Adenoma versus Carcinoid Tumor of the Middle Ear: a
Study of 48 Cases and Review of the Literature
Kevin R. Torske, D.D.S., M.S., Lester D.R. Thompson, M.D.
Department of Endocrine and Otorhinolaryngic–Head and Neck Pathology, Armed Forces Institute of
Pathology, Washington, D.C.
Carcinoid tumors and adenomas of the middle ear
are rare neoplasms of indeterminate relationship to
one another. Indeed, the literature is devoid of a
large comprehensive series that evaluates the clini-
cal, histologic, and immunophenotypic features of
these tumors and their potential relationship.
Forty-eight cases of middle ear adenoma between
1970 and 1995 were identified in the files of the
Armed Forces Institute of Pathology. All cases were
evaluated for cytomorphology and architectural
pattern, in addition to their reactivity with various
immunohistochemical reagents. Clinical follow-up
was also obtained. A comprehensive review of the
literature was performed with an eye toward corre-
lating any distinct differences or similarities be-
tween carcinoid tumors and adenomas of the mid-
dle ear. The patients included 21 women and 27
men, aged 20 to 80 years (mean, 45.0 y). Patients
experienced hearing loss, mass, and/or pain for a
mean duration of 1.7 years. The mean tumor size
was 0.8 cm, with six tumors extending beyond the
middle ear. Histologically, the tumors were moder-
dular, trabecular, and solid patterns composed of
small cells with “salt and pepper” nuclear chroma-
tin distribution. The tumor cells were immunoreac-
tive with keratin, keratin 7, chromogranin, and hu-
man pancreatic polypeptide. All patients had
surgery. No patients died with their disease (mean
follow-up, 15.7 y). Eight patients developed recur-
rences that were treated surgically and were with-
out evidence of disease at last follow-up (mean,
15.1 y). Our study and the review of the literature
dle ear to be essentially indistinguishable benign
tumors. Middle ear adenoma most correctly de-
scribes their morphologic features and clinical be-
havior, although neuroendocrine adenoma of the
middle ear may be a more accurate designation.
KEY WORDS: Adenoma, Carcinoid, Immunohisto-
chemistry, Middle ear, Prognosis.
Mod Pathol 2002;15(5):543–555
Adenomas and carcinoid tumors of the middle ear
are rare neoplasms with similar, if not indistin-
guishable, morphologies. First described in 1976 (1,
2) and further elaborated upon in 1980 (3), these
tumors have been the subject of much debate with
regard to their similarities, differences, etiologies,
and prognoses. Limited mostly to case reports and
small series, the English-language literature is de-
void of a large comprehensive evaluation of these
tumors with respect to their histomorphology, im-
comes, and clinical behavior. We elected to under-
take such a study with an eye toward identifying
any distinct separation of these two tumors.
MATERIALS AND METHODS
The records of 68 patients with tumors diagnosed
as “middle ear adenoma,” “ceruminal gland adeno-
ma,” and “atypical middle ear adenoma” were
identified in the files of the Otorhinolaryngic-Head
& Neck Registry at the Armed Forces Institute of
pathology from 1970 to 1995. No records of “carci-
noid tumors” of the middle ear were located in the
registry. This lack was considered not to be due to
the true absence of such a tumor but more to the
preferred designation of this tumor as “middle ear
adenoma” by Dr. Hyams and his colleagues within
the Department of Otorhinolaryngic Pathology.
These 68 patients were identified in a review of
1,703 patients with primary benign or malignant
neoplasms of the ear seen in consultation during
this same time period. However, 20 patients were
Copyright © 2002 by The United States and Canadian Academy of
VOL. 15, NO. 5, P. 543, 2002 Printed in the U.S.A.
Date of acceptance: January 30, 2002.
The opinions or assertions contained herein are the private views of the
authors and are not to be construed as official or as reflecting the views of
the Department of the Navy or Department of Defense.
