ORIGINAL ARTICLE Polymorphous Low-Grade Adenocarcinoma...ORIGINAL ARTICLE Polymorphous Low-Grade Adenocarcinoma The University of Pittsburgh Experience Raja R. Seethala, MD; Jonas

ORIGINAL ARTICLE

Polymorphous Low-Grade Adenocarcinoma

The University of Pittsburgh Experience

Raja R. Seethala, MD; Jonas T. Johnson, MD; E. Leon Barnes, MD; Eugene N. Myers, MD

Objective: To reappraise the clinical and histologic vari-ables associated with a more aggressive outcome in poly-morphous low-grade adenocarcinoma (PLGA).

Design: Retrospective cohort.

Setting: University hospital.

Patients: Twenty-four patients with PLGA treated fromJanuary 1, 1973, through December 31, 2005.

Main Outcome Measure: Analysis of clinical andpathologic variables in 30 biopsy or resection speci-mens from 24 patients.

Results: Only 4 PLGAs were not initially diagnosed assuch. However, 8 non-PLGAs (thus excluded) were in-correctly diagnosed as PLGA. Most carcinomas (14 of 24[58%]) were palatal. Recurrent carcinomas had a signifi-cantly higher mitotic rate (2.7 mitoses per 10 high-power fields) compared with primary tumors (1.2 mito-

ses per high-power fields, P=.046), and 3 of 7 (43%)recurrences showed progression to an intermediate-grade histologic type. No patient died of disease. Me-dian disease-free survival was 12.8 years. Four of 24 pa-tients (17%) had regional lymph node metastases, 3 withcarcinomas of the base of the tongue. One PLGA metas-tasized to the subcutaneous tissue of the face, orbit, andlungs at 19.6 years. An extrapalatal site was the only sig-nificant determinant of disease-free survival (P=.03).

Conclusions: Diagnosis of PLGA remains a challenge.Extrapalatal carcinomas appear to behave in a more ag-gressive fashion than those of the palate, and cancer aris-ing from the base of the tongue frequently metastasizesto the cervical lymph nodes, suggesting a role for neckdissection in these patients. Recurrent cancers show evi-dence of histologic progression, justifying an aggressiveapproach to achieving initial complete excision.

Arch Otolaryngol Head Neck Surg. 2010;136(4):385-392

T HE TERM POLYMORPHOUS

low-grade adenocarcinoma(PLGA) was introduced byEvans and Batsakis1 in 1984to describe a cytologically

bland but architecturally diverse malig-nant neoplasm of minor salivary gland ori-gin that had been previously recognizedas lobular carcinoma,2 terminal duct car-cinoma,3 and low-grade papillary adeno-carcinoma.4 Despite the fact that this termhas existed for nearly 25 years, PLGA re-mains a diagnostic challenge.5 Althoughoriginally described as cancer of a minorsalivary gland origin in the oral cavity,PLGA has also been described at severalsites outside the oral cavity, including ma-jor salivary glands.6-8 Polymorphous low-grade adenocarcinoma should be thoughtof as distinct from adenoid cystic carci-noma, a common differential diagnosticconsideration, because of the more relent-less and aggressive behavior of the lat-ter.9 However, with sufficient long-termfollow-up,10 the recurrence rate for PLGAis high at almost 33%, and distant metas-

tasis or even transformation to a high-grade adenocarcinoma11,12 has been noted.The surprisingly aggressive behavior ofthese adenocarcinomas in some of our pa-tients despite the term low grade promptedthe present study.

Perhaps the oldest controversy iswhether to consider papillary predomi-nant carcinomas as variants of PLGA oras separate tumors altogether.10,13-15 Re-gardless of classification, predominantlypapillary cancers have been reported tohave a more aggressive biological behav-ior, although this has been validated inonly 1 series.10 Despite the reported fre-quent occurrence of these tumors,16,17 largeseries in which patients were treated at asingle institution are rare.5,7,10 To reap-praise and validate prior findings and con-cepts, we present the clinicopathologicfindings of our PLGA cohort.

METHODS

The Head and Neck Oncology Registry of theUniversity of Pittsburgh School of Medicine,

Author Affiliations:Departments of Pathology(Drs Seethala and Barnes) andOtolaryngology (Drs Johnsonand Myers), University ofPittsburgh School of Medicine,UPMC Presbyterian UniversityHospital, Pittsburgh,Pennsylvania.

