clinicopathologic conference cases presented at the annual ... · oral and maxillo facial pathology...

Vol. - No. - Month 2014

Clinicopathologic conference cases presented at the Annual Meetingof the American Academy of Oral and Maxillofacial Pathology,June 14-19, 2013

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Fig. 1-1. A, Clinical mirror image of patient’s left tongue dem-onstrates a 2.5 � 2-cm well-delineated plaque with a yellow hueand subtle verrucous architecture. Located anteriorly on the lateralborder of the tongue is a homogenous leukoplakia. B, Clinicalimage of patient’s left tongue 1 week after biopsy. Biopsy wastaken from the center of the leukoplakia and the anterosuperiormargin of the well-delineated plaque with a yellow hue.

CLINICOPATHOLOGIC CONFERENCE CASE 1: INCI-DENTAL FINDING ON LEFT POSTERIOR TONGUETM Gibson, BD Martin, University of MissourieKansas City,School of Dentistry, Kansas City, MO, USA; David GrantMedical Center, Travis Air Force Base, CA, USA

Clinical Presentation: An asymptomatic 67-year-old Indianman presented for routine dental care. His medical history wassignificant only for insulin-dependent diabetes and remote cere-brovascular accident. The patient denied history of cigarettesmoking, betel nut use, and alcohol consumption.

On initial examination, a sessile, uniformly elevated plaqueof the left posterolateral tongue was observed, measuringapproximately 2.5 � 2 cm (Figure 1-1, A). The lesion exhibited ayellowish hue and a subtle verrucous architecture. The area wasnontender to palpation. The entirety of the well-delineated le-sion’s anterior border was visible within the oral cavity.

In addition to the aforementioned lesion, the clinical exam-ination also found a large unrelated homogeneous white plaque ofthe left lateral tongue. A biopsy was taken of the leukoplakia,which was diagnosed as hyperparakeratosis without dysplasia.

Differential Diagnosis: The list of differential diagnosesfor epithelial lesions affecting the posterior tongue is quitebroad. Considerations including potentially malignant condi-tions, neoplastic conditions, and developmental anomalies wereentertained.

Any well-defined plaque of the posterolateral tongue, a high-risk site, with associated architectural and color change, should beinvestigated to rule out an epithelial process such as oral epithelialdysplasia (OED) or oral squamous cell carcinoma (OSCC). OED,a potentially malignant condition, typically presents as anasymptomatic erythroplakia or leukoplakia.1,2 Architectural al-terations range from nearly imperceptible in early lesions to apapillary or nodular appearance in later-stage lesions. As alter-ations in color, texture, ulceration, and firmness are observed,they raise the index of suspicion that the preneoplastic OED hastransformed into OSCC.3 OED cannot be completely excludedclinically, but the lack of ulceration induration argues againstOSCC.

Oral mucosal lymphangioma is a hamartomatous tumor oflymphatic tissue.4 This benign proliferation is usually diagnosedat a young age, with 50% occurring congenitally and theremainder typically discovered by the third year of life.5,6 Nearly75% of all lymphangiomas are found in the head and neck, withoral lesions most often arising on the anterior two-thirds of thetongue.3,6 There is no gender predilection.5 Lymphangiomas ofthe tongue can be situated deep or superficially, with the moresuperficial lesions presenting as a pebbly or cluster-like accu-mulation of translucent to red-purple vesicles. These changes arecommonly described as having a “frog egg” or “tapioca pudding”appearance. Although the tongue is a common location for orallymphangiomas, the patient’s age and lack of vesicular-appearinglesional tissue was inconsistent with this diagnosis.

Linear epidermal nevus is a hamartomatous lesion of theskihat rarely involves the oral cavity.7 The prevalence is

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estimated at 1:1000 live births, with nearly equal gender distri-bution.7,8 In contrast to our patient’s lesions, oral linear epidermalnevi (OLEN) present during childhood and typically stabilizeduring adolescence. Clinically they appear as verrucous papulesand plaques and follow a linear distribution. Unlike the skin le-sions, which are usually pigmented, OLEN tend to range fromnormal to yellow-white. Although oral involvement is rare, thetongue is the most common location, and solitary oral lesionshave been reported.7-10

Acanthosis nigricans (AN) is an acquired cutaneous alter-ation associated with a number of systemic conditions includinggastrointestinal adenocarcinoma and insulin-resistant diabetesmellitus.3 Because of these associations, AN is generallyobserved in older patients. Oral involvement occurs in 15% to40% of cases, with the higher end of the spectrum associated withmalignancy.11 Oral involvement presents as finely papillary sur-face alterations that generally lack pigment as seen in the

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Fig. 1-2. Photomicrograph of a representative histology sectionshowing hyperplastic stratified squamous epithelium withplunging parakeratin (hematoxylin-eosin, original magnification�100).

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Fig. 1-4. A collection of foamy histiocytes is noted between therete ridges (hematoxylin-eosin, original magnification �200).

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cutaneous lesions.11 The tongue is a common location.3 To helpmanage his diabetes mellitus, he was taking metformin at the timeof diagnosis. Interestingly, metformin is used to manage ANassociated with insulin resistance, and thus argues against thisbeing diabetes-associated AN.12

Verruciform xanthoma (VX) is a benign hyperplastic con-dition most often affecting the oral mucosa, although skin andgenitalia may be involved.13 The cause is unknown but may bereactive or immune related. VX generally arises in the fifth andsixth decades, slightly more often in men. Intraorally it presentsmost often on the gingiva and alveolar mucosa.14 VX tends to besessile, slightly elevated with subtle papillary surface alterations,

Fig. 1-3. Photomicrograph of a representative histology sectionshowing collection of foamy histiocytes located between reteridges. Plugging of the parakeratin is also noted (hematoxylin-eosin, original magnification �200).


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well-delineated, and ranging in color from red to yellow.14,15

Most oral lesions are 2 cm or smaller, although lesions up to 4 cmhave been reported.3 The overall clinical presentation of thisplaque of the posterolateral tongue was most consistent with adiagnosis of VX.

Diagnosis and Management: The patient subsequently hadan incisional biopsy performed of the anterior leukoplakic lesionand the posterior papillary sessile lesion with a yellowish hue (seeFigure 1-1, B).

The histopathology of the lesion revealed papillary para-keratinized oral epithelium with elongated rete ridges and para-keratin plugging of the crypts located between the epithelialprojections (Figures 1-2 and 1-3). In the connective tissue papillaewere large macrophages with granular cytoplasm and roundnuclei (Figure 1-4). These macrophages have been shown tocontain lipids16 and are often referred to as xanthoma cells. Theaccumulation of lipid contributes to the yellowish clinicalappearance.

The final diagnosis was verruciform xanthoma. Althoughlesional tissue of the verruciform xanthoma remains, no furthertreatment is planned. Malignant transformation of verruciformxanthoma has not been reported.3 The leukoplakic area willcontinue to be followed clinically.

Discussion: Verruciform xanthoma is a hyperplastic muco-cutaneous condition first described in the oral cavity by Shafer in1971.3 It most often occurs on the masticatory mucosa surfaces,with the gingiva being the most frequent site of occurrence.16

The penis, scrotum, and vulva have been reported as extraorallocations.15 It is not uncommon for a VX to be clinicallymistaken for a squamous papilloma, condyloma acuminatum, oreven a squamous cell carcinoma.3 Verruciform xanthomas aremore often found in middle-aged adults, with a slight malepredilection.

A definitive etiology for verruciform xanthoma has yet to bedefined. The human papillomavirus has been implicated, butonly a few cases have been positive for human papillomavirusand a viral pathogenesis has yet to be established. The most

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prevalent and accepted theory is that verruciform xanthomaoccurs as a result of an inflammatory response to localizedepithelial damage or trauma or an unusual reaction. VX may beseen in association with conditions involving epithelial distur-bances, such as lichen planus, lupus erythematosus, epi-dermolysis bullosa, epithelial dysplasia, squamous cellcarcinoma, pemphigus vulgaris, warty dyskeratoma, and graft-vs-host disease.3

Verruciform xanthomas are not associated with diabetes, li-poprotein metabolism, hyperlipidemia, or any other metabolicdisorder. Xanthomatous infiltrates of the skin are usually asso-ciated with lipoprotein metabolism disorders. This does notpertain to verruciform xanthomas of the skin; lipid metabolism isusually normal.13

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Fig. 2-1. Multiple well-defined punctate lesions are noted. Asingle, well-defined area of exposed bone is present on thegingival mucosa adjacent to the left maxillary central incisor. A,Right side. B, Left side.

References1. Petti S. Pooled estimate of world leukoplakia prevalence: a

systematic review. Oral Oncol. 2003;39:770-780.2. Reibel J. Prognosis of oral pre-malignant lesions: Signifi-

cance of clinical, histopathological, and molecular biologicalcharacteristics. Crit Rev Oral Biol Med. 2003;14:47-62.

3. Neville B, Damm D, Allen C, Bouquot J. Oral & Maxillo-facial Pathology. 3rd ed. St Louis, MO: Saunders; 2009.

4. Fliegelman L, Friedland D, Brandwein M, et al. Lymphaticmalformation: predictive factors for recurrence. OtolaryngolHead Neck Surg. 1999;123:706-710.

5. Gnepp D. Lesions of the oral cavity, In: Diagnostic SurgicalPathology of the Head and Neck. 2nd ed. Philadelphia, PA:Saunders; 2009:239.

6. Ikeda H, Fujita S, Nonaka M, Uehara M, Tobita T,Inokuchi T. Cystic lymphangioma arising in the tip of thetongue in an adult. Int J Oral Maxillofac Surg. 2006;35:274-276.

