Family With Low-Grade NeuroendocrineCarcinoma of Salivary Glands, SevereSensorineural Hearing Loss, andEnamel Hypoplasia

L. Michaels,1* K. Lee,2 S.L. Manuja,3 and S.O. Soucek4

1Department of Histopathology, UCL Medical School, and Royal National Throat, Nose and Ear Hospital, RoyalFree Hospital Trust, London, United Kingdom

2Formerly of the Institute of Dental Surgery, University of London, London, United Kingdom3ENT Department, Noble’s Isle of Man Hospital, Douglas, Isle of Man, Great Britain4ENT/Audiology Department, St. Mary’s Hospital, London, United Kingdom

Four sibs in a family on the Isle of Man, twobrothers and two sisters ranging in age from33 to 45 years, presented with low-grade ma-lignant tumors of the submandibular glandin three cases and of the nasal cavities andmaxillary sinuses in one. The neoplasmswere all of the same histological type, ap-parently hitherto undescribed, showingwell-differentiated neoplastic ducts, sur-rounded by neoplastic myoepithelial cells,together with sheets of epithelial cells ex-pressing neuroendocrine markers by immu-nohistochemistry. Cervical neck node me-tastases have developed in all four cases. Inthe sib with a primary sinonasal neoplasm,widespread bloodstream metastases also be-came manifest and a single such metastasisin his brother. All four sibs have severeenamel hypoplasia and the same lesion ispresent in 5 of their 11 children. In the twomale patients, severe sensorineural hearingloss has developed in adult life, unilateral inthe left ear in one brother, bilateral in theother. In the brother with bilateral sensori-neural hearing loss, magnetic resonanceimaging revealed a vestibular schwannomaon the left side, which is currently undertreatment. The inherited hearing loss isthought to be unilateral in this case also.Am. J. Med. Genet. 83:183–186, 1999.© 1999 Wiley-Liss, Inc.

KEY WORDS: salivary gland neoplasia;neuroendocrine carcinoma;amelogenesis imperfecta; he-reditary sensorineural hear-ing loss

INTRODUCTION

We present here a small family of which in four sibsthere is a slowly-growing salivary gland malignantneoplasm, enamel hypoplasia (amelogenesis imper-fecta, AI), and in two of them, sensorineural hearingloss (SNHL); AI is present in some of the offspring ofthe four sibs. The neoplasm shows the features of ahitherto undescribed type of neuroendocrine carcinomaof salivary glands.

PEDIGREE

This is the pedigree of the three generations of thefamily who live on the Isle of Man, Great Britain (Fig.1). All four sibs, two males and two females, of thesecond generation (cases II-2, II-3, II-6, and II-7) havedeveloped a low-grade neuroendocrine carcinoma ofsalivary glands, the submandibular glands in threecases and the minor salivary-type glands of the nasalcavities and maxillary sinuses in one. Three of the foursibs of the second generation (cases II-3, II-6, and II-7)are edentulous, probably as the result of enamel hypo-plasia (amelogenesis imperfecta, AI) and the latter le-sion is present in 4 of the 11 children of the third gen-eration (cases III-2, III-3, III-4, and III-7). Both malesof the second generation have developed severe hearingloss in adult life, one now having a “dead ear” on bothsides and the other having a “dead ear” on one side only(cases II-3 and II-7).

Contract grant sponsor: Isle of Man Health Services.*Correspondence to: Professor L. Michaels, Department of His-

topathology, UCL Medical School, Rockefeller Building, Univer-sity Street, London, WC1E 6JJ, U.K. E-mail: l.michaels@ucl.ac.uk

Received 9 July 1998; Accepted 2 December 1998

American Journal of Medical Genetics 83:183–186 (1999)

© 1999 Wiley-Liss, Inc.

Histories of Family Members With Definite orPossible Neoplasms, Amelogenesis Imperfecta,

or Hearing Loss

Case I-2: female age 67 years. The left subman-dibular gland was removed for swelling at age 37 years.The pathology record cannot be found. However, it ispossible that the submandibular salivary gland con-tained a neoplasm of the same type as that which de-veloped in her four children.

This person was edentulous, but on questioning shestated that her teeth became brownish yellow and allhad to be removed. It must be presumed that she suf-fered from AI.

Case II-2: female age 46 years. This person, theoldest of the four sibs affected by the neoplasm, wasconceived when her mother was 21 years old. Promi-nent swelling was present on the left side of jaw fromage 10 years. A left submandibular gland neoplasmwith a cervical lymph node metastasis was removed in1984. Now she has large spherical swelling of the rightupper neck and a diffuse swelling of the left floor ofmouth, but has refused additional surgical treatment(Fig. 2).