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Pittsburgh, Pennsylvania, was assessed retrospectively. This re-view was approved by the University of Pittsburgh institu-tional review board. All patients classified as having PLGA werereevaluated by one of us (R.R.S.). Material from patients treatedin our institution from January 1, 1973, through December 31,2005, was available. For patients who presented after the rec-ognition of PLGA at our institution (in 1985), the search termsused included the following: polymorphous low-grade adeno-carcinoma; adenocarcinoma, not otherwise specified (NOS); pap-illary adenocarcinoma; and cribriform adenocarcinoma of tongue.For patients who presented before the use of the term PLGA,search terms included the following: adenocarcinoma, papil-lary adenocarcinoma, adenoid cystic carcinoma, terminal duct car-cinoma, pleomorphic adenoma, and monomorphic adenoma.

The histologic definition of PLGA used for inclusion in thisstudy was a modification of the World Health Organization defi-nition,16 with additional descriptors derived from the histo-logic variables gathered from previous series:1,10,15 “a mono-phasic malignant salivary gland adenocarcinoma withpolymorphous growth patterns (tubular, cribriform, papillaryand/or solid), but bland, monomorphic cytonuclear features in-cluding characteristic ovoid nuclei with open vesicular chro-matin.” Carcinomas arising in the major salivary glands, phar-ynx, and base of the tongue that fulfilled this definition werealso included.

Gross and histologic variables were recorded. The solidand papillary (because of its reported importance)10 compo-nents were evaluated as separate variables in all patients andestimated to the nearest fifth percentile. Mitotic counts wererecorded as number per 10 high-power fields (HPF) (�40mi-croscopic objective lens). Other oncologically relevant histo-logic variables, including the status of the margins of resec-tion, perineural invasion (PNI), angiolymphatic invasion(ALI), and bone invasion, were recorded as well. For patientswith PNI, the presence of intraneural invasion or large nervePNI was also recorded. A large nerve was defined arbitrarily asa nerve with a cross-sectional diameter of 0.25 mm or larger(roughly half of 1 HPF, �40 microscopic objective lens).These histologic variables were linked with clinical anddemographic data, including age at diagnosis, sex, treatment,

lymph node status, locoregional recurrence, distant metasta-sis, and survival.

Statistical analyses were performed using SPSS statistical soft-ware, version 14.0 (SPSS Inc, Chicago, Illinois). For papillarycomponents, solid percentiles, and mitotic indices, the non-parametric Mann-Whitney test was used for comparison be-tween the 2 groups. For comparison of frequencies of categori-cal variables between groups, a Fisher exact test was used witha 2-tailed distribution. Overall survival was reported descrip-tively, and the arithmetic median survival was used. Disease-free survival (DFS) was assessed using the Kaplan-Meier methodwith groupwise comparisons made via a univariate Cox pro-portional hazards model. The Kaplan-Meier median (the timeat which 0.5 patient remained disease free) was reported. P� .05was considered statistically significant.

RESULTS

INITIAL DIAGNOSIS

Twenty-eight patients were initially diagnosed as hav-ing PLGA. Eight of 28 patients diagnosed as having PLGA(29%) were excluded from this study. Their tumors didnot fulfill our definition of PLGA and were compatiblewith other specific salivary gland malignant neoplasmsin 5 patients. Diagnoses for these patients included 3 epi-thelial-myoepithelial carcinomas (Figure 1); 3 low-grade to intermediate-grade adenocarcinomas, NOS; 1 ad-enoid cystic carcinoma; and 1 low-grade salivary ductcarcinoma (also known as low-grade cribriform cystad-enocarcinoma). The low-grade salivary duct carcinomawas seen at our institution before the description of thisentity in 1996.18

Four additional patients treated at our institution werenot initially diagnosed as having PLGA but, on review,fulfilled the criteria for PLGA. Three of these 4 patients(75%) had their conditions diagnosed before 1984, theyear the term PLGA was first used.1 The original diag-noses for these patients included 1 adenocarcinoma, NOS;1 pleomorphic adenoma; 1 monomorphic adenoma; and1 mucoepidermoid carcinoma. Thus, in total, 24 pa-tients were satisfactorily diagnosed as having PLGA.