7. Tesi D, Ficarra G. Oral linear epidermal nevus: a review ofthe literature and report of two new cases. Head Neck Pathol.2010;4:139-143.

8. Haberland-Carrodeguas C, Allen CM, Lovas JGL, et al.Review of linear epidermal nevus with oral mucosal invol-vementdseries of five new cases. Oral Dis. 2008;14:131-137.

9. Kumar AC, Yeluri G, Raghav N. Inflammatory linear ver-rucous epidermal nevus syndrome with its polymorphicpresentationda rare case report. Contemporary ClinicalDentistry. 2012;3:119-122.

10. Brown HM, Gorlin RJ. Oral mucosal involvement in nevusunius lateris (ichthyosis hystrix). Arch Dermatol. 1960;81:61-67.

11. Damm DD, Roddy SC, White DK. Diffuse oral papil-lomatosis with corrugated lesions of skin. Oral Surg OralMed Oral Pathol Oral Radiol Endod. 2008;106:630-636.

12. Romo A, Benavides S. Treatment options in insulin resis-tance obesity-related acanthosis nigricans. Ann Pharmac-other. 2008;42:1090-1094.

13. Weedon D. Weedon’s Skin Pathology. 3rd ed. London, En-gland: Elsevier; 2010.

14. Philipsen HP, Reichart PA, Takata T, Ogawa I. Verruciformxanthoma: biological profile of 282 oral lesions based onliterature and survey with nine new cases from Japan. OralOncol. 2003;39:325-336.

15. Oleiveria PT, Jaegar RG, Cabral LAG, et al. Verruciformxanthoma of the oral mucosa: report of four cases and a re-view of the literature. Oral Oncol. 2001;37:326-331.


16. Yu CH, Tsai TC, Wamg JT, et al. Oral verruciform xan-thoma: A clinicopathologic study of 15 cases. J Formos MedAssoc. 2007;106:141-147.

CLINICOPATHOLOGIC CONFERENCE CASE 2: A MANWITH PROGRESSIVE ALVEOLAR BONE LOSS ANDSPONTANEOUSTOOTHEXFOLIATION BC Jham, R Hill,M Mulholland, PC Edwards, Midwestern University, Collegeof Dental Medicine, Downers Grove, IL, USA; Private Prac-tice, Periodontics, Bay City, MI, USA; Private Practice, Oraland Maxillofacial Surgery, Bay City, MI, USA; Indiana Uni-versity, School of Dentistry, Indianapolis, IN, USA

Clinical Presentation: A 46-year-old man was seen with a2-year history of increasing maxillary anterior and left premolartooth mobility. On interview, the patient reported frequent puru-lent, foul tasting drainage from the immediate area that was un-responsive to conventional periodontal therapy. Medical historyincluded hypertension, treated with Losartan (50 mg/d) for thepast 3 years.

Clinical examination found multiple well-defined punctatelesions on the attached maxillary gingiva, each measuring be-tween 0.1 and 0.3 cm; they were red, and several had a sur-rounding white halo, creating a target-like appearance (Figure2-1, A, B). In addition, a single, well-defined, white, linear area ofexposed bone with irregular borders, measuring approximately

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Fig. 2-2. Periapical radiographic examination reveals a largeosseous defect extending from the distal surface of the leftmaxillary canine to the mesial surface of the left first maxillarymolar (A). Vertical bone loss (B) is noted around the anteriorteeth, with irregular loss of the lamina dura and widening of theperiodontal ligament.



0.5 � 0.1 cm, was present on the gingival mucosa adjacent to theleft maxillary central incisor. A large osseous defect extendingfrom the distal surface of the left maxillary canine to the mesialsurface of the left first maxillary molar was evident radiographi-cally (Figure 2-2, A). Vertical bone loss was noted around theanterior teeth, with irregular loss of the lamina dura and wideningof the periodontal ligament (see Figure 2-2, B). Root resorptionwas absent. Two weeks after the periapical radiographs wereobtained, the left second premolar spontaneously exfoliated.

Differential Diagnosis: Given the clinical presentation ofextensive bone loss, periodontal disease (PD) was the firstconsideration. Periodontal disease is a chronic inflammatory


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disease that involves the periodontium and gradually destroys thealveolar bone.1 Chronic periodontitis is the most common form ofPD, representing the primary cause of tooth loss in adults over 35years of age. In the current case, the patient’s gingival tissuesappeared uninflamed, with small amounts of plaque and calculus,which would not favor a diagnosis of periodontal disease. Also,chronic periodontitis typically develops over a period of years todecades. However, certain diseases can modify the course andbehavior of chronic periodontitis. In this context, poorlycontrolled diabetic individuals show an exaggerated inflammatoryresponse to the bacterial challenge of periodontal disease,2

increasing the severity of periodontal disease3,4 and potentiallyaccelerating bone and tooth loss. However, even in periodontaldisease associated with diabetes mellitus, some degree of gingivalinflammation would be expected. Also, the absence of bleedingand the presence of minimal plaque did not favor this diagnosis.

Patients with neutropenia present with a variety of oralmanifestations, including gingivitis and periodontitis.5,6 Deepperiodontal pockets, generalized bone loss, and advanced toothmobility have been reported.3,7 However, a decrease in host de-fenses and a history of infections elsewhere in the body would beexpected in a patient with severe neutropenia.6

Chronic leukemias can affect middle-aged adults and lead tomucosal ulceration and gingival enlargement.3 Osseous changeshave also been described.8 However, gingival and bony infiltra-tion by leukemic cells is more common in acute forms of thedisease.8,9 Intense bleeding, which was absent in the current case,is also commonly noted.

The evolution period favored a benign or low-grade malig-nant neoplasm, whereas the aggressive pattern of bone destruc-tion was more characteristic of a malignant process. However,more localized change would be expected, in contrast to the moregeneralized (2 quadrants) presentation noted in this case. Thus,systemic malignancies, including lymphoma, multiple myeloma,and metastases, were also considered in the differential diagnosis.

Langerhans cell histiocytosis (LCH) can mimic periodontaldisease.10,11 The intraoral presentation of LCH classically in-cludes punched-out necrotic ulcers with considerable amounts ofassociated granulation tissue, tissue necrosis, marked bone loss,and loosening of teeth.3,12 The current case showed some featuresconsistent with LCH. However, LCH is more commonly a dis-ease of the late teens to early adulthood.12 Also, the radiographicpresentation of LCH is classically that of multiple punched-outradiolucent lesions, often exhibiting a “teeth floating in the air”radiographic presentation.

One of the most striking features of the present case was thefact that the left secondary maxillary premolar had self-exfoliated.In children, a number of diseases are known to cause early exfo-liation of deciduous teeth, including Papillon-Lefèvre syndrome,hypophosphatasia, Chédiak-Higashi syndrome, and leukocyteadhesion deficiency.13 Exfoliation of permanent teeth has beenreported in the context of bone osteonecrosis associated with tri-geminal herpes zoster.14-17 Also, as previously mentioned, painlessexfoliation of teeth could ensue secondary to necrosis of the bone.Findings inconsistent with herpes zoster in this case included themultiple-year duration, the absence of obvious surface epithelialnecrosis, the lack of classic clinical symptoms such as pain, and theobservation that the process clearly crossed the midline.

Diagnosis and management: An incisional biopsy wasperformed, revealing fragments of surface epithelium containinga subsurface proliferation of hyperplastic stratified squamousepithelium demonstrating marked hyperortho- and hyper-parakeratinization (Figure 2-3, A). Lesional tissue harvested from

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Fig. 2-3. A, Low-magnification photomicrograph of the biopsyspecimen demonstrates normal surface epithelium overlyingstrands of markedly hyperkeratinized epithelium that is bur-rowing into the underlying connective tissue (hematoxylin-eosin). B, The maxillary bone is replaced by ribbons ofepithelium demonstrating prominent keratinization and formingkeratin-filled crypts (hematoxylin-eosin). C, The epithelialribbons are deceptively bland looking, with no significantcellular pleomorphism and minimal mitotic activity. Thisepithelium surrounds a fragment of nonviable bone (hema-toxylin-eosin).


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within the bone consisted of ribbons of hyperkeratinized epithe-lium surrounding numerous fragments of necrotic bone. Thisneoplastic epithelium lacked the classic cytologic features ofmalignancy, absent significant cellular or nuclear pleomorphismor mitotic activity, a feature that characterizes the deceptivelybland features of the entity.

The final diagnosis, based on the clinical, radiographic, andhistologic presentation, was carcinoma cuniculatum.

Discussion: Carcinoma cuniculatum (CC) is a rare, distinctclinicopathologic variant of squamous cell carcinoma (SCC), firstdescribed in 1954.18 CC was originally believed to involveexclusively the skin of the sole of the foot, but involvement ofother sites is now accepted.19 The etiology of CC is unknown,although tobacco and alcohol use have been suggested as possiblepredisposing factors.20,21 Trauma has also been suggested as apossible etiologic factor,21 although there is no evidence to sup-port this. The possibility of an association with human papillo-mavirus infection has also been raised,19,22,23 but this remainsdoubtful.

