotic figures per 10 high-power fields.

The extent of the malignant component and its rela-tionship to the PA capsule varied between cases. Tu-mors could be classified into 3 main groups: those con-fined within PA (noninvasive; 3 cases) (Figure 4), thosethat invaded less than 1.5 mm from the capsule (mini-mally invasive; 1 case) (Figure 5), and those that hadspread more than 1.5 mm beyond the capsule into sur-rounding tissue (invasive; 5 cases) (Figure 6). Two ad-enocarcinomas arose as minor components (approxi-mately 30% and �50%) completely surrounded by typical

PA with intact capsules. One of these was mainly a cel-lular PA with a prominent myoepithelial component, andthe other had both cellular and stromal areas. We calledthe malignant transformation in these cases noninvasiveas it was completely contained within the surroundingPA. In a third case, the adenocarcinoma composed morethan half of the tumor but remained within the preex-isting PA, and the malignant component appeared to bereplacing the ductal epithelium of the adenoma.

In a fourth case, considered minimally invasive, themalignant component invaded through the capsule of amixed cellular and stromal PA but not more than 0.1 mmbeyond. In a fifth case, the PA comprised a small noduleof intermediate cellularity with a prominent myoepithe-lial component in a densely hyalinized stroma, com-pletely surrounded by an invasive adenocarcinoma ex-tending up to 18 mm beyond its border. The sixth casewas similar except that the remnants of the cellular com-ponents of the PA were almost unrecognizable in the cen-tral hyaline nodule of the high-grade mucoepidermoidcarcinoma.

Three additional tumors diagnosed as CEPA had norecognizable cellular elements of a PA but shared the com-

A B

C D

Figure 1. Pleomorphic adenoma (hematoxylin-eosin). A, Typical pleomorphic adenoma with a myxoid stroma and cellular myoepithelial area. Focal squamousmetaplasia is present (arrows) (original magnification �100). B, Atypical pleomorphic adenoma with focal nuclear enlargement and prominent nucleoli withinepithelial cells lining glands (original magnification �200). C, Atypical pleomorphic adenoma with moderate nuclear enlargement and pleomorphism and prominentnucleoli (original magnification �200). D, Focus of marked nuclear pleomorphism within a pleomorphic adenoma. In this tumor, myoepithelial cells, some withplasmacytoid or hyaline morphology, are the cells with pleomorphic nucleoli. Note the absence of mitotic activity or necrosis (original magnification �400).




mon feature of a circumscribed hyalinized nodule withina malignant tumor. One nodule had a scattering of cellsof benign appearance within it, and the other 2 had no

significant cellular elements at all. The original pathol-ogy report of one of these gave a diagnosis of CEPA. Giventhe 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-coepidermoid carcinoma, had some hyalinization withinthe stroma but lacked a circumscribed nodule and there-fore were not considered to have arisen in PA.

OTHER PRIMARY CARCINOMAS

Adenocarcinoma

We had 3 cases of primary adenocarcinoma. One hadsheets of very high-grade anaplastic cells with promi-nent gland formation, extensive necrosis, and a very highmitotic rate (85 mitotic figures per 10 high-power fields).A second had lower-grade pleomorphism, highly differ-entiated gland formation throughout, and a very low mi-totic rate of less than 1 mitotic figure per 10 high-powerfields. The third had variable gland formation com-bined with nests of clear cells and areas resembling solid-

Table 3. Histologic Features of 57 Pleomorphic Adenomas

Histologic FeatureCases, No. (%)

(n=57)

Tumor cellularityPredominantly cellular 41 (72)Predominantly stromal 9 (16)Mixed cellular and stromal 7 (12)

Stromal componentsMyxoid 57 (100)Chondroid 25 (44)Hyaline 20 (34)

Squamous metaplasia 30 (53)Plasmacytoid cells 27 (47)Myoepithelial prominence 5 (9)Cellular atypia 5 (9)Oncocytic metaplasia 3 (5)Osseous metaplasia 2 (4)a

Calcification without metaplasia 2 (4)a

Crystalloid inclusions 1 (2)Adipose metaplasia 1 (2)Bordering or extending into pseudocapsule 27 (87)b

Extending beyond pseudocapsule 4 (13)b

aOne case of primary tumor and 1 case of recurrent tumor.bOnly 31 cases had adequate sections to analyze the full extent of the

tumor.