Fourteen of these 24 patients were initially diag-nosed as having PLGA at outside institutions. Of these,6 (43%) were diagnosed as having PLGA, whereas otherdiagnoses were 4 adenocarcinomas, NOS; 2 adenoid cys-tic carcinomas; 1 mucoepidermoid carcinoma; and 1 pleo-morphic adenoma.

CLINICAL AND DEMOGRAPHIC FEATURES

The mean age at diagnosis was 59.4 years (range, 26-85years). There was a female predilection with a female tomale ratio of 2.4:1.0. The site distribution was as fol-lows: palate, 14 (hard palate, 9; and soft palate, 5); baseof the tongue, 3; nasopharynx, 3; upper lip, 2; tonsil, 1;and parotid, 1.

PATHOLOGIC FEATURES: PRIMARY TUMORS

The slides and reports from the primary cancers, includ-ing cancers originally diagnosed at an outside hospital,

Figure 1. A carcinoma commonly misclassified as polymorphous low-gradeadenocarcinoma (hematoxylin-eosin staining used in both parts of Figure).This parotid epithelial-myoepithelial carcinoma shows a solid growth patternwith scattered tubules and mostly shows elongated nuclei with openchromatin and delicate nuclear membranes reminiscent of polymorphouslow-grade adenocarcinoma (original magnification �200). However, even atthis magnification the tumor is biphasic, consisting of a clear cell populationsurrounding compressed, lightly eosinophilic cuboidal epithelium-linedtubules (arrows). Inset, This dual population is readily apparent on highermagnification, and there are central nucleoli evident in the ductal componentbut not the outer myoepithelial component (original magnification �400).




were available in 23 of 24 patients; 1 patient had onlythe recurrences available for review. A gross measure-ment of tumor size was available in 16 patients. The meansize of the tumor was 2.4 cm (range, 1.1-6.8 cm). Themean size of extrapalatal tumors (3.6 cm; range, 2.2-6.8cm) was significantly greater than that of palatal tumors(1.4 cm; range, 1.1-1.8 cm) (P=.01).

Margin status was available in 20 patients. Final mar-gins (even after reexcision of initially positive margins)were positive in 9 patients (45%) (palate, 5; nasophar-ynx, 2; base of the tongue, 1; and parotid, 1). Gross and/ormicroscopic bone invasion was present in 6 of 23primary tumors (26%) overall. All 3 nasopharyngealPLGAs invaded bone (Figure 2A), whereas 3 of 13 pri-mary palatal tumors (23%) invaded bone.

Overall, PNI was identified in 12 of 23 tumors (52%)(Figure 2B). Relative frequencies based on site are as fol-lows: palate, 8 of 14 (57%); upper lip, 1 of 2 (50%); baseof the tongue, 1 of 3 (33%); nasopharynx, 1 of 3 (33%);and parotid, 1 of 1 (100%). Seven of 12 PLGAs with PNI(58%) showed large nerve involvement: palate, 3; baseof the tongue, 1; nasopharynx, 1; upper lip, 1; and pa-rotid, 1. Three of 12 tumors with PNI (25%) also showedintraneural invasion (palate, 2; and parotid, 1). Angio-lymphatic invasion was identified in 7 of 23 patients (30%)overall (Figure 2C). Site distribution was as follows: baseof the tongue, 3 of 3 (100%); upper lip, 2 of 2 (100%);nasopharynx, 1 of 3 (33%); and palate, 1 of 13 (8%). The1 parotid tumor in this study did not show angiolym-phatic invasion.

Palatal PLGA had a slightly higher prevalence of PNI(58%) than extrapalatal PLGA (40%). Extrapalatal car-cinomas had a significantly higher prevalence of ALI(60%) than those of the palate (8%) (P=.02). The meanmitotic count for primary PLGA was 1.3 per 10 HPF(range, 0-3.0 per 10 HPF). Mean mitotic counts for pala-

tal PLGA (1.2 per 10 HPF) were similar to those for ex-trapalatal PLGA (1.3 per 10 HPF).