There is disagreement over whether there is a sex predilec-tion, with some studies reporting the lesion as more common inmen,19,20,24 whereas others indicate an equal distribution betweenthe sexes.21 CC appears to primarily affect older adults, with 3studies20,21,24 reporting a mean age of approximately 50 years,and a more recent investigation suggesting a mean age of 67years.21 However, CC can affect patients over a wide age range,from 7 years25 to 92 years.21

Clinically, CC presents initially as a slow-growing mass. The2-year evolution of the current case is in agreement with theliterature, which documents periods ranging from 1 to 24 months(mean, 8.5 months) before diagnosis.21 The most common clin-ical presentation is that of an indurated, occasionally painful,surface ulcer. However, signs and symptoms vary and mayinclude swelling, white patches,26 bleeding, and exudation.21 Ofthe cases occurring in the oral cavity, 78% involved the alveolargingiva or palate, with burrowing into the underlying bone rep-resenting a defining feature.19,24 Bony involvement often leads toloosening of teeth.19 Radiographically, radiolucent lesions withill-defined margins and resorption of adjacent cancellous andcortical bone may be observed in more advanced lesions.20

Macroscopically, CC shows both exophytic and endophyticgrowth patterns. Cords and ribbons of heavily keratinizedepithelium penetrate deeply into the underlying tissue and bone,creating ramified sinuses and crypts similar to rabbit burrows(cuniculus, hence the name cuniculatum).18 The keratin-filledcrypts tend to discharge a yellowish, foul-smelling secretion.19

Microscopically, CC is defined by its characteristic infiltrativepattern of deep proliferation of stratified squamous epitheliumforming keratin cores and keratin-filled crypts that are charac-teristically devoid of significant atypia. The diagnosis is chal-lenging because of the rarity of this lesion and lack of familiaritywith the condition by many clinicians and pathologists. Thehistopathologic differential diagnosis includes verrucous carci-noma, which generally does not present with the prominentinfiltrative invasion into bone, and well-differentiated SCC.19,21

In fact, CC is often mistakenly considered to represent a variant ofverrucous carcinoma. Lesions demonstrating heavy orthokerati-nization, as in the current case, may be potentially misdiagnosedas an orthokeratinizing odontogenic cyst, particularly if theclinical and radiographic features are overlooked.

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CC is a locally aggressive tumor, and the preferred treatmentis en bloc resection with the goal of achieving tumor-free mar-gins.21,24 Chemotherapy and radiotherapy have been used in afew cases, but their benefit is controversial.21,27

Prognosis is favorable, as CC is rarely associated withregional or distant metastasis.24 Although recurrence is not ex-pected,19,24 when it does occur, pathologic transformation intoconventional SCC is sometimes noted, resulting in a moreaggressive clinical presentation.21

As is clearly highlighted in the current case, a definitivediagnosis of carcinoma cuniculatum is dependent on correlatingthe classic, but unusually bland, cytology of the lesion with theclinical and radiographic findings.

References1. Di Benedetto A, Gigante I, Colucci S, Grano M. Periodontal

disease: linking the primary inflammation to bone loss. ClinDev Immunol. 2013;2013:503754. http://dx.doi.org/10.1155/2013/503754.

2. Otomo-Corgel J, Pucher JJ, Rethman MP, Reynolds MA.State of the science: chronic periodontitis and systemichealth. J Evid Based Dent Pract. 2012;12(3 suppl):20-28.

3. Kinane DF, Marshall GJ. Periodontal manifestations of sys-temic disease. Aust Dent J. 2001;46:2-12.

4. Armitage GC. Development of a classification system forperiodontal diseases and conditions. Ann Periodontol.1999;4:1-6.

5. Deasy MJ, Vogel RI, Macedo-Sobrinho B, Gertzman G,Simon B. Familial benign chronic neutropenia associatedwith periodontal disease: a case report. J Periodontol.1980;51:206-210.

6. Deas DE, Mackey SA, McDonnell HT. Systemic disease andperiodontitis: manifestations of neutrophil dysfunction.Periodontol 2000. 2003;32:82-104.

7. Reichert PA, Dornow H. Gingivo-periodontal manifestationsin chronic benign neutropenia. J Clin Periodontol. 1978;5:74-80.

8. Benson RE, Rodd HD, North S, Loescher AR, Farthing PM,Payne M. Leukaemic infiltration of the mandible in a younggirl. Int J Paediatr Dent. 2007;17:145-150.

9. Dreizen S, McCredie KB, Keating MJ, Luna MA. Malignantgingival and skin “infiltrates” in adult leukemia. Oral SurgOral Med Oral Pathol. 1983;55:572-579.

10. Piattelli A, Paolantonio M. Eosinophilic granuloma of themandible involving the periodontal tissues: a case report. JPeriodontol. 1995;66:731-736.

11. Komp DM. Langerhans cell histiocytosis. N Engl J Med.1987;316:747-748.

12. Merglová V, Hru�sák D, Boudová L, Muken�snabl P,Valentová E, Hosti�cka L. Langerhans cell histiocytosis inchildhooddreview, symptoms in the oral cavity, differentialdiagnosis and report of two cases. J Craniomaxillofac Surg2013; pii:S1010-5182(13)00091-7. http://dx.doi.org/10.1016/j.jcms.2013.03.005.

13. Sharma G, Whatling R. Case report: premature exfoliation ofprimary teeth in a 4-year-old child, a diagnostic dilemma. EurArch Paediatr Dent. 2011;12:312-317.

14. Manz HJ, Canter HG, Melton J. Trigeminal herpes zostercausing mandibular osteonecrosis and spontaneous toothexfoliation. South Med J. 1986;79:1026-1028.

15. Mostofi R, Marchmont-Robinson H, Freije S. Spontaneoustooth exfoliation and osteonecrosis following a herpes zoster


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infection of the fifth cranial nerve. J Oral Maxillofac Surg.1987;45:264-266.

16. Pillai KG, Nayar K, Rawal YB. Spontaneous tooth exfolia-tion, maxillary osteomyelitis and facial scarring followingtrigeminal herpes zoster infection. Prim Dent Care. 2006;13:114-116.

17. Lambade P, Lambade D, Saha TK, Dolas RS, Pandilwar PK.Maxillary osteonecrosis and spontaneous teeth exfoliationfollowing herpes zoster. Oral Maxillofac Surg. 2012;16:369-372.

18. Aird I, Johnson HD, Lennox B, Stansfeld AG. Epitheliomacuniculatum: a variety of squamous carcinoma peculiar to thefoot. Br J Surg. 1954;42:245-250.

19. Thavaraj S, Cobb A, Kalavrezos N, Beale T, Walker DM,Jay A. Carcinoma cuniculatum arising in the tongue. HeadNeck Pathol. 2012;6:130-134.

20. Allon D, Kaplan I, Manor R, Calderon S. Carcinoma cuni-culatum of the jaw: a rare variant of oral carcinoma. OralSurg Oral Med Oral Pathol Oral Radiol Endod. 2002;94:601-608.

21. Sun Y, Kuyama K, Burkhardt A, Yamamoto H. Clinico-pathological evaluation of carcinoma cuniculatum: a variantof oral squamous cell carcinoma. J Oral Pathol Med.2012;41:303-308.

22. Wastiaux H, Dreno B. Recurrent cuniculatum squamous cellcarcinoma of the fingers and virus. J Eur Acad DermatolVenereol. 2008;22:627-628.

23. Knobler RM, Schneider S, Neumann RA, et al. DNA dot-blot hybridization implicates human papillomavirus type11-DNA in epithelioma cuniculatum. J Med Virol. 1989;29:33-37.

24. Pons Y, Kerrary S, Cox A, et al. Mandibular cuniculatumcarcinoma: apropos of 3 cases and literature review. HeadNeck. 2010;27:1-5.

25. Hutton A, McKaig S, Bardsley P, Monaghan A, Parmar S.Oral carcinoma cuniculatum in a young child. J Clin PediatrDent. 2010;35:89-94.

26. Suzuki J, Hashimoto S, Watanabe K, Takahashi K,Usubuchi H, Suzuki H. Carcinoma cuniculatum mimickingleukoplakia of the mandibular gingiva. Auris Nasus Larynx.2012;39:321-325.

27. Mora RG. Microscopically controlled surgery (Mohschemosurgery) for treatment of verrucous squamous cellcarcinoma of the foot (epithelioma cuniculatum). J Am AcadDermatol. 1983;8:354-362.

CLINICOPATHOLOGIC CONFERENCE CASE 3: A 75-YEAR-OLD MAN WITH PROGRESSIVE RIGHT-SIDEDHEARING LOSS AND DIZZINESS N Said-Al-Naief,A Pourian, J Cure, R Lopez, Loma Linda University, Schoolof Dentistry, Loma Linda, CA, USA; University of Iowa,School of Dentistry, Iowa City, IA, USA; University of Ala-bama, School of Medicine, Birmingham, AL, USA; CharlotteRadiology PA, Charlotte, NC, USA

Clinical Presentation: A 57-year-old man presented to theotolaryngologyehead and neck surgery department by referralfrom a Veterans Affairs hospital for further evaluation ofdizziness and lightheaded unsteadiness. This was accompaniedby vague, nonspecific right-sided temporal bone and temporo-mandibular discomfort. He also had had progressive hearing losssince 1973 but denied any otologic or any other head and necksymptoms. Thorough head and neck evaluation found intact

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http://dx.doi.org/10.1155/2013/503754

http://dx.doi.org/10.1016/j.jcms.2013.03.005

http://dx.doi.org/10.1016/j.jcms.2013.03.005

Fig. 3-2. Axial T1-weighted magnetic resonance imaging scanwith no contrast, showing a well-demarcated isointense lesion (todura) (arrow) in the right cerebellopontine enclosing distincthyperintense foci.