Table 4. Histologic Growth Patterns for 38 Casesof Adenoid Cystic Carcinoma

HistologicGrowth Pattern

Cases, No. (%)(n=38)

Pattern Present Pattern Predominant

Cribriform 35 (92) 21 (55)Solid 13 (34) 7 (18)Tubular 11 (29) 2 (5)Mixed NA 8 (21)

Abbreviation: NA, not applicable.

A B

Figure 2. Adenoid cystic carcinoma, dedifferentiated (hematoxylin-eosin). A, Cribriform-patterned adenoid cystic carcinoma on the left, and nests of poorlydifferentiated carcinoma on the right (original magnification �40). B, Nest of anaplastic cells with marked nuclear pleomorphism and central necrosis (originalmagnification �400).

Figure 3. Carcinoma (carcinosarcoma) that arose in a pleomorphicadenoma. Nests of squamoid cells appear on the right and on the upper left,with central necrosis within a cellular stroma with spindled and polygonalcells exhibiting marked nuclear pleomorphism (hematoxylin-eosin, originalmagnification �200).




pattern ACC but had nuclei more pleomorphic than istypical of ACC. The mitotic rate of this tumor was 6 mi-totic figures per 10 high-power fields, and apoptosis was

prominent. This third tumor had originally been diag-nosed as ACC, whereas the first 2 were originally diag-nosed as adenocarcinomas.

A B

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) (originalmagnification �20). B, High-power view of the carcinoma (original magnification �200).

A B

Figure 5. Minimally invasive carcinoma arising in pleomorphic adenoma (hematoxylin-eosin). A, The tumor in this field is composed predominantly of glandularelements. There is a small focus of the residual capsule of pleomorphic adenoma (green arrows), with tumor bulging out into the adjacent lacrimal gland andadipose tissue (black arrows) (original magnification �40). B, High-power view of invasive focus, showing single-layered glands lined by cells with moderatelyatypical nuclei, prominent nucleoli, and occasional mitotic figures (arrows) (original magnification �200).

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-gradecarcinoma infiltrating beyond the capsule of the pleomorphic adenoma on the right is shown (hematoxylin-eosin, original magnification �20). B, Higher-powerview. 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 �200). C, Other fields contain mucinous cells, warranting a diagnosis of mucoepidermoid carcinoma. Mucin is seenwithin cells (periodic acid–Schiff with diastase, original magnification �200).




Mucoepidermoid Carcinoma

We had 2 cases of mucoepidermoid carcinoma (Figure7).One was highly cellular with a large proportion of inter-mediate cells (approximately 50%), poorly formed glan-dular elements with intracellular mucin, and a minor epi-dermoid component. The other tumor was composed ofislands of cystic mucin-filled glands and epidermoid nestswith few intermediate cells embedded in a dense desmo-plastic reaction. Both were grade 3 (high-grade) muco-epidermoid carcinomas.65

Ductal Carcinoma

Ductal carcinoma, defined by its resemblance to mam-mary ductal carcinoma, has only recently been reportedin the lacrimal gland, and to our knowledge 1 of our 2cases was the first reported in the lacrimal gland.18 In thiscase, the tumor was arranged in lobules composed largelyof solid epithelial nests, some of which showed centralnecrosis resembling comedonecrosis of mammary duc-

tal carcinoma in situ. Mitotic figures were common, witha rate of 9 mitotic figures per 10 high-power fields. Thesecond case had similar lobules but comedonecrosis wasmore prominent, and the epithelium had a micropapil-lary architecture (Figure 8). The mitotic rate was lessthan 1 mitotic figure per 10 high-power fields. The origi-nal pathology report diagnosed this as high-grade pap-illary adenocarcinoma.