All carcinomas showed a mixture of tubular, cribri-form, and papillary growth patterns (Figure 3A-C). Themean solid component (Figure 3D) overall was 47%(range, 0%-90%). Extrapalatal PLGA had only a slightlyhigher mean solid component (49%) than palatal PLGA(45%). The mean papillary component overall was 11%,although the range was wide (0%-90%). ExtrapalatalPLGA had a slightly higher mean papillary component(18%; range, 0%-90%) than palatal PLGA (6%; range, 0%-40%). These differences were not statistically signifi-cant. However, more specific subsite stratification wasnot attempted because of the small sample size. Never-theless, descriptively, all PLGAs of the base of the tonguewere predominantly solid and papillary and showed byfar the highest mean papillary composition (47%; range,20%-90%) of all sites. All nasopharyngeal PLGAs werepredominantly solid to cribriform with only focal pap-illary areas (mean, 13%; range, 10%-20%).

CarcinomaswithALIhadasignificantlyhigherpercent-ageofpapillaryareas(mean,30%;range,0%-90%)thanthosewithout (mean, 3%; range, 0%-20%) (P=.003). All carci-nomaswithmore than20%papillaryareas showedALI.Nosignificant correlations were noted between solid and pap-illary percentage and PNI of any type or bone invasion.

PATHOLOGIC FEATURES: RECURRENCES

Seven of 24 patients (29%) had a local recurrence.Three patients had regional recurrences in cervicallymph nodes (13%), 2 of whom had local recurrences aswell, yielding a total locoregional recurrence rate of33% (8 patients). Slides of these recurrences were avail-able in 7 of 8 patients, from whom 6 paired primary tu-mors were also available. The mean percentage of solid

A B C

Figure 2. Forms of invasion seen in polymorphous low-grade adenocarcinoma (PLGA) (hematoxylin-eosin staining used in all parts of Figure). A, NasopharyngealPLGA demonstrating bone invasion (original magnification �40). B, This PLGA arising in the parotid gland demonstrates invasion around this large nerve (originalmagnification �200). C, This carcinoma of the lip shows a large tumor embolus (original magnification �200).




areas in recurrent disease was similar to primary disease(46%; range, 20%-80%). The mean percentage of thepapillary component was, however, increased (26%;range, 0%-70%) in recurrence disease, although thisdifference was not significant. Mean mitotic countswere, however, significantly higher in recurrent disease(2.7 per 10 HPF; range, 1-5 per 10 HPF) (P=.046). Inaddition, 3 of 7 recurrent cancers showed evidence ofhistologic progression to an intermediate-grade mor-phologic type (Figure 4). These 3 patients constitutedthe higher end of the mitotic range in recurrent cancers(mean, 3.7 per 10 HPF; range, 3-5 per 10 HPF), with 1patient even showing atypical mitoses. No recurrentdisease had high-grade transformation based on criteriareported previously.12

TREATMENT, OUTCOME,AND CLINICOPATHOLOGIC CORRELATIONS

Nineteen patients received primary treatment within ourhealth care system. The other 5 were initially treated else-where. Initial treatment included surgery in 19 patients,surgery and adjuvant radion therapy in 4 patients, andradion therapy alone in 1 patient.

One patient was lost to follow-up. Seven of 22 pa-tients (32%) died (median time, 13.7 years; range, 1.2-16.3 years), but no deaths were attributed to PLGA. Me-dian follow-up on surviving patients was 6.6 years (range,2.7-35.1 years). As noted herein, the locoregional recur-rence rate was 33% (8/24), with a median DFS of 12.8years. Four of 24 patients (17%) had lymph node me-tastases, 1 on presentation and 3 as regional recurrencesas mentioned herein. One patient with the palate as theprimary site had a recurrence on the soft palate 7 yearslater and metastases to the subcutaneous tissues of theface, orbit, and lungs at 19.6 years (Figure 5).

Univariate correlations with DFS are summarized inthe Table. Site was the only significant determinant ofDFS in this small series (P=.03). Although patients withpositive margins, large nerve PNI, bone invasion, and ahigh percentage of papillary component showed a shorterDFS, differences were not statistically significant.