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cranial nerves II to XII except for decreased hearing on the rightside. His vision was also normal. Review of his medical historyfound hypertension and diabetes mellitus. He was on insulin,omeprazole, citalopram, metoprolol, metformin, potassium,enalapril, and meclizine. He also reported the surgical removalof a right heal spur several years ago with uneventful healing.The physical examination was within normal limits. Examina-tion of the oral cavity and oropharynx demonstrated no abnor-malities, and examination of the neck found no palpablelymphadenopathy, thyromegaly, or masses noted. Similarly, theexamination of the external auditory canals was clean, and thetympanic membranes appeared translucent and mobile. Therewere no middle ear effusions, and the nasal passages were clear.However, he underwent an audiogram, which found a profoundright sensorineural hearing loss. He does not use any tobaccoproducts and does not drink alcohol. Additionally, there were noknown drug allergies to report. Family history was positive forhypertension and diabetes mellitus, and he had a half-brotherwho was diagnosed with a brain tumor, but he did not recall theexact type.

Axial computed tomography (CT) without contrast foundmarked endosteal scalloping of the right posterior petrous bonecentered over the retrolabyrinthine area, and a slightly enlargedadjacent vestibular aqueduct with respect of mastoid (Figure 3-1).At magnetic resonance imaging, a 3-cm, expansile, well-cir-cumscribed mass could be seen arising from the right petrousbone with an exophytic component extending into the cer-ebellopontine angle. The mass appeared heterogeneous on bothT1- and T2-weighted images, with focal high signal intensities,possibly owing to subacute hemorrhages. The lesion encroachedon the vestibular aqueduct. On T1, the majority of the lesion wasisointense with the cerebellum, with a nodular area of hyper-intensity, which may represent blood- or protein-filled cysts(Figure 3-2). The lesion is mostly hyperintense on T2, with

Fig. 3-1. An axial computed tomography scan without contrastshowing marked endosteal scalloping of the right posteriorpetrous bone at the cerebellopontine angle (arrow) and a slightlyenlarged adjacent vestibular aqueduct with respect of mastoid.


intensity equal to that of the surrounding cerebrospinal fluid,except for a focal nodule centrally (Figure 3-3).

Differential Diagnosis: Considering the radiographic andhistomorphologic pattern combined, a thorough clinical,

Fig. 3-3. T2-weighted postgadolinium magnetic resonance im-aging scan showing a well-circumscribed lesion present in theright cerebellopontine angle with heterogeneous enhancing signalwith the exception of a central hypotenuse nodule (arrow).

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histomorphologic, immunohistochemical, and (most importantly)radiographic evaluation is necessary to exclude endolymphaticsac tumor (ELST) from various other entities that involve themiddle ear and temporal bone. Approximately 6% to 10% of allintracranial tumors develop within the cerebellopontine angle,and the majority of these represent schwannomas.1-3

Schwannomas arising in the posterior portion of the petrousbone are commonly located over the jugular foramen or internalacoustic canal and cause erosion of either site.4 Schwannomascharacteristically have smooth scalloped margins on CT anduniform enhancement on postcontrast T2 weighted studies; thesefeatures would reliably differentiate this tumor from ELST.4

Widening of the fallopian canal in the temporal bone is alsoconsidered characteristic.1,5 Histologically, schwannomas arespindle cell neoplasms with the palisaded nuclear cell patternsand haphazardly arranged patterns known as Antoni A (Verocaybodies) and Antoni B patterns, respectively. The tumor alsocharacteristically stains positively with anti S-100 protein anti-bodies and collagen IV immunohistochemistry (IHC) stains,among other peripheral nerve sheath IHC staining markers.

Meningioma is the second most common tumor found in thecerebellopontine angle.1-3 Primary extracranial meningiomas,especially those arising in temporal bone and ear, are rarecompared with those seen as a result of secondary extension froman intracranial tumor, constituting fewer than 1% of all menin-giomas.6 Meningiomas may be confused with ELSTs,7 especiallywhen arising in the posterior aspect of petrous bone, at the jugularforamen; however, unlike ELSTs, meningiomas tend to extend tothe path of least resistance, grow along dural planes, and haveslow-growing pushing or scalloped margins. They are typicallyassociated with hyperostosis of the bone in juxtaposed position tothe tumor.4 Furthermore, homogeneous enhancement is identifiedon T1-weighted scans with contrast compared with the hetero-geneous pattern seen in ELSTs and T2-weighted imaging ofmeningiomas; the hypointense uniform features reflect thecellular density of the tumor. Middle ear meningiomas are morecommon in women during the fifth decade of life, and symptomsmay also overlap with those of ELST, in which patients typicallyreport loss of hearing and equilibrium, headaches, obstruction,and cranial nerve involvement. Meningioma may have varioushistomorphologic patterns, especially the meningothelial type(which has lobules of tumor cells with indistinct borders andround to oval nuclear contours) and the psammomatous variants(which display similar histomorphologic features as seen in themeningothelial, with the addition of concentric lamellar calcificdeposits called psammoma bodies). Immunohistochemistrystaining is not particularly helpful in distinguishing ELST frommeningioma; meningioma typically reacts positively withvimentin, exhibits focal weak positive staining with epithelialmembrane antigen (EMA), and may occasionally react with antiS-100 protein immunohistochemical stains.

Paragangliomas (PGs) of the head and neck are rare tumors,comprising approximately 3% of all paragangliomas.8 Primarycerebellopontine angle paragangliomas are rare, with the majorityof tumors encountered in this region representing glomus jugulareor glomus tympanicum tumors with secondary extension to thisregion.9 These tumors also should be considered in the differ-ential diagnosis of ELST, especially when involving the posteriorportion of the temporal bone. PG may be distinguished by theprecontrast T1-weighted pepper pattern, reflecting the high-flowvoids observed within the tumor accompanied by the permeativedestructive bony changes seen. The typical hyperintense salt-likefoci, reflecting the low-flow nature of the lesion seen with ELST,


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is rarely or never observed in paragangliomas, which typicallyexhibit a salt-and-pepper pattern on imaging.8,10

Lipomas of the cerebellopontine angle are rare and representfewer than 1% of tumors in that region; they may cause hearingloss, vertigo, dizziness, unsteadiness, and tinnitus.11 They arebelieved to be derived from the persistence and abnormal lipo-matous differentiation of meninx primitive; an essential mesen-chymal tissue, which covers the brain and gives rise to the duraand other important tissues in that region. Histologically, theselesions have mature adipose tissue with well-vascularized back-ground, and they therefore appear with low density on CT scansand are characteristically without contrast uptake. Furthermore,they appear hyperintense (to brain tissue) on T1 images andhypointense on T2 imaging.12

Metastatic tumors should also be included in the list of pa-thologies involving the cerebellopontine angle. Several malig-nancies may potentially metastasize to the cerebellopontine angle,such as breast, lung, prostate, skin, cervix, liver, brain, gastroin-testinal, and oral cavity tumors.13 The presence of primary diseaseelsewhere, especially papillary renal cell carcinoma and papillarythyroid carcinoma, should definitely raise that possibility, espe-cially because both tumor types exhibit a comparable papillarypattern on histomorphologic examination. A thorough clinicaland pathologic examination supplemented by a tedious micro-scopic examination, which may or may not require additionalimmunohistochemical or molecular work-up, would help indifferentiating ELST from metastatic tumors.

Middle ear adenoma (MA) may also exhibit clinical andhistomorphologic overlap with ELST; however, the coexpressionof epithelial and neuroendocrine markers in an adenomatous tu-mor of the inner ear that is typically confined to this region anddoes not exhibit bone involvement14 can readily distinguishELST from MA. Similarly, a thorough clinical and radiographicas well as histologic work-up can help in separating ELST fromother pathologies such as chondrogenic sarcoma, epidermoidcyst, and choroid plexus papilloma, among several others.

Diagnosis and Management: The patient underwent aresection of the neoplasm at the base of the posterior cranial fossaand jugular foramen extradurally, via a transcochlear approach tothe posterior cranial fossa, including the jugular foramen. Totalexcision of the tumor also necessitated labyrinthectomy andcomplete mastoidectomy with decompression of the facial nervewithout mobilization. He also received free abdominal fat andtemporoparietal facial grafts. Histomorphologic examinationfound a cystic tumor with a papillary, cystic, or glandular archi-tecture that exhibited rich vascularity and exhibited an ill-defined,locally infiltrative growth pattern with destruction of petrousbone. On higher magnification, the papillary and glandularstructures were found to be lined by a single layer of flattenedcuboidal-to-short columnar cells, and the stroma supporting thepapillary fronds was richly vascularized and chronically inflamedand supported marked hemorrhage and hemosiderin pigmentdeposition. The epithelial cells had uniform nuclei that wereusually situated either in the cell center or toward the luminalaspect. The cells had pale eosinophilic to clear cytoplasm andwell-defined to vaguely defined borders; assuming plant-likemorphology (Figures 3-4 and 3-5). There was minimal cellularpleomorphism, and only rare mitotic activity was seen. Many ofthe cystic glandular spaces were filled with colloid-like materialthat was remarkably similar to thyroid tissue but stained posi-tively with periodic acideSchiff special stains and negativelywith TTF-1 (thyroid transcription factor) immunohistochemicalstaining (Figures 3-5 and 3-6). The tumor also reacted positively

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Fig. 3-4. Low-power photomicrographs of ELST showingprominent papillary pattern (A) and admixture (B) of cysticpattern (white arrow) and solid pattern (black arrow). Markedhemorrhage was identified (C, D), and hemosiderin pigmentdeposition was also prominent (D) (arrow) (hematoxylin-eosin,original magnification �10 [A, B] and �20 [C, D]).

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Fig. 3-6. The tumor reacted positively with antipancytokeratin(A), cytokeratin 7 (B), epithelial membrane antigen (C), andvimentin (D) immunohistochemical stains.

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and diffusely with pancytokeratin, cytokeratin 7, and EMA andvimentin immunohistochemical stains (Ventana, predilute; Ven-tana Medical Systems Inc, CA, USA).

The final diagnosis was ELST.The patient’s recovery was uneventful, and he healed well.