Myoepithelial and Squamous Cell Carcinoma

We had 1 case each of myoepithelial and squamous cellcarcinoma. The myoepithelial carcinoma had nests of myo-epithelial cells with nuclear atypia, a mitotic rate of 1 mi-totic figure per 10 high-power fields, and no gland for-mation (Figure9). Immunohistochemical staining resultswere positive for keratin, irregularly positive for S-100 pro-tein, and weakly positive for actin. The review diagnosisdiffered from the original diagnosis, which was “malig-nant epithelial neoplasm, most consistent with ACC.” Thesingle case of squamous cell carcinoma had areas of mod-erately well-differentiated epithelial cells with occasionalkeratin pearls, and other foci of more poorly differenti-ated carcinoma, embedded in a desmoplastic stroma. Nogoblet cells or mucin production were seen. There was ahigh mitotic rate of 15 mitotic figures per 10 high-powerfields. The tumor was infiltrative with no capsule. The re-view diagnosis concurred with that of the original.

Unclassifiable Carcinoma

There were 2 cases of carcinoma that did not clearly matchthe features of any entity in the recent lacrimal and sali-vary gland tumor classification schemes. One was a bi-phasic tumor with a hypercellular area containing cells withpleomorphic nuclei and a high mitotic rate of 12 mitoticfigures per 10 high-power fields forming multiple squa-mous eddies as well as a hypocellular area with cells ar-ranged in nests within a hyaline stroma. Neither area hadfeatures to support the original diagnosis of ACC. The sec-ond was a tumor with sheets of eosinophilic, epithelioid

Figure 7. Mucoepidermoid carcinoma, with nests of cells within a reactivestroma. Within the nests, cells are arranged in a “paving stone” configurationadmixed with vacuolated cells (hematoxylin-eosin, original magnification�400). Inset, Mucin is noted within some of the vacuolated cells (periodicacid–Schiff with diastase, original magnification �400).

A B

Figure 8. Lacrimal ductal carcinoma (hematoxylin-eosin, original magnification �200). 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.




cells with pleomorphic nuclei and a high mitotic rate of 6mitotic figures per 10 high-power fields. There was no glandformation and no intracellular or extracellular mucin de-tected by histochemical analysis. A recurrence of the tu-mor excised 2 years later had sheets of cells with a moreanaplastic appearance. The original diagnosis of muco-epidermoid carcinoma was not supported by our review.

COMMENT

EXPANDED EPITHELIAL LACRIMALGLAND TUMOR CLASSIFICATION

The WHO’s classification scheme for lacrimal gland epi-thelial neoplasia14 has provided the context for our un-derstanding of them and included 2 broad categories of“other adenomas” and “other carcinomas.” An updatedpathologic classification is needed to include the recog-nition of the advances in salivary gland histologic clas-sification and the identification of several new entities.In addition, the behavior of various benign and malig-nant lacrimal gland tumors has been further eluci-

dated.10,28,66 Since the expanded salivary gland classifi-cations were published,67-69 the use of the salivary glandclassification for lacrimal gland tumors has been re-ported.5,18-62 In 2006 the AFIP monograph on lacrimalgland tumors17 showed an expanded classification basedon the 1991 WHO classification of salivary gland tu-mors. Our study reviewed 118 cases from 4 institutions,successfully applying the updated salivary gland classi-fication scheme to lacrimal gland tumors and resultingin a revision of the diagnosis in 14% of cases.

Table 5 lists our proposed histologic classificationfor lacrimal gland epithelial neoplasia based on our se-ries and recently published series (Table 6) and casereports.* The most significant aspect of this listing is theincreased diversity of diagnoses and the inclusion ofsubtypes within the diagnostic categories that may in-fluence clinical prognosis. Furthermore, review of thepathologic specimens revealed no consistent sampling,orientation, or pathologic preparation of samples withinand between the various institutions. In response to these

*References 5, 12, 13, 15, 20, 24-26, 28, 44-46, 54, 55, 70.