Address reprint requests to: Lester D.R. Thompson, M.D., Department of
Endocrine and Otorhinolaryngic–Head and Neck Pathology, Building 54,
Room G066–11, Armed Forces Institute of Pathology, 6825 16th Street
NW, Washington, DC 20306–6000; e-mail: email@example.com; fax:
excluded from further consideration because of at
least one of the following reasons: (1) paraffin
blocks were unavailable for additional sections or
immunophenotypic analysis (2); the original sub-
mitted case did not have sufficient demographic
information supplied from which to obtain ade-
quate follow-up information; and (3) the cases were
diagnosed indefinitely, using terms such as consis-
tent with, suggestive of, or suspicious for, which
usually indicated a lack of sufficient diagnostic ma-
terial from which to proffer a definitive diagnosis.
Therefore, the remaining 48 patients with middle-
ear adenomas (2.8% of all ear neoplasms within the
files of the AFIP) compose the subject of this study
based on adequate hematoxylin and eosin-stained
slides to make a definitive diagnosis and adequate
demographic information for initial attempt at
follow-up. Forty-three cases were obtained from
civilian sources, including university medical cen-
ters and foreign contributors, four cases from mil-
itary hospitals, and one case from a Veterans Ad-
ministration medical center.
Materials within the Institute’s files were supple-
mented by a review of the patient demographics
(gender, age) and symptoms at presentation (mass,
hearing loss, bleeding, infection, pain, nerve paral-
and/or popping), including duration. In addition,
we reviewed radiographic, surgical pathology, and
operative reports, and obtained follow-up informa-
tion from oncology data services by written ques-
tionnaires or direct communication with the treat-
ing physician(s) or the patient. Follow-up data,
available for 45 patients, included information re-
garding tumor location, presence of recurrent or
metastatic disease, treatment modalities used, and
the current patient and disease status. This clinical
investigation was conducted in accordance and
compliance with all statutes, directives, and guide-
lines of the Code of Federal Regulations, Title 45,
Part 46, and the Department of Defense Directive
3216.2 relating to human subjects in research.
The macroscopic pathologic observations noted
within this study were garnered from the individual
gross descriptions of the neoplasms by the contrib-
uting pathologists. Hematoxylin and eosin–stained
slides from all patients were reviewed for morpho-
logic assessment of middle-ear adenoma/carci-
noid, as originally defined by both Hyams et al. and
Murphy et al. (2, 3) A number of macroscopic and
histologic observations were recorded for each tu-
mor as follows: exact tumor location; tumor size
(greatest dimension in centimeters); tumor encap-
sulation (presence or absence); tumor extension
(mastoid bone, eustachian tube, and/or external
auditory canal); architectural pattern of growth
(solid, trabecular, organoid, infiltrating, and/or
glandular); surface origin or pagetoid spread; pres-
ence or absence of necrosis; tumor cellularity (low,
moderate, or high); mitotic figures (number of mi-
totic figures per 10 high power fields [magnification
at 40? with a 10? objective lens using an Olympus
BX40 microscope]); atypical mitotic figures (present
or absent, and defined by abnormal chromosome
spread, tripolar or quadripolar forms, circular
forms, or indescribably bizarre); nuclear pleomor-
phism (mild, moderate or severe); presence or ab-
sence of nucleoli; and the presence of other micro-
scopic pathologic findings.
Immunophenotypic analysis was performed in
all cases with suitable material by the standardized
avidin–biotin method of Hsu et al. (4) employing
sections. Table 1 documents the pertinent, com-
mercially available immunohistochemical antibody
panel used. The analysis was performed on a single
representative block in each primary tumor. When
required, proteolytic antigen retrieval was per-
formed by predigestion for 3 minutes with 0.05%
Protease VIII (Sigma Chemical Co., St. Louis, MO)
in a 0.1 M phosphate buffer, pH of 7.8, at 37 ° C.