There was no evidence of recurrence 1 year postoperatively.Long-term follow-up was not available for relocation purposes.

Discussion: The ear is derived from ectodermal thickening inthe auditory placode during the fourth week of embryonicdevelopment and consists of an external compartment and middleand inner ear portions. The inner ear is encased within the bony

Fig. 3-5. A, The semicomplex papillary architecture of ELST. B,Well-defined papillary architecture of ELST, where the cellsexhibited well-defined outlines, eosinophilic to clear cytoplasm,and plantlike cytomorphology and nuclei situated in central orbasilar position (arrow). C, D, Intracytoplasmic (C) and intra-cyctic-luminal dense colloid-like periodic acideSchiffepositivematerial (D) was evident in this tumor (A, B, hematoxylin-eosin,original magnification �20 [A] and �40 [B]; C, D, special stainwith periodic acideSchiff; original magnification �40 [C] and�20 [D]).


labyrinth of the temporal bone, which comprises 2 functionalparts, the cochlea and vestibular system; together they areresponsible for hearing and balance/equilibrium, respectively.15,16

The vestibular system comprises the utricle, the 3 semicircularcanals, and the saccule. The endolymphatic duct arises from theposterior wall of the saccule and ends up in a blind pouch: theendolymphatic sac. Studies have suggested that the endolym-phatic duct and sac possess absorptive, secretory phagocytic andimmune properties and functions.17-18

Adenomatous tumors of the temporal bone and middle ear inparticular are rare and share many overlapping clinical and oftenradiographic features and exhibit pleomorphic morphology,which contributes to the difficulty of classification by both cli-nicians and pathologists. In 1976, Hyams and Michaels19 andDerlacki and Barney,20 working independently, spearheaded thedefining of middle ear adenoma (MEA), recognizing its deriva-tion from modified ear mucosa and its indolent, nonaggressive,nonresorptive biologic behavior, while Murphy et al.21 recog-nized the bimodal epithelial-neuroendocrine features of thesetumors. Later on, Gaffey et al.22 described an aggressive, middleear/temporal bone tumor that occurred in association with vonHippeleLindau (VHL) syndrome, and they adopted the termi-nology “aggressive papillary tumor,” capable of bone resorptionand locally aggressive biologic behavior, distinguishing it fromMEA; currently equivalent to ELST. ELST is a rare, low-gradepapillary adenocarcinoma that arises from ectodermally derivedepithelial tissues of endolymphatic duct or sac or neuro-ectodermal tissues adjacent to an intermediate portion of thepetrous bone, within the vestibular canal,23,24 which accounts forthe propensity of these tumors to involve and erode the temporalbone and cerebellopontine angle.23,25

ELST was first recognized by Hassard et al.26 in 1984 andfurther characterized as a separate entity by Heffner in 1989,24

who reported 20 similar cases of low-grade papillary adenocar-cinoma from the files of the Armed Forces Institute of Pathology,including the one reported by Hassard et al.26 Patients typicallypresent with unilateral hearing loss (which may be sudden),vertigo, and tinnitus, and a minority of patients also report facialnerve paralysis and cerebellar disorders. The clinical features mayoften simulate those seen in Meniere disease, which include(among others) the presence of aura, headaches, increased earpressure, dizziness, tinnitus, and hearing loss. ELSTs may be

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encountered as sporadic cases, in which tumors are typicallyunilateral, whereas bilateral tumors are more commonlyencountered as part of VHL, where ELSTs are considered to bean integral and essential part of the diseases.23,27,28 VHL is anuncommon autosomal dominant condition, characterized by thepresence of several neoplasms including cerebellar, spinal, andretinal hemangioblastomas, pheochromocytomas, and renal cellcarcinoma,29 and approximately 11%27,30,31 to 15%24,32 of pa-tients with VHL also develop ELSTs. VHL disease is charac-terized by the presence of an abnormality of the VHL gene (vonHippeleLindau tumor suppressor, E3 ubiquitin protein ligase,which is located on the short arm of chromosome 3), which oc-curs in association with the other copy of the VHL gene. Thisgenetic alteration is observed in all tumor types occurring in as-sociation with VHL, including ELST; significantly, even thesporadic, non-VHL-associated ELSTs have the aforementionedVHL gene mutation.23,30-36

The tumor occurs in a wide age range, which extends fromchildhood to the elderly.22,36-38 Female prevalence andyounger age of occurrence are well documented in tumors seenin the context of VHL disease compared with sporadic tu-mors.22-25,33,37-38 Endolymphatic sac tumors have a low-gradepapillary architecture with prominent stromal vascularity thatis typically devoid of high mitotic activity and necrosis.However, it has propensity for local infiltration and focal bonedestruction. The tumor may show a follicular pattern withcystic or glandular spaces (which contain colloid-like material)or a combination of papillary and solid architecture, wherecells lining the cystic spaces display plantlike to clear cellfeatures,34 as observed in the present case. ELST is best andmost effectively managed by total excision with or withoutradiation therapy. Radiation is mostly implemented in largetumors that are unresectable and difficult to manage, primarilyowing to anatomic limitation. Resection is well documented,particularly with incomplete removal, and preoperative embo-lization may play a role in limiting tumor recurrence, espe-cially in large tumors.38 In general, prognosis is excellent withcomplete excision, but distant metastasis has been rarelyreported.36,39

References1. Springborg JB, Poulsgaard L, Thomsen J. Nonvestibular

schwannoma tumors in the cerebellopontine angle: a struc-tured approach and management guidelines. Skull Base.2008;18:217-227.

2. Moffat DA, Ballagh RH. Rare tumours of the cer-ebellopontine angle. Clin Oncol (R Coll Radiol). 1995;7:28-41.

3. Bonneville F, Cattin F, Czorny A, Bonneville JF. Hyper-vascular intracisternal acoustic neuroma. J Neuroradiol.2002;29:128-131.

4. Patel NP, Wiggins RH 3rd, Shelton C. The radiologic diag-nosis of endolymphatic sac tumors. Laryngoscope. 2006;116:40-46.

5. Lalwani AK. Meningiomas, epidermoids, and other non-acoustic tumors of the cerebellopontine angle. OtolaryngolClin North Am. 1992;25:707-728.

6. Thompson LD, Bouffard JP, Sandberg GD, Mena H. Primaryear and temporal bone meningiomas: a clinicopathologicstudy of 36 cases with a review of the literature. Mod Pathol.2003;16:236-245.


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7. Al-Anazi AR, Holliday W, Sheikh B, Gentili F. Extraosseousendolymphatic sac low-grade adenocarcinoma mimickingposterior fossa meningioma. J Neurosurg. 2001;95:893-896.

8. Said-Al-Naief N, Ojha J. Hereditary paraganglioma of thenasopharynx. Head Neck Pathol. 2008;2:272-278.

9. Deb P, Sharma MC, Gaikwad S, Gupta A, Mehta VS,Sarkar C. Cerebellopontine angle paragangliomadreport ofa case and review of literature. J Neurooncol. 2005;74:65-69.

10. Noujaim SE, Pattekar MA, Cacciarelli A, Sanders WP,Wang AM. Paraganglioma of the temporal bone: role ofmagnetic resonance imaging versus computed tomography.Top Magn Reson Imaging. 2000;11:108-122.

11. Tankéré F, Vitte E, Martin-Duverneuil N, Soudant J. Cer-ebellopontine angle lipomas: report of four cases and reviewof the literature. Neurosurgery. 2002;50:626-632.

12. Schuhmann MU, Ludemann WO, Schreiber H, Samii M.Cerebellopontine angle lipoma: a rare differential diagnosis.Skull Base Surg. 1997;7:199-205.

13. Nelson EG, Hinojosa R. Histopathology of metastatic tem-poral bone tumors. Arch Otolaryngol Head Neck Surg.1991;117:189-193.

14. Torske KR, Thompson LD. Adenoma versus carcinoid tumorof the middle ear: a study of 48 cases and review of theliterature. Mod Pathol. 2002;15:543-555.

15. Torres M, Giraldez F. The development of the vertebrateinner ear. Mech Dev. 1998;71:5-21.

16. Hyman LH, Wake MH. Hyman’s Comparative VertebrateAnatomy. Chicago, IL: University of Chicago Press; 1979.

17. Rask-AndersenH,Danckwardt-LilliestromN,LinthicumFHJr,House WF. Ultrastructural evidence of a merocrine secretionin the human endolymphatic sac. Ann Otol Rhinol Laryngol.1991;100:148-156.

18. Wackym PA, Friberg U, Bagger-Sjoback D, Linthicum FH Jr,Friedmann I, Rask-Andersen H. Human endolymphatic sac:possible mechanisms of pressure regulation. J Laryngol Otol.1987;101:768-779.

19. Hyams VJ, Michaels L. Benign adenomatous neoplasm(adenoma) of the middle ear. Clin Otolaryngol Allied Sci.1976;1:17-26.

20. Derlacki EL, Barney PL. Adenomatous tumors of the middleear and mastoid. Laryngoscope. 1976;86:1123-1135.

21. Murphy GF, Pilch BZ, Dickersin GR, Goodman ML,Nadol JB Jr. Carcinoid tumor of the middle ear. Am J ClinPathol. 1980;73:816-823.

22. Gaffey MJ, Mills SE, Boyd JC. Aggressive papillary tumor ofmiddle ear/temporal bone and adnexal papillary cys-tadenoma: manifestations of von Hippel-Lindau disease. AmJ Surg Pathol. 1994;18:1254-1260.