A B

C D

Figure 9. Myoepithelial carcinoma (hematoxylin-eosin). A, Tumor composed of multiple lobules (original magnification �40). B, Most of the lobules, such asthose 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 �100). C, A lobule of tumor with greatercellularity 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 �400). D, Hypocellular tumor lobules with abundant mucohyaline stroma. Cells in thecenter of the image have clear cytoplasm (original magnification �400).




findings, Rootman and White71 have given recommen-dationsonsampling,orientation, andpreparationofpatho-logic specimens of lacrimal gland tumors.

PROGNOSTIC SIGNIFICANCEOF TUMOR SUBTYPING

PA and CEPA

The 2 major factors determining the prognosis of PA areits likelihood of recurrence and evidence of malignant trans-formation. Recurrence rates as high as 30% have been re-ported in the older literature and literature from main-land China, increasing with the length of follow-up.5,8,72

In contrast, the chance of recurrence is negligible, if noteliminated, by proper initial surgical management includ-ing en bloc excision.6,8,10,12,70,73-75 With a mean (SD) fol-low-up of 4.47 (4.58) years, no recurrences occurred inour series for PA handled in this manner.

The likelihood of malignant transformation of PA ap-pears to be related to tumor age,8,76 with reports of trans-formation in recurrent tumors 40 years or longer after ini-

tial excision.70,74,77 The salivary gland literature reports upto a 9% incidence of transformation over 15 years.76 In ourseries, none of the 3 recurrent tumors had transformed, butpatients presenting with CEPA were significantly older thanthose with PA (median age difference, 20 years). Tumorhyalinization has been shown to correlate with malignanttransformation in the salivary gland.78 Extensive hyalin-ization has been reported previously for lacrimal glandCEPA50,74 and was a prominent feature in 5 of the 9 casesof CEPA in our series. If hyalinization is taken as a sign oftumor age, then this histologic marker supports the asso-ciation between malignant transformation and patient age.

Our series included 5 cases of PA with cellular atypia;all were predominantly cellular tumors and 3 had promi-nent myoepithelial components, 1 of which had origi-nally been diagnosed as CEPA. High cellularity or myo-epithelial prominence was a feature in 3 of the 9 cases ofCEPA in our series. It is unknown whether high cellu-larity, atypia, and myoepithelial prominence may in-crease the likelihood of eventual malignant transforma-tion, and we thus recommend retaining these descriptionsin examining PA.

The extent of invasion of the malignant component ofCEPA in the salivary gland has been shown to be stronglycorrelated with subsequent behavior. A number of studiesof salivary gland neoplasms have demonstrated that tu-mors inwhich themalignant component is confinedwithinthe capsule or shows minimal invasion (variably definedas extension 8 mm,79 5 mm,80 or 1.5 mm81 beyond the PAcapsule)areassociatedwithabenigncourse.There isasinglereport of cervical lymph node metastases from a parotidgland CEPA that was apparently well sampled and showedno capsular invasion.82 Despite this isolated case, we feelthat there is sufficient evidence to support the contentionthat the extent of invasion is an important prognostic find-ing. We suggest adopting the WHO terminology of non-invasive, minimally invasive, and invasive to recognize thesedifferences in outcome. In our series, 3 patients with non-invasive carcinoma and 1 patient with minimally invasivecarcinoma (extension �1.5 mm beyond the PA capsule)had no recurrence, whereas only 1 of 4 patients with in-vasive carcinoma remained disease-free in follow-up.