This person has normal teeth and no evidence ofhearing loss.

Case II-3: male age 45 years. Nine years ago atage 36 he developed bilateral maxillary antral tumors.These were removed at bilateral Caldwell-Luc opera-tions. After a year recurrence in left antrum, the lymphnode metastases in the neck and both submental andfloor of mouth masses were noted. A year ago metas-tases became manifest in the 12th thoracic vertebraand left wrist.

This person is now edentulous with a history that hisdentition showed evidence of AI in early adulthood re-quiring that all teeth should be removed.

He was found to be completely hearing impaired onthe right side at age 7 years. At age 25 years the hear-ing on the left side started to deteriorate, but unlikethat on the right, this was at first correctable with a

Fig. 1. Pedigree of family.

Fig. 2. Face and neck of case II-2, showing large swelling of low-gradeneuroendocrine carcinoma metastatic to cervical lymph nodes on theleft.

184 Michaels et al.

hearing aid. At age 29 years he had numerous bouts ofvertigo. These became less frequent, but were presentup to the age of 42. Audiogram showed no hearing ineither ear. Promontory stimulation demonstrated noresponse on right side but some response on left side.Magnetic resonance imaging demonstrated a tumor,possibly a small vestibular schwannoma confined tothe left internal auditory canal.

The findings would suggest that the inherited hear-ing loss is right-sided only; the loss on the left sideprobably was caused by a vestibular schwannoma. Thelatter is presently being treated by local irradiationusing the gamma knife technique with the object ofpreserving some acoustic nerve function so as to enablecochlear implantation to be carried out later on thisside.

Case II-6: female age 43 years. Developed bilat-eral submandibular neoplasms and cervical lymphnode swellings 13 years ago. These were misdiagnosedas lymphoma, and she was treated by chemotherapy.Additional swellings developed in both submandibularglands, which were removed, but there are recurrencesin the floor of the mouth.

This person was edentulous with a history that thedentition showed evidence of AI in early adulthood re-quiring all teeth to be removed.

There was no evidence of hearing loss in either ear.Case II-7: male age 33 years. Submandibular

masses were present for some years but he refused bi-opsy until 1 year ago when biopsy removal showed bi-lateral submandibular gland low-grade neuroendo-crine carcinoma with lymph node metastases. Recentlyhe developed a nodular metatastasis in the right tra-pezius muscle.

This person was edentulous with a history that thedentition showed evidence of AI in early adulthood re-quiring all teeth to be removed.

Eight years ago he suffered numerous attacks of ver-tigo over a period of approximately 9 months. Follow-ing this he underwent gradual increase of deafness inhis left ear and now has complete sensorineural loss inthat ear. Audiogram demonstrated no hearing in theleft ear. Computed tomography scan demonstrated noabnormality of bony labyrinth on either side.

Case III-2: male age 16 years.

Teeth present: 7654321 1234567

7654321 1234567

All teeth are affected by AI; all are brown. The an-terior teeth are of normal shape, but cusp structures inthe posterior teeth appear deficient. The findings aretypical of type IIB in the Witkop modification of Winterand Brookes classification [Witkop, 1988] as pigmentedhypomaturation.

This person has no evidence of a neoplasm and hishearing is normal.

Case III-3: female age 10 years.

Teeth present: 65421 12C4E6

654321 12C456

The maxillary anterior teeth are most severely af-fected and display vertical bands especially on the rightincisors and second premolar and also on the mandibu-lar second molar. Transverse striae are seen on thelateral surfaces of all four mandibular incisors, corre-sponding to perikymata. The lateral surface of theright first maxillary incisor is deficient in enamel on itsright half. The presence of the vertical bands is highlysuggestive of X-linked hypoplasia/hypomineralization(type IIB).

This girl has no evidence of a neoplasm, and herhearing is normal.

Case II-4: female age 9 years.

Teeth present: 6E421 12CDE6

6EDC1 12CDE6

Both sets of teeth are affected with brown yellowsurfaces. Vertical bands are also seen especially in themaxillary anterior teeth. This patient appears to ex-hibit the same type of defect as her sister.

This girl has no evidence of a neoplasm, and herhearing is normal.

Case II-7: female age 6 years.

Teeth present: EDCBA ABCDE

EDCBA ABCDE6

All maxillary incisors and the left first maxillary pre-molar appear to be the only teeth showing grossenamel deficiency, which is present on the incisal sur-face. The findings are suggestive of partial enamelagenesis (type IG) hypoplasia.