23. Bell D, Gidley P, Levine N, Fuller GN. Endolymphatic sactumor (aggressive papillary tumor of middle ear and temporalbone): sine qua non radiology-pathology and the Universityof Texas MD Anderson Cancer Center experience. AnnDiagn Pathol. 2011;15:117-123.

24. Heffner DK. Low-grade adenocarcinoma of probable endo-lymphatic sac origin: a clinicopathologic study of 20 cases.Cancer. 1989;64:2292-2302.

25. el-Naggar AK, Pflatz M, Ordonez NG, Batsakis JG. Tumorsof the middle ear and endolymphatic sac. Pathol Annu.1994;29:199-231.

26. Hassard AD, Boudreau SF, Cron CC. Adenoma of theendolymphatic sac. J Otolaryngol. 1984;13:213-216.

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27. Poletti AM, Dubey SP, Barbo R, et al. Sporadic endolym-phatic sac tumor: its clinical, radiological, and histologicalfeatures, management, and follow-up. Head Neck. 2013;35:1043-1047.

28. Friedrich CA. Von Hippel-Lindau syndrome: a pleomorphiccondition. Cancer. 1999;86:2478-2482.

29. Sano T, Horiguchi H. Von Hippel-Lindau disease. MicroscRes Tech. 2003;60:159-164.

30. Vortmeyer AO, Choo D, Pack SD, Oldfield E, Zhuang Z. vonHippel-Lindau disease gene alterations associated withendolymphatic sac tumor. J Natl Cancer Inst. 1997;89:970-972.

31. Vortmeyer AO, Huang SC, Koch CA, et al. Somatic vonHippel-Lindau gene mutations detected in sporadic endo-lymphatic sac tumors. Cancer Res. 2000;60:5963-5965.

32. Lavoie M, Morency RM. Low-grade papillary adenomatoustumors of the temporal bone: report of two cases and reviewof the literature. Mod Pathol. 1995;8:603-608.

33. Stendel R, Suess O, Prosenc N, Funk T, Brock M. Neoplasmof endolymphatic sac origin: clinical, radiological and path-ological features. Acta Neurochir (Wien). 1998;140:1083-1087.

34. Kempermann G, Neumann HP, Scheremet R, et al. Deafnessdue to bilateral endolymphatic sac tumours in a case of vonHippel-Lindau syndrome. J Neurol Neurosurg Psychiatry.1996;61:318-320.

35. Skalova A, Sima R, Bohus P, Curik R, Lukas J, Michal M.Endolymphatic sac tumor (aggressive papillary tumor ofmiddle ear and temporal bone): report of two cases withanalysis of the VHL gene. Pathol Res Pract. 2008;204:599-606.

36. Bambakidis NC, Megerian CA, Ratcheson RA. Differentialgrading of endolymphatic sac tumor extension by virtue ofvon Hippel-Lindau disease status. Otol Neurotol. 2004;25:773-781.

37. Schipper J, Maier W, Rosahl SK, et al. Endolymphatic sactumours: surgical management. J Otolaryngol. 2006;35:387-394.

38. Sun YH, Wen W, Wu JH, et al. Endolymphatic sac tumor:case report and review of the literature. Diagn Pathol.2012;7:36. http://dx.doi.org/10.1186/1746-1596-7-36.

39. Tay KY, Yu E, Kassel E. Spinal metastasis from endolym-phatic sac tumor. AJNR Am J Neuroradiol. 2007;28:613-614.

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Fig. 4-1. Oral examination found large, superficial ulcerations ofthe right ventrolateral tongue (A), right buccal mucosa (B), anduvula (C).

CLINICOPATHOLOGIC CONFERENCE CASE 4: PAINFULNONHEALING ORAL ULCERATIONS KK McNamara,P Pugalagiri, Ohio State University, College of Dentistry, Co-lumbus, OH, USA; Private Practice, Plano, TX, USA

Clinical Presentation: A 58-year-old white woman pre-sented with a painful nonhealing ulcer of the right ventrolateraltongue. She reported that the lesion had been present for 8 weeksand that painful ulcerations of the uvula and right buccal mucosaarose within the past 2 weeks. Her medical history was significantfor hypothyroidism and autoimmune hepatitis. She had had a livertransplant 4 months earlier and was taking levothyroxine (Syn-throid), tacrolimus (Prograf), mycophenolate mofetil (CellCept),and a daily multivitamin.

The patient was initially evaluated by a local otolaryngolo-gist, and recent blood studies were unremarkable. After 2 hos-pitalizations for dehydration and malnutrition, an oral andmaxillofacial surgeon was consulted, who decided to perform anincisional biopsy of the right tongue lesion. A diagnosis of


“nonspecific ulcer” was rendered, and the patient was referred forevaluation by an oral and maxillofacial pathologist.

Oral examination found a 1.5-cm-diameter shallow ulcera-tion of the right ventrolateral surface of the tongue, exhibitingmild peripheral erythema and an irregular superior marginconsistent with recent biopsy site (Figure 4-1, A). A 0.5-cmdiameter shallow ulceration surrounded by a hint of white striae-like changes was noted on the right posterior buccal mucosa (seeFigure 4-1, B), and a 0.8-cm diameter ulceration was seen on theuvula, without evidence of any peripheral mucosal alterations (seeFigure 4-1, C).

Differential Diagnosis: Considerations in the differentialdiagnosis included infectious diseases, drug-induced ulcerations,and immune-mediated disorders, such as aphthous ulcerations.

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Fig. 4-2. This photomicrograph shows ulcerated surface epithe-lium overlying granulation tissue (A) (hematoxylin-eosin, orig-inal magnification �10). The granulation tissue supports apredominantly chronic inflammatory cell infiltrated with scatteredeosinophils and occasional mononuclear cells exhibiting rela-tively large nuclei (B) (hematoxylin-eosin, original magnification�40).



Given the patient’s posttransplant immunosuppressive ther-apy, an infectious etiology was initially considered. Viral diseasescaused by herpes simplex virus, varicella zoster virus, and cyto-megalovirus can present with multiple, chronic oral mucosal ul-cerations in an immunocompromised patient.1-3 Theses ulcers areoften larger and more irregular than those seen in immunocom-petent individuals and will persist and spread until the infection istreated or the immune function returns.3

Fungal disease, such as histoplasmosis, and bacterial disease,such as tuberculosis and syphilis, were also considered in thedifferential diagnosis. Although most oral lesions of histoplas-mosis present as a solitary, variably painful ulceration, occa-sionally multiple oral ulcers may be seen.4,5 Tuberculosis, causedby Mycobacterium tuberculosis, can also occasionally present asmultiple oral ulcers with irregular borders and thus appear clini-cally similar to the current case.6 Additionally, syphilis, a ve-nereal disease caused by Treponema pallidum, in its secondary ordisseminated stage may occur as multiple, shallow oral mucosalulcerations.7

The patient was on an immunosuppressive regimen ofmycophenolate mofetil (CellCept) and tacrolimus (Prograf), bothof which have been associated with oral ulcerations in transplantpatients. Although relatively uncommon, 7 cases of oral ulcersassociated with use of mycophenolate mofetil and 1 case of oralulcerations associated with tacrolimus have been previously re-ported.8-14 Whereas ulcers due to mycophenolate mofetil may becaused by either drug toxicity or leukopenia, ulcers caused bytacrolimus are due to direct drug toxicity.10,14 Although recentblood studies ruled out the possibility of leukopenia in this pa-tient, the rather nonspecific histopathologic features could beconsistent with a drug reaction.

The lichenoid appearance of the buccal mucosal lesion (whitestriae-like changes surrounding an ulcer bed) provided furthersupport for the possibility of a drug-induced process, specificallya lichenoid drug reaction.3 However, graft-vs-host disease(GVHD) was also a consideration, as it can present with oralulcerations in association with reticular white striae involving theoral mucosa.3 Although GVHD occurs most commonly afterbone marrow transplantation, any procedure that introducesviable allogeneic lymphocytes is capable of inducing GVHD.15

More than 40 cases of GVHD in liver transplant patients havebeen reported since the first case report in 1988.16

Ultimately, a diagnosis of aphthous ulcerations was favored.Large, superficial and atypical ulcerations that clinically resemblemajor aphthous ulcerations have frequently been reported inimmunocompromised patients. A strong association has beenseen in patients infected with human immunodeficiencyvirus,17,18 but this process has also been well documented inassociation with immunosuppressive therapy, particularly withsirolimus and less frequently with tacrolimus.19,20 The nonspe-cific histopathologic findings supported this workingdiagnosis.21,22

Diagnosis and Management: Review of the previous his-tologic sections confirmed the diagnosis of nonspecific ulcer.Ulcerated surface oral epithelium was seen in association withgranulation tissue (Figure 4-2, A). The granulation tissue sup-ported a predominantly chronic inflammatory cell infiltrate,including scattered eosinophils and occasional mononuclear cellsexhibiting relatively large nuclei (see Figure 4-2, B). No evidenceof granuloma formation was seen. In situ hybridization forEpstein-Barr virus (EBV) via Epstein-Barr virus-encoded smallRNAs (EBERs) and immunohistochemical probe analysis forcytomegalovirus (CMV) were both negative. The epithelial


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pattern of maturation was unremarkable, and no evidence of viralcytopathic effect was observed.

Based on the nonspecific histopathologic findings, inconjunction with the clinical setting, a working diagnosis ofmajor aphthous ulcerations was rendered. An oral fungal culturewas performed, which proved to be strongly positive for Candidaalbicans, and the patient began a course of clotrimazole (Myce-lex) oral troches. After the antifungal regimen, she was instructedto commence use of prednisolone (Prelone) syrup (15 mg/5 mL),with 2 teaspoons used as a mouthrinse and swallowed once dailyfor 6 days, then 1 teaspoon used as a mouthrinse and expectoratedtwice daily until the mucosa felt comfortable.