COMMENT

Polymorphous low-grade adenocarcinoma remains a chal-lenge in diagnosis and management almost a quarter-

A B

C D

Figure 3. Common patterns in polymorphous low-grade adenocarcinoma (hematoxylin-eosin staining used in all parts of Figure). A, Tubular growth in thiscarcinoma of the palate (original magnification �200). B, Cribriform growth in this tumor of the upper lip with adenoid cysticlike cylindrical hyaline matrixdeposition (original magnification �200). C, Papillary growth in this tumor of the palate (original magnification �200). D, Tumor of the base of the tongue withsolid areas (original magnification �200).




century after its initial description.1 However, our seriesdemonstrates an improved awareness of PLGA as a di-agnostic entity. Only 4 PLGAs were initially diagnosedas another entity by us, and 3 of these were diagnosedbefore the description of this entity in 1984.1 This in-creased awareness is also reflected in the original diag-noses from outside institutions in which almost half werecorrectly identified as PLGAs, which is an improvementcompared with the 22% reported by Pogodzinski et al.5

In contrast, however, another challenge has emerged:more than one-fourth of the patients originally diag-nosed as having PLGA actually had other salivary glandmalignant neoplasms. Thus, we report for the first time,to our knowledge, a more frequent overdiagnosis of thisentity rather than the underdiagnosis that is tradition-ally reported.5,15 Our analysis of this series demon-strates 2 fundamental patterns of error. The first is thefailure to differentiate truly biphasic tumors (namely, ad-enoid cystic carcinoma and epithelial-myoepithelial car-cinomas) from PLGAs. Although the PLGA has a mul-titude of patterns, it is a monophasic tumor. Althoughmyoepithelial differentiation in PLGA is described, tran-sition to these areas is subtle and gradual, typically only

discernible focally on immunohistochemical stains.19 Incontrast, a luminal ductal and abluminal myoepithelialconfiguration is integral to adenoid cystic carcinoma andepithelial-myoepithelial carcinoma and is typically evi-dent on routine histologic examination. The second pat-tern of error is the failure to recognize the characteristicnuclear features of PLGA. All cancers reclassified as ad-enocarcinoma, NOS did not have the monomorphic ovoidand open nuclei with delicate nuclear membranes thatessentially define PLGA. To prevent these errors, we sug-gest that the monophasic nature and classic nuclear fea-tures of PLGA be emphasized in the working definitionfor this entity. The remaining patient misdiagnosed ashaving a PLGA had a low-grade salivary duct carci-noma, which was not recognized as a distinct entity un-til the description by Delgado et al18 in 1996. Of note,three-quarters of these tumors erroneously diagnosed asPLGA were of parotid gland origin, suggesting that trueparotid PLGAs are indeed rare.

For the remaining cancers in the PLGA category, find-ings were generally in keeping with prior series.7,10,15 De-spite the innocuous name, PLGA is indeed a malignantneoplasm of salivary gland origin that, in our series,

A B

C D

Figure 4. Two paired cancers with histologic progression (hematoxylin-eosin staining used in all parts of Figure). A, A primary polymorphous low-gradeadenocarcinoma (PLGA) in the parotid gland showing typical nuclear features (original magnification �400). B, The recurrence of this carcinoma shows morepronounced nuclear enlargement, coarser chromatin, and central nucleoli (original magnification �400). C, A primary PLGA in the palate with papillary growth butmonomorphic nuclei (original magnification �400). D, The recurrence shows a transition from a more typical morphologic type to scattered solid areas withenlarged nuclei, enhanced clearing, and increased mitotic activity (original magnification �400). A tripolar mitosis is highlighted by the arrow.




showed a locoregional recurrence rate of more than 30%.Lymph node metastases were uncommon, and distant me-tastases were rare. Primary treatment was surgical. Be-cause few patients received initial radiotherapy, the im-pact of this treatment modality is unclear. However, ourlimited findings of recurrence despite radiotherapy sug-gest it is likely of little benefit, as noted in prior series.15

Similar to what has been reported previously, PLGA inour series most commonly occurred in the palate. How-ever, the site distribution was slightly skewed toward un-usual locations, such as the base of the tongue and thenasopharynx, probably because ours is a tertiary care cen-ter. These extrapalatal PLGAs appeared to display moreaggressive features, clinically and pathologically.