Cellular conditioning to achieve antigen enhance-
ment (recovery) was performed by using formalin-
fixed, paraffin-embedded tissue treated with a buff-
Table 1. Immunohistochemical Panel
Antigen or Antibody
Human pancreatic polypeptide
Biochemicals, Indianapolis, IN,
and DAKO, Carpinteria, CA
Becton Dickson, San Jose, CA
Ventana, Tucson, AZ
BioGenex Labs, San Ramon, CA
mm, mouse monoclonal; rp, rabbit polyclonal.
ered citric acid solution and heated for 20 minutes
in a calibrated microwave oven. Afterwards, the
sections were allowed to cool at room temperature
in a citric acid buffer solution for 45 minutes before
continuing the procedure. Standard positive con-
trols were used throughout, with serum used as the
negative control. The antibody reactions were
graded as absent to weak (0–1?), moderate (2?–
3?), and strong (4?) staining, and the fraction of
positive cells was determined by separating them
into four groups: ?10%, 11–50%, 51–90%, and
Our review of the literature was extensive, based
on a MEDLINE search from 1966 to 2001. However,
for purposes of succinctness, we limited our inclu-
sion to articles with pathology descriptions written
Clinical Demographics and Presentation
A summary of the clinical information on the
patients in this series is provided in Table 2. The
patients included 21 women and 27 men, aged 20 to
80 years with a mean of 45.0 years at the time of
initial clinical presentation (Table 2). The women
had a slightly older mean age at presentation (47.9
y) than the men (42.7 y), but this difference was not
Patients presented with a variety of symptoms,
but the most frequently identified single symptom
was hearing loss (n ? 33 patients; Table 2). A variety
of other more nonspecific symptoms were noted
and included mass (n ? 12 patients), pain (n ? 11
patients), discharge (n ? 7 patients), equilibrium
changes (n ? 7 patients), tinnitus or popping (n ?
6 patients), nerve paralysis (n ? 4 patients), infec-
tion (n ? 2 patients), and bleeding (n ? 1 patient).
Obviously, many patients (n ? 24 patients) pre-
sented with more than one symptom. Tumors were
discovered incidentally during routine physical ex-
amination or diagnostic radiographic studies per-
formed for nonrelated reasons in four patients.
The duration of symptoms lasted from 1 to 228
months, with a mean of 20.8 months (Table 2).
Female patients had a longer average duration of
symptoms (29.4 mo) than males (14.1 mo); how-
ever, this finding was skewed by two female pa-
tients with extraordinarily long symptom duration
(120 and 228 mo, respectively).
Radiographic assessments were only available for
two patients. Both depicted nondestructive mass
lesions within the middle ear without evidence of
bone invasion. Opacification of the middle ear and
mastoid air cells was noted in both patients.
All patients presented with unilateral disease, al-
though more tumors presented on the right (n ? 26
patients) than the left (n ? 22 patients; Table 3).
Most of the lesions were excised in a piecemeal
fashion. The overall aggregate mean tumor size was
0.8 cm, with a range of 0.2 to 3.0 cm (Table 3), with
no difference in the mean tumor size between
women (0.74 cm) versus men (0.84 cm) or between
the right (0.81 cm) and left (0.80 cm). The tumors
were noted to extend into the external auditory
canal alone (n ? 2 tumors), the external auditory
canal and mastoid bone (n ? 1 tumor), the mastoid
bone alone (n ? 1 tumor), eustachian tube and the
mastoid bone (n ? 1), and the eustachian tube
alone (n ? 1 tumor). The lesions most commonly
filled the middle-ear cavity and were intimately as-
sociated with the ossicular chain.
Table 2. Clinical Features in Middle-Ear Adenomas
Clinical Characteristic Data (N ? 48)
Age at presentation (y)
Symptoms at presentationa
Bleeding, infection, discharge, nerve paralysis,
equilibrium changes, and/or tinnitus or
Asymptomatic (identified incidentally during
Duration of symptoms (mo)
aPatients may have presented with more than one symptom; therefore
the numbers do not add up to the total number of patients.