The patient returned for reevaluation after 1 week of corti-costeroid use; there was minimal response to treatment. She wasasked to continue the corticosteroid regimen and return forfollow-up the following week. At 2.5 weeks of corticosteroid use,she presented with low-grade fever and malaise and minimal tono improvement in the oral lesions. She also reported a 5-dayhistory of cutaneous lesions on her back. Examination found acluster of two 0.3-cm to 0.4-cm intact cutaneous vesicles and 3crusted lesions of her right upper back (Figure 4-3, A). Thevesicles appeared somewhat translucent with an erythematousbase (see Figure 4-3, B). Based on these findings, a viral etiology

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Fig. 4-4. Microscopic examination found an intraepithelialvesicle with acantholytic changes (A) (hematoxylin-eosin,original magnification �10) and virally altered epithelial cellsexhibiting ballooning degeneration of epithelial cell nuclei andmultinucleation (B) (hematoxylin-eosin, original magnification�40). Immunohistochemical probe analysis for antibodiesdirected against varicella zoster virus was positive in the ma-jority of the altered keratinocytes (C) (original magnification�10).

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Fig. 4-3. A cluster of intact cutaneous vesicles and crustedlesions was noted on the patient’s right upper back (A). Thevesicles appeared somewhat translucent with an erythematousbase (B).

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was suspected, and the patient was instructed to discontinuecorticosteroid use, with immediate referral for dermatologicevaluation.

A cutaneous shave biopsy of the right upper back was per-formed, which found an intraepithelial vesicle with acantholyticchanges and virally altered epithelial cells (Figure 4-4, A).Ballooning degeneration of epithelial cell nuclei and multi-nucleation were occasionally observed (see Figure 4-4, B).Immunohistochemical probe analysis for antibodies directedagainst varicella zoster virus was positive in the majority of thealtered keratinocytes (see Figure 4-4, C), consistent with infectionby varicella zoster virus. Probes for herpes simplex virus types 1and 2 were negative.

The histopathologic and immunohistochemical findings, inconjunction with the clinical setting, supported a diagnosis ofdisseminated herpes zoster. The patient was immediatelyadmitted to the hospital, and intravenous acyclovir (Zovirax) wasadministered, resulting in swift resolution of the cutaneous andoral mucosal lesions. At the 2-month follow-up, the patient waswithout recurrence.

Discussion: Primary infection with varicella zoster virus(VZV), yielding chickenpox, usually presents in children. Afterinitial infection, VZV establishes latency in dorsal-root gangliaand can undergo future reactivation as herpes zoster (HZ), that is,shingles.3 Up to 20% of individuals develop HZ during theirlifetime, and the prevalence is rising in the elderly and in in-dividuals with impaired immune function or underlying malig-nancy.23-25 Because of the need for lifetime immunosuppression,solid organ transplant recipients are at increased risk for


developing HZ, with an incidence 10-fold to 100-fold greater thanthe general population.24 The overall incidence of zoster aftersolid organ transplant is 8.6%, and it is 5.7% when limited to livertransplant recipients.25

The clinical features of HZ typically include intense pain,followed by an eruption of clusters of vesicles that quickly

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rupture and result in small ulcerations and crusted lesions. Themucocutaneous lesions occur along an area innervated by a singlesensory nerve (dermatome). By definition, HZ is considered“disseminated” when the viral exanthema affects 3 or more der-matomes24; and in an immunocompromised host, disseminateddisease is of increased incidence.24,26 In this clinical setting, le-sions are also frequently larger and more irregular, and they willpersist and spread until the infection is treated or the immunefunction returns.3 In contrast, the clinical course of disease inimmunocompetent individuals typically results in complete res-olution of lesions within 2 to 3 weeks. Persistent pain, referred toas postherpetic neuralgia, occurs in up to 15% of affected patientsand is a complication seen with greater frequency in elderly orimmunosuppressed patients.23-25 In addition, visceral involve-ment and disseminated intravascular coagulation may occur withdisseminated zoster, making it a potentially fatal illness, with amortality rate as high as 30%.24 In solid organ transplant re-cipients, the median time to onset of HZ is 9 months posttrans-plant, and the independent risk factors include female gender andmycophenolate mofetil therapy,25,26 which are consistent with thecurrent case.

A strong presumptive diagnosis of HZ can often be madebased on the clinical presentation alone. However, laboratoryprocedures may be desirable for confirmation and may be anecessity for atypical cases. In the present case, the diagnoses ofherpes zoster was supported by histopathologic and immuno-histochemical findings of the cutaneous biopsy. The lack ofcharacteristic histologic features of viral cytopathic effect in theinitial oral mucosal biopsy is somewhat perplexing but mostlikely represents sampling error. Although it is possible that thispatient had 2 unrelated conditions, complete resolution of thelong-standing oral mucosal ulcerations after intravenousadministration of acyclovir supported the diagnosis of dissemi-nated HZ.

This case represents an unusual presentation of HZ in a livertransplant recipient. The annual number of solid organ transplantsthat are performed in the United States has dramatically increasedover the past few decades,27 and although improvements inimmunosuppression have increased survival, complications of aninfectious etiology are prevalent and should be a diagnosticconsideration for any nonhealing oral ulceration.

References1. Jones AC, Freedman PD, Phelan JA, Baughman RA,

Kerpel SM. Cytomegalovirus infections of the oral cavity: areport of six cases and review of the literature. Oral Sur OralMed Oral Pathol. 1993;75:76-85.

2. Lopez-Pintor RM, Hernandez G, de Arriba L, Morales JM,Jimenez C, de Andres A. Oral ulcers during the course ofcytomegalovirus infection in renal transplant recipients.Transplantation Proc. 2009;41:2419-2421.

3. Neville BW. Oral and Maxillofacial Pathology. 3rd ed. StLouis, MO: Saunders; 2009.

4. Sharma LC, Falodia J, Kalla K, et al. Esophageal histoplas-mosis in a renal allograft recipient. Saudi J Kidney DisTranspl. 2013;24:764-767.

5. Sinha S, Sardana K, Garg VK. Photoletter to the editor:disseminated histoplasmosis with initial oral manifestations. JDermatol Case Rep. 2013;7:25-26.

6. Sezer B, Zeytinoglu M, Tuncay U, Unal T. Oral mucosalulceration: a manifestation of previously undiagnosed pul-monary tuberculosis. J Am Dent Assoc. 2004;135:336-340.


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7. Czerninski R, Pikovski A, Meir K, et al. Oral syphilislesionsda diagnostic approach and histologic characteristicsof secondary stage. Quintessence Int. 2011;42:883-889.

8. Apostolou T, Tsagalis G, Koutroubas G, Hadjiconstantinou V,Drakopoulos S. Mycophenolate mofetil and oral ulcerations.Transplantation. 2004;77:1911-1912.

9. Garrigue V, Canet S, Dereure O, et al. Oral ulcerations in arenal transplant recipient: a mycophenolate mofetil-inducedcomplication? Transplantation. 2001;72:968-969.

10. Hernandez G, Jimenez C, Arriba L, Moreno E, Lucas M.Resolution of oral ulcerations after decreasing the dosage oftacrolimus in a liver transplantation recipient. Oral Surg OralMed Oral Pathol Oral Radiol Endod. 2001;92:526-531.

11. Miquel O, Chaby G, Andrejak M, et al. Mouth ulcers inducedby enteric-coated mycophenolate sodium [Myfortic]. AnnDermatol Venereol. 2007;134:855-857.

12. Naranjo J, Poniachik J, Cisco D, et al. Oral ulcers producedby mycophenolate mofetil in two liver transplant patients.Transplantation Proc. 2007;39:612-614.

13. Savas N, Sevmis S, Karakayali H, Yilmaz U, Haberal M.Orogenital ulcers in a liver transplant recipient: Discerningbetween mycophenolate-mofetil-induced complication andBehcet’s disease. Clin Transplant. 2009;23:147-149.

14. Weng RR, Foster CE 3rd, Hsieh LL, Patel PR. Oral ulcersassociated with mycophenolate mofetil use in a renal trans-plant recipient. Am J Health Syst Pharm. 2011;68:585-588.

15. Rogulj IM, Deeg J, Lee SJ. Acute graft versus host diseaseafter orthotopic liver transplantation. J Hematol Oncol.2012;5:50.

16. Wang B, Lu Y, Yu L, Liu C, Wu Z, Liu X. Diagnosis andtreatment for graft-versus-host disease after liver trans-plantation: two case reports. Transplantation Proc. 2007;39:1696-1698.

17. MacPhail LA, Greenspan D, Feigal DW, et al. Recurrentaphthous ulcers in association with HIV infection: descriptionof ulcer types and analysis of T-lymphocyte subsets. OralSurg Oral Med Oral Pathol. 1991;71:678-683.

18. Piluso S, Ficarra G, Lucatorto FM, et al. Causes of oral ulcersin HIV-infected patients: a study of 19 cases. Oral Surg OralMed Oral Pathol Oral Radiol Endod. 1996;82:166-172.

19. Chuang P, Langone AJ. Clobetasol ameliorates aphthousulceration in renal transplant patients on sirolimus. Am JTransplant. 2007;7:714-717.

20. Habib N, Salaro C, Al-Ghaithi K, et al. Severe aphthousstomatitis associated with oral calcineurin and mTOR in-hibitors. Int J Dermatol. 2010;49:91-94.

21. Boldo A. Major recurrent aphthous ulceration: case reportand review of the literature. Connecticut Medicine. 2008;72:271-273.