We required frank cytologic and/or architectural evi-dence of malignancy to render a diagnosis of noninva-sive CEPA. Cases that exhibited nuclear enlargement andpleomorphism without evidence of significantly in-creased mitotic activity or necrosis were considered atypi-cal PAs. We adopted a conservative approach to the di-agnosis of noninvasive CEPA to prevent overtreatmentas noninvasive CEPA has a prognosis similar to that ofPA, with possible rare exceptions.82

Adenoid Cystic Carcinoma

Several studies have shown that solid-pattern ACC por-tends a worse prognosis than the cribriform or tubularpattern for both salivary83-86 and lacrimal87-89 gland tu-mors. Our series shows a similar tendency as patients withtumors with a solid component had a lower survival rate.The absence of a cribriform pattern was also associatedwith poor survival. We recommend retaining histologicpattern descriptions within the ACC category.

Table 5. Proposed Classification for EpithelialLacrimal Gland Tumors

Classification Epithelial Lacrimal Gland Tumor Description

Benign Pleomorphic adenomaPleomorphic adenoma with atypia

MyoepitheliomaOncocytomaCystadenoma

MalignantLow grade Carcinoma ex pleomorphic adenoma/malignant

mixed tumor (where the carcinoma is noninvasiveor minimally invasive [�1.5 mm] as defined bythe World Health Organization classification)

Polymorphous low-grade carcinomaMucoepidermoid, grades 1 and 2Epithelial-myoepithelial carcinomaAcinic cell carcinomaBasal cell carcinomaMucinous adenocarcinoma

High grade Carcinoma ex pleomorphic adenoma/malignantmixed tumor, which includes adenocarcinoma andadenoid cystic carcinoma arising in a pleomorphicadenoma (where the carcinoma is invasive[�1.5 mm] as defined by the World HealthOrganization classification)

Adenoid cystic carcinoma not otherwise specifiedAdenocarcinoma not otherwise specifiedMucoepidermoid, grade 3Ductal adenocarcinomaSquamous cell carcinomaSebaceous adenocarcinomaMyoepithelial carcinomaLymphoepithelial carcinomaOther rare and unclassifiable carcinomasDedifferentiation in any of the above carcinomas

Histologicgrade

Grade cannot be assessedWell differentiatedModerately differentiated, includes adenoid cystic

carcinoma without basaloid (solid) patternPoorly differentiated, includes adenoid cystic

carcinoma with basaloid (solid) patternUndifferentiated




The phenomenon of dedifferentiation in ACC is a re-cently described rare event in tumors of minor and ma-jor salivary glands.90-94 Most commonly, the malignantneoplasm arising within ACC is a high-grade adenocar-cinoma. A small number of undifferentiated carcinomashave been described. In 1 case, the malignant compo-nent was a sarcomatoid neoplasm with focal myoepithe-lial features.90 In 2 of 3 dedifferentiated ACCs, molecu-lar analysis demonstrated mutation of the p53 gene inonly the dedifferentiated component, suggesting a rolefor this oncogene in the pathogenesis.91,93 In most of thereported cases, the finding of dedifferentiation has beenassociated with poor outcome.90,93,94

Two cases of dedifferentiated ACC, to our knowledgethe only known cases of dedifferentiated lacrimal glandACC, were seen in our series. In one case, the patient hasremained disease-free for more than 10 years of follow-up; in the other, the patient died of lung metastases 7.3years after exenteration. Our classification includes thissubtype of ACC as its prognostic significance may be-come evident as additional cases are reported.

PROGNOSTIC SIGNIFICANCEOF RARE DIAGNOSES

Benign Epithelial Neoplasia

Myoepithelioma. Lacrimal gland myoepithelioma hasbeen reported rarely,5,43,58-62 but it is well described in thesalivary gland literature and is widely held to representone end of the spectrum of benign tumors showing epi-thelial and myoepithelial differentiation. Although somestudies suggest it may be aggressive,1,95 others have in-dicated an excellent outcome.96,97 We include it as a sepa-rate entity because of its unusual microscopic appear-ance that may make diagnosis difficult.