Our subset of 3 patients with PLGA of the nasophar-ynx represents the largest series to date. Skeptics may sug-gest that our patients have nasopharyngeal papillary ad-enocarcinomas, which are distinct carcinomas notincluded in the PLGA family.20 However, all our pa-tients had disease that fulfilled the morphologic criteriawe delineated herein and, in addition, did not have pap-

illary-predominant disease. These cancers characteristi-cally invaded bone and invariably recurred locally. Clearmargins could not be obtained in any patients in whichthe original margin status was known, which likely con-tributed to this high recurrence rate. Two patients re-ceived radiotherapy but nevertheless experienced dis-ease recurrence. Although any conclusions aboutnasopharyngeal PLGAs are limited based on these fewpatients and those described previously,8 PLGAs arisingin the nasopharynx are still intrinsically low grade withlow metastatic capacity. Because of the propensity of thesetumors for bone involvement and the limited surgical ex-posure and anatomic limitations, these tumors remain achallenge in surgical management. Radiotherapy is cur-rently of unproven benefit.

The PLGAs that arise in the base of the tongue alsorepresented an interesting subset. Michal et al21 sug-gested that cribriform adenocarcinoma of the tongue wasa more appropriate designation for their series of 8 car-cinomas of the base of the tongue that were initially di-agnosed as PLGA. The authors’ justification was that thesolid and microcystic cribriform pattern was suffi-ciently unique to recognize even without site designa-tion and that these tumors, unlike PLGAs, invariably me-tastasized to lymph nodes. In our 3 patients, a solid andpapillary architecture was the norm. In addition, we foundno histologic novelty in the patterns seen in tumors inthe base of the tongue compared with other sites. Simi-lar to cribriform adenocarcinomas of the tongue, how-ever, all patients showed lymph node metastases on pre-sentation or as regional recurrences. Because none of ourpatients’ conditions fit the description of cribriform ad-enocarcinoma of the tongue, we cannot confirm or re-fute the validity of this entity. However, we contend thatit is the site of origin of the base of the tongue that im-

A B

Figure 5. One patient with the palate as the primary site had a recurrence on the soft palate 7 years later and metastases to the subcutaneous tissues of the face,orbit, and lungs at 19.6 years. A, Computed tomogram demonstrating multiple pulmonary nodules (arrows point to right and left lung nodules). B, Fine needleaspiration biopsy specimen demonstrated metastatic polymorphous low-grade adenocarcinoma to the lung (Papanicolaou, original magnification �400). Thiscluster of cells shows the characteristic ovoid nuclei with delicate chromatin.

Table. Univariate Correlation of Clinicopathologic VariablesWith Disease-Free Survival

Variable Hazard Ratio (95% CI) P Value

Site (palatal vs extrapalatal) 10.68 (1.28-88.72) .03ALI 5.22 (0.98-27.89) .05Margin status 4.48 (0.46-43.43) .20Large nerve PNI 1.93 (0.42-8.87) .40Bone invasion 1.71 (0.38-7.67) .48Papillary component 1.01 (0.99-1.03) .41

Abbreviations: ALI, angiolymphatic invasion; CI, confidence interval;PNI, perineural invasion.




parts the propensity for lymph node metastasis rather thanthe tumor morphologic type. This is not a unique con-cept because squamous cell carcinoma of the base of thetongue with its rich lymphatic network has a relativelyhigh propensity for lymph node metastases.22,23 Other sali-vary gland carcinomas involving the base of the tonguemay also have an aggressive course.24 From a practicalstandpoint, current evidence suggests that a cancer of thebase of the tongue in the PLGA family, regardless of itsname, will metastasize to cervical lymph nodes. The factthat most of the lymph node metastases in our series werefound as recurrence suggests that they were occult. Anelective neck dissection should be performed even in aclinically node-negative patient with a PLGA of the baseof the tongue.

Evaluations of prognostic markers in PLGA are diffi-cult based on the numbers available in most series, in-cluding our own. In addition, many of these variables arelikely interdependent. For instance, we found that allPLGAs with papillary components comprising greater than20% of tumor showed ALI. As noted herein, the distinc-tion between palatal and extrapalatal sites appears to affectoutcome the most. Positive margins and bone invasionaffected DFS, but the differences were too small to be sig-nificant in this series. Similarly, although ALI, papillary-predominant histologic type, and PNI predicted a shorterDFS, none of these factors were statistically significant,perhaps in a larger series similar to that of Evans andLuna,10 statistical significance; for these variables may bereached.