22. Ship JA. Recurrent aphthous stomatitis: an update. Oral SurgOral Med Oral Pathol Oral Radiol Endod. 1996;81:141-147.

23. Pergam SA, Forsberg CW, Boeckh MJ, et al. Herpes zosterincidence in a multicenter cohort of solid organ transplantrecipients. Transpl Infect Dis. 2011;13:15-23.

24. Rommelaere M, Maréchal C, Yombi JC, et al. Disseminatedvaricella zoster virus infection in adult renal transplant re-cipients: outcome and risk factors. Transplantation Proc.2012;44:2814-2817.

25. Gourishankar S, McDermid JC, Jhangri GS, et al. Herpeszoster infection following solid organ transplantation: inci-dence, risk factors and outcomes in the current immunosup-pressive era. Am J Transplant. 2004;4:108-115.

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Fig. 5-2. Fine-needle aspiration of the parotid.

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Fig. 5-3. Hematoxylin-eosin and cytokeratin (Lu-5).

OOOO ABSTRACTS


26. Lauzurica R, Bayés B, Frías C, et al. Disseminated varicellainfection in adult renal allograft recipients: role of myco-phenolate mofetil. Transplantation Proc. 2003;35:1758-1759.

27. US Department of Health and Human Services. Organ Pro-curement and Transplantation Network, 2011. Available at:http://optn.transplant.hrsa.gov.

CLINICOPATHOLOGIC CONFERENCE CASE 5: PA-TIENT PRESENTING WITH FACIAL ABSCESS ANDAGGRESSIVE OSTEOLYSIS WITH PROMINENT PERI-OSTEAL REACTION OF THE MANDIBLE H. Chehal,JW Rohrer, JA Kini, MJ Palazzolo, Creighton University,School of Dentistry, Omaha, NE, USA; San Antonio MilitaryMedical Center, Fort Sam Houston, TX, USA

Clinical Presentation: A 78-year-old man, a nonsmokerand nondrinker, presented with right-sided facial swelling of thecheek and neck for 2 months. He reported periodic drainage intohis oral cavity. Eventually, the facial swelling involved the areafrom his ear to the area under his chin and made talking andretaining saliva difficult. Additionally, his right eye wasbecoming difficult to open, owing to the edema. He reported 20lb of recent weight loss over the last month that he attributed tostress from a financial situation. Clinical evaluation found CNVII near complete paralysis, House-Brackmann grade 6, and afirm mass in the area of the parotid. He was admitted to themedicine service with a large parotid gland/jaw abscess forintravenous antibiotics and further work-up. The patient wasstarted on broad-spectrum antibiotics, underwent incision anddrainage, and had an additional diagnosis of bacterial endo-carditis. Magnetic resonance imaging of the face found a 2.5 �3.0 � 2.8-cm enhancing parotid mass with associated calcifi-cations and central necrosis (Figure 5-1, B). In addition,aggressive osteolysis, with a prominent periosteal reaction of theadjacent mandible (standardized uptake value, 12.7) was noted(see Figure 5-1, A, B).

Differential Diagnosis: Jaw lesions that frequently exhibit aperiosteal reaction include osteomyelitis, trauma, and

Fig. 5-1. A, Aggressive osteolysis, with a prominent periostealreaction of the adjacent mandible. B, Magnetic resonance imag-ing and positron emission tomography scan.


bisphosphonate-related osteonecrosis. Less commonly, such re-actions may be seen in association with osteosarcoma, chon-drosarcoma, and metastatic lesions to the jaws. Other rarer butimportant lesions presenting with periosteal reactions includeEwing sarcoma, lymphoma, and leukemia. Periosteal reactionscan be of varying radiographic presentations, including solid,single-layered, multilamellated, spiculated, disorganized, andCodman triangle. Spiculated periosteal reaction, considered to beaggressive, can be of hair-on-end or sunray type. Hair-on-endperiosteal reaction may be seen most often in Ewing sarcoma,osteosarcoma, or metastatic lesions, whereas a sunray reactionmay be seen commonly in osteosarcoma, hemangioma, or oste-oblastic metastasis (prostatic, bronchioalveolar, and breast).Osteomyelitis, an inflammatory process of bone, may also show anonspecific periosteal reaction with cortical plate disruption.

Diagnosis and Management: Further imaging, after theinitial control of the infection, found extensive disease in the areaof the parotid gland, extending to the parapharyngeal space,wrapping around the carotid vessels and extending to the base ofthe skull. This made the tumor surgically unresectable. Fine-needle aspiration of the parotid gland found abundant groups ofmalignant cells with large, pleomorphic nuclei and no obviousstromal component. Some of these groups formed glandularstructures (Figure 5-2). Immunohistochemical stains were posi-tive for a keratin cocktail (Lu-5). However, the tumor cells were

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Fig. 5-4. Cytokeratin CK7 and CK20 immunohistochemicalstains.

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Fig. 5-5. Prostate-specific antigen and positive control.



negative for CK5/CK6. Prostate-specific antigen, CdX-2, smoothmuscle actin, S-100, and monoclonal carcinoembryonic antigen.

These findings were consistent with adenocarcinoma withhigh-grade features. A positron emission tomographyecomputedtomography scan found diffuse cervical lymphadenopathy. Therewas a 6.0 � 5.6 � 4.0-cm fluorodeoxyglucose (FDG)-avid mass(maximum standardized uptake value [SUV], 21.2) in the rightparotid with corresponding 2.0-cm FDG-negative component,representing the central necrosis (see Figure 5-1, B). Theremaining enlarged parotid gland had significant FDG avidity(SUV, 10.2). An incisional biopsy of the right mandible foundadenocarcinoma involving bone. In the absence of a distant tu-mor, the patient was staged at T4 N2B M0 and combinedchemotherapy and radiation therapy were recommended, ac-cording to the multidisciplinary tumor board. After 12 months offollow-up, re-imaging of the patient found that the tumor in thearea of the parotid had increased in size with marked soft tissuethickening and enhancement of the right face extending inferiorlyinto the neck, concerning for dermal lymphatic invasion. Inaddition, at 12 months of follow-up, no evidence of anotherdistant tumor was found. Other images from this case are shownin Figures 5-3 to 5-5.

Discussion: Salivary gland tumors account for about 5% ofall neoplasms of the head and neck. Most occur in the parotidgland.1 Only about 15% to 32% of parotid gland tumors aremalignant.2 The average annual incidence rate of salivary glandmalignancies in the United States is reported at 1.41 cases per 100000 males and 1.00 cases per 100 000 in females.3 According tovarious studies, the peak incidence of salivary gland tumors oc-curs in the sixth and seventh decades of life.2,4 The factorsresponsible for carcinogenesis in the major salivary glands remainunclear; however, one of the well-established risk factors isexposure to ionizing radiation, as supported by studies on atomicbomb survivors.5-8 Therapeutic radiation and radioactive iodinehave also been linked to salivary gland carcinogenesis.9-11 The5-year relative survival rate for salivary gland cancer depends onthe stage. From stage I to IV, the rates are 96%, 77%, 73%, and37%, respectively.12 Although parotid malignancies are relatively


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rare, they still constitute a serious disease burden because of theirpoor prognosis, particularly in patients with high-grade malig-nancies with advanced disease.

Disclaimer: The opinions and assertions expressed hereinare those of the authors and are not to be construed as official oras reflecting the views of the Department of the Air Force or theDepartment of Defense.

References1. Ho K, Lin H, Ann DK, Chu PG, Yen Y. An overview of the

rare parotid gland cancer. Head Neck Oncol. 2011;3:40.2. Ellis GL, Auclair PL. AFIP Atlas of Tumor Pathology, Series

4, Fascicle 9: Tumors of the Salivary Glands. Silver Spring,MD: American Registry of Pathology Press; 2008.

3. Surveillance, Epidemiology, and End Results (SEER) Pro-gram, National Cancer Institute, DCCPS, SurveillanceResearch Program, Cancer Statistics Branch. released April2011.

4. Eveson JW, Cawson RA. Salivary gland tumours: a review of2410 cases with particular reference to histological types, site,age and sex distribution. J Pathol. 1985;146:51-58.

5. Saku T, Hayashi Y, Takahara O, et al. Salivary gland tumorsamong atomic bomb survivors, 1950-1987. Cancer. 1997;79:1465-1475.

6. Land CE, Saku T, Hayashi Y, et al. Incidence of salivarygland tumors among atomic bomb survivors, 1950-1987:evaluation of radiation-related risk. Radiat Res. 1996;146:28-36.

7. Takeichi N, Hirose F, Yamamoto H, Ezaki H, Fujikura T.Salivary gland tumors in atomic bomb survivors, Hiroshima,Japan, II: pathologic study and supplementary epidemiologicobservations. Cancer. 1983;52:377-385.

8. Belsky JL, Tachikawa K, Cihak RW, Yamamoto T. Salivarygland tumors in atomic bomb survivors, Hiroshima-Nagasaki,1957 to 1970. JAMA. 1972;219:864-868.

9. Beal KP, Singh B, Kraus D, Yahalom J, Portlock C,Wolden SL. Radiation-induced salivary gland tumors: areport of 18 cases and a review of the literature. Cancer J.2003;9:467-471.

10. Kaste SC, Hedlund G, Pratt CB. Malignant parotid tumors inpatients previously treated for childhood cancer: clinical andimaging findings in eight cases. AJR Am J Roentgenol.1994;162:655-659.

11. Hoffman DA, McConahey WM, Fraumeni JF Jr, Kurland LT.Cancer incidence following treatment of hyperthyroidism. IntJ Epidemiol. 1982;11:218-224.

12. American Cancer Society, from the National Cancer Data-base, based on people who were diagnosed with cancer of themajor salivary glands between 1998 and 1999.

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