Oncocytoma. The few cases of oncocytoma reported inthe lacrimal gland literature, including 1 case in our se-ries, have shown no evidence of recurrence throughoutfollow-up.55,56 Our case was initially reported as a War-thin tumor; thus, with this review, Warthin tumor in thelacrimal gland remains an unreported entity.98 Al-

Table 6. Described Epithelial Lacrimal Gland Tumors and Comparison of Recently Published Case Seriesa

Epithelial LacrimalGland Tumor

Source

Totalb

(N=647)

CurrentStudy

(n=118)

Ni et al,5

1992(n=235)

Riedelet al,55 1990

(n=29)

Paulino andHuvos,20 1999

(n=14)

Wrightet al,28 1992

(n=125)

Hendersonet al,12 1994

(n=58)

McLeanet al,15 1994

(n=38)

Shieldset al,13 2004

(n=30)

Benign epithelial neoplasmsPleomorphic adenoma 57 (48) 140 (60) 12 (41) 3 (21) 78 (62) 25 (43) 19 (50) 11 (37) 345

Pleomorphic adenomawith atypia

5c

Myoepithelioma 1 (1) 2 (1) 8Oncocytoma 1 (1) 2 (7) 5Cystadenomad 1

Malignant epithelial neoplasmsAdenoid cystic carcinoma 38 (32) 68 (29) 9 (31) 9 (64) 38 (30) 22 (38) 13 (34) 14 (47) 211

Dedifferentiated 2c

Carcinoma ex pleomorphicadenoma

9 (8) 25 (11) 3 (10) 2 (14) 6 (5) 10 (17) 5 (13) 4 (13) 64

Circumscribed 3c

Noncircumscribed 6c

Mucoepidermoid carcinoma 2 (2) 2 (1) 3 (21) 1 (1) 2 (3) 1 (3) 14Adenocarcinoma 3 (3) 5 (2) 2 (7) 2 (14) 4 (3) 5 (9) 2 (5) 23Undifferentiated carcinoma 20 (9) 20Primary sebaceous

adenocarcinoma2 (1) 8

Myoepithelial carcinoma 1 (1) 1 (�1) 1 (7) 6Lacrimal duct carcinoma 2 (2) 1 (7) 5Polymorphous low-grade

adenocarcinoma3 (1) 5

Primary squamous cellcarcinoma

1 (1) 1 (1) 1 (2) 4

Oncocytic carcinoma 1 (3) 1 (7) 3Acinic cell carcinomad 3Lymphoepithelial carcinomad 2Carcinosarcoma 1 (�1) 2Basal cell adenocarcinomad 1Cystadenocarcinomad 1Epithelial-myoepithelial

carcinomad1

aValues are expressed as number (percentage) or as number.b Including 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.




though the tumor had a prominent lymphocytic infil-trate suggestive of a Warthin tumor, the oncocytes them-selves were not found in the highly ordered bilayeredarrangement typical of Warthin tumors.68

Malignant Epithelial Neoplasia

Adenocarcinoma. Adenocarcinoma was the third mostcommon lacrimal gland malignant neoplasm, account-ing for 5% of carcinomas in our series and 4% to 13% inother recent series.5,12,15,20,28,55 Generally, lacrimal glandadenocarcinoma carries a dismal prognosis (fatality rang-ing from 50%-80%)8,12,28 and an average survival of 1.5years.12 It is therefore important to distinguish adeno-carcinoma from low-grade polymorphous adenocarci-noma or mucoepidermoid carcinoma (grades 1 and 2),both of which carry a better prognosis.