Similar to primary PLGA, recurrences are typically slowgrowing and often amenable to reexcision with subse-quent favorable outcomes. Only 1 patient in our serieshad multiple recurrences and a distant metastasis. Ac-cording to the literature, distant metastases are excep-tionally rare, with the lung being the most common siteinvolved. Metastases usually occurred only after poor lo-cal control.5,10,15 Although biologically, recurrent tu-mors appear to retain their indolence, pathologic fea-tures of recurrent PLGA have not been well characterized.Cases of transformation to a high-grade adenocarci-noma have been reported, suggesting the capacity for his-tologic transformation, but this appears to be a rareevent11,12; no carcinomas in our series fit this descrip-tion. However, we noticed that almost half of the recur-rences in our series progressed to an intermediate-grademorphologic type with more nuclear size variation,nucleolation, and an overall higher mean mitotic rate. Ofnote, the 1 patient with lung metastases had been pre-ceded by 2 local recurrences during a 19-year period withintermediate-grade morphologic type. Thus, the poten-tial for histologic progression is a legitimate concern indisease recurrences. Because adjuvant therapy is un-proven at best, adequate surgical excision even of recur-rent disease may be the only useful safeguard against high-grade transformation.

In summary, familiarity with PLGA has increased dur-ing the past few decades, although now the current diag-nostic challenge may be the prevention of this entity frombecoming a default diagnosis for all low-grade carcino-mas of salivary gland origin. Although polymorphous inpattern, this carcinoma is actually cytologically mono-

typic with pathognomonic delicate vesicular nuclei. Poly-morphous low-grade adenocarcinoma may follow an in-dolent course with a favorable outcome, although withadequate follow-up, recurrence may be encountered in al-most one-third of patients. This finding suggests the needfor lifelong monitoring. Limited experience with radio-therapy fails to support its usefulness.

Extrapalatal PLGAs, particularly those of the base ofthe tongue and nasopharynx, appear to be more aggres-sive, and carcinomas of the base of the tongue may pre-sent with cervical lymph node metastases. Our patientsdemonstrate sufficient morphologic overlap to suggestthat site-specific differences in PLGA behavior may havean anatomic basis (with regard to resectability and ac-cess to lymphatics) rather than a taxonomic one. Carci-nomas with positive margins, bone invasion, papillary-predominant growth, and/or ALI may be more aggressiveas well, although the size of our series probably pre-vented these variables from achieving statistical signifi-cance. Almost half the recurrent PLGAs showed some de-gree of histologic progression, supporting the importanceof adequate excision of even recurrent disease to pre-vent the rare but catastrophic outcome of high-grade trans-formation.

Submitted for Publication: April 27, 2009; final revi-sion received June 24, 2009; accepted November 6, 2009.Correspondence: Raja R. Seethala, MD, Department of Pa-thology, University of Pittsburgh School of Medicine,UPMC Presbyterian University Hospital, 200 Lothrop St,Ste A614, Pittsburgh, PA 15213 ([email protected]).Author Contributions: All authors had full access to allthe data in the study and take responsibility for the in-tegrity of the data and the accuracy of the data analysis.Study concept and design: Seethala, Johnson, Barnes, andMyers. Acquisition of data: Seethala. Analysis and inter-pretation of data: Seethala and Johnson. Drafting of themanuscript: Seethala. Critical revision of the manuscriptfor important intellectual content: Seethala, Johnson,Barnes, and Myers. Statistical analysis: Seethala. Admin-istrative, technical, and material support: Johnson andMyers. Study supervision: Johnson and Barnes.Financial Disclosure: None reported.Previous Presentation: This study was presented at theAmerican Head and Neck Society 2009 Annual Meet-ing; May 30, 2009; Phoenix, Arizona.

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ORIGINAL ARTICLE Polymorphous Low-Grade Adenocarcinoma...ORIGINAL ARTICLE Polymorphous Low-Grade Adenocarcinoma The University of Pittsburgh Experience Raja R. Seethala, MD; Jonas