This girl has no evidence of a neoplasm, and herhearing is normal.

PATHOLOGY

The neoplasm in each of the four sibs displays simi-lar histological appearances (Fig. 3). Normal salivarygland tissues (or, in case II-3, the nasal tissues includ-ing the normal seromucinous salivary type glands) areinfiltrated in each case by a neoplasm with three dis-tinct cellular elements. Most of the tumor tissue is com-posed of loose regular-appearing cells. These cells con-tain numerous Grimelius-positive granules, stronglyexpress neuron specific enolase, and protein gene prod-uct (neuroendocrine characteristics), but not cytoker-atins or S-100 protein. Scattered uniformly among theneuroendocrine cells are small well-formed duct struc-tures. The cells lining these ducts appear epithelial intype and express cytokeratins. Surrounding most ofthese duct structures are attenuated cells with longthin cytoplasmic processes that stain with S-100 pro-tein, indicating their myoepithelial origin.

Salivary, Dental, and Hearing Disorder 185

Electron microscopy of paraffin-embedded tumor tis-sue was carried out in three of the cases. Although thetissue was not well preserved, in each case neuro-secretory-like granules could be detected in most tumorcells. These were membrane-bound, dense-cored struc-tures measuring 90–160 nm in diameter.

From the light microscopy, ultrastructure, histo-chemistry, and immunohistochemistry of the neo-plasms together with their clinical behavior we havedesignated them as “low-grade neuroendocrine carci-nomas.”

DISCUSSION

This is a pleiotropic X-linked or autosomal dominantsyndrome of cancer, AI and SNHL, of most unusualtype apparently previously unclassified. Undifferenti-ated small cell carcinomas of salivary glands with neu-roendocrine characteristics are well known, but wehave not been able to find a published description of thehistological type of neoplasm, low-grade neuroendo-crine carcinoma, exhibited by four of the sibs in thiskindred. Moreover, although other neuroendocrine tu-mors of the head and neck, in particular paraganglio-mas, frequently are familial, salivary tumors of anytype are rarely so.

Another component manifestation in this family isthe presence of presumed (cases I-2, II-3, II-6, and II-7)and definite (cases III-2, III-3, III-4, and III-7) amelo-genesis imperfecta. Fourteen different subgroups of AIhave been identified based on differences in clinicalmanifestations and Mendelian inheritance pattern.Autosomal dominant forms of inheritance have beenestablished in some families and candidate genes havebeen identified on chromosome 4 in this group

[Karrman et al., 1997]. X-linked inheritance of AI hasalso been recorded and the gene defects have been iden-tified by molecular-genetic methods in such families[Lagerstrom et al., 1991]. Two members of the family,brothers in the second generation (cases II-3 and II-7),have severe, adult-onset, hearing loss. It is possiblethat this too is a manifestation of the syndrome inher-ited in this family. The syndrome segregating in thisfamily may be caused by an X-chromosomal or autoso-mal mutation.

The recent discovery of a unilateral possible vestib-ular schwannoma in case II-3 is of interest, but cannotat present be explained on a hereditary basis.

ACKNOWLEDGMENTS

Professor B.A.J. Ponder of the CRC Human CancerGenetics Research Group, University of Cambridge,Dr. W. Reardon of the Department of Genetics, Insti-tute of Child Health, London, and Dr. N. Lench of theDepartment of Molecular Medicine, University ofLeeds, advised on the genetic aspects. The study wasfunded by the Isle of Man Health Services.

REFERENCES

Karrman C, Backman B, Dixon M, Holmgren G, Forsman K. 1997. Map-ping of the locus for autosomal dominant amelogenesis imperfecta(AIH2) to a 4-MB YAC contigon chromosome 4q11- q21. Genomics 39:164–170.

Lagerstrom M, Dahl N, Nakahori Y, Nakagome Y, Backman B, LandegrenU, Pettersson U. 1991. A deletion in the amelogenin gene (AMG) causesX-linked amelogenesis imperfecta. Genomics 10:971–975.

Witkop CJ Jr. 1988. Amelogenesis imperfecta, dentinogenesis imperfectaand dentin dysplasia revisited: problems in classification. J Oral Pathol17:547–553.

Fig. 3. Histological appearances of submandibular neoplasm in case II-1, showing loose, regular-appearing cells that display neuroendocrine char-acteristics on immunohistochemistry, and duct-like structures with central epithelial cells and peripheral myoepithelial cells (arrows).

186 Michaels et al.