Mucoepidermoid Carcinoma. The prognosis of muco-epidermoid carcinoma varies with tumor grade, with al-most no recurrence for grades 1 and 2 tumors and greaterthan 50% mortality from grade 2 tumors.35

Ductal Carcinoma. This series includes the first reportedcase of lacrimal ductal carcinoma to our knowledge18 anda second, originally unrecognized case diagnosed as ad-enocarcinoma. Both of these cases were disease-free afterexcision and radiotherapy. Of the 5 other cases reportedin the literature, 3 fared well after a single operation andadjunct radiation.18-23 A fourth patient has had local re-currences with surgery alone,19 and the fifth had lym-phaticmetastasisdetectedprior toscheduledradiotherapy.23

Myoepithelial Carcinoma. Our case of myoepithelial car-cinoma was initially misdiagnosed and is one of few re-ported cases.41,43 With so few cases, it is impossible to drawconclusions regarding clinical behavior. Our patient diedwithin months of diagnosis without definitive treat-ment. In the salivary glands, there is a reported recur-rence rate greater than 50%.99,100

Squamous Cell Carcinoma. Including our single case,there are 8 cases of squamous cell carcinoma of the lac-rimal gland reported in the literature.28-31 No clinical his-tory is available for our case, and no recurrences werenoted in the other published reports.

Carcinosarcoma. Carcinosarcoma, a biphasic tumor com-posed of both carcinoma and sarcoma, is a rare tumor ofthe salivary gland. Approximately 33 cases have been re-ported in the English-language literature, both as a pri-mary malignant neoplasm and as CEPA.69 A single caseis listed without description in a large lacrimal gland tu-mor series.5 No follow-up data were available for our caseof carcinosarcoma that arose in a PA and had spindle cellsarcoma and adenocarcinomatous components.

Malignant Tumor Types Not Seen in Our Series. Iso-lated cases of several other tumor types have been re-ported in the lacrimal gland, including polymorphous low-grade adenocarcinoma,5,40 acinic cell carcinoma,24-27 basalcell adenocarcinoma,54 epithelial-myoepithelial carcino-

ma,42 and cystadenocarcinoma,46 all of which appear to below grade, as well as primary sebaceous adenocarci-noma5,47-53 and lymphoepithelial carcinoma,44,45 both ofwhich are considered high grade. Since completing thisreview, we have seen a single case each of epithelial-myoepithelial carcinoma, acinic cell carcinoma, and myo-epithelial carcinoma in the Orbit Clinic, University of Brit-ish Columbia.

CONCLUSIONS

This study and review of the literature evokes 3 impor-tant conclusions. First, the use of a more diverse classi-fication can be successfully applied to epithelial lacri-mal gland neoplasms. Second, the expanded classificationsystem led to reclassifying 14% of cases in our review.Finally, there are currently no pathologic standards forprocessing and evaluating these lesions.

Submitted for Publication: January 30, 2009; final re-vision received April 2, 2009; accepted April 6, 2009.Author Affiliations: Department of Ophthalmology, Uni-versity of Alberta, Edmonton, Alberta, Canada (Dr Weis);Departments of Ophthalmology and Visual Science(Drs Weis, Rootman, Joly, and White), Pathology andLaboratory Medicine (Drs Rootman, Berean, and White),and Radiology (Dr Lapointe), Vancouver General Hospi-tal and the University of British Columbia, Vancouver,British Columbia, Canada; Department of Ophthalmol-ogy, Security Forces Hospital, Riyadh, Saudi Arabia(Dr Al-Katan); Department of Pathology, Dalhousie Uni-versity, Halifax, Nova Scotia, Canada (Dr Pasternak);Department of Ophthalmology, University of Naples,Naples, Italy (Drs Bonavolontà and Strianese); Depart-ment of Ophthalmology, University of Amsterdam,Amsterdam, the Netherlands (Dr Saeed); Department ofOphthalmology, Kaiser Permanente Medical Center,Harbor City, California (Dr Feldman); and Departmentof Ophthalmology, Siriraj Hospital, Bangkok, Thailand(Dr Vangveeravong).Correspondence: Jack Rootman, MD, 2550 Willow St,Vancouver, BC V5Z 3N9, Canada ([email protected]).Financial Disclosure: None reported.

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CLINICAL SCIENCES Epithelial Lacrimal Gland Tumors

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