Table 3. Macroscopic Features of Middle-Ear Adenomas
Macroscopic Feature Data
Primary site, (n)
Tumor size (cm)
Tumor extensiona, (n)
External auditory canal
aExtension may have involved mastoid bone and eustachian tube or
mastoid bone and external auditory canal.
Adenoma of the Middle Ear (K.R. Torske et al.) 545
The tumors were described macroscopically as
avascular, soft or rubbery unencapsulated masses
with a variegated cut surface. The lesions tended to
be gray-tan, brown-red, or pale yellow.
The microscopic findings are displayed in Table
4. All tumors were unencapsulated and most were
of moderate cellularity. The tumors were predomi-
nantly composed of cuboidal-to-columnar cells
with indistinct cytoplasmic borders (Fig. 1). Flat-
tened, irregular, plasmacytoid, and spindled mor-
phologies were also noted. The cytoplasm was eo-
sinophilic and homogenous to finely granular.
The nuclei tended to be round to oval with min-
imal pleomorphism. Moderate to severe nuclear
pleomorphism was only occasionally observed. The
chromatin tended to display a “salt-and-pepper”
pattern consistent with neuroendocrine origin, es-
pecially in the cells comprising the trabecular and
solid patterns and those comprising the external
cellular layer of the ductal structures (see below).
Otherwise, the chromatin was fine and even in ap-
pearance. The nuclei were centrally or eccentrically
placed, giving some cells a “plasmacytoid” appear-
ance. Intranuclear cytoplasmic inclusions were in-
frequently identified. Nucleoli were inconspicuous,
and mitoses were essentially absent.
Architectural patterns included glandular, tra-
becular, solid, organoid, and infiltrative (Fig. 2). The
architecture varied between tumors and even
within the same tumor (Fig. 3), with 81% (37/48)
displaying more than one pattern. The glandular
pattern predominated and was seen in 73% (35/48)
of the cases, followed by trabecular (60%), solid
(33%), infiltrative (15%), and organoid (8%).
The glandular pattern consisted of duct-like
structures with focal “back-to-back” gland configu-
ration. The ducts were lined by a dual cell popula-
tion composed of an inner (luminal), flattened,
slightly more intensely eosinophilic cell surrounded
by a basally positioned cuboidal to short columnar
cell (Fig. 4). The glandular lumen was occasionally
filled with an amorphous, pink substance. Papillary
structures were not identified.
The trabecular pattern was composed of variably
sized columnar cells with round to elongated nu-
clei. Clefting (considered artifactual) between the
trabecular epithelial cells and the fibrous stroma
was consistently identified. The solid pattern dis-
played variable cellular cohesiveness and also
showed artifactual clefting between the solid is-
lands and the fibrous stroma. The “infiltrative” pat-
tern was characterized by small irregular groups
and strands of cells in a moderately desmoplastic
stroma. This pattern gave the illusion of the tumor
cells dissecting the collagen bundles in an uncon-
trolled and aggressive fashion. The cells tended to
be smaller than those within the other patterns with
a higher nuclear-to-cytoplasmic ratio; however,
other features of true aggressiveness such as mitotic
activity, pleomorphism, necrosis, bone, perineural,
or lymph–vascular space invasion were not noted.
Finally, the organoid pattern consisted of variably
sized, rounded nests of tumor cells with a polygonal
or spindled morphology.
Definitive surface derivation was not seen in this
clinical series. Pagetoid-like spread was noted in
only two tumors. In both cases orthokeratinized
squamous epithelium showed focal nests of tumor
cells at all levels (Fig. 5). As the surface mucosa of
the middle ear is usually a nonkeratinized, modified
respiratory epithelium, the orthokeratinized squa-
mous epithelium noted within the two cases of
pagetoid spread may have indicated perforation
into the external auditory canal. Reactive squamous
metaplasia of the middle-ear muscosa or tympanic
membrane to the presence of the underlying tumor
may also explain this finding. As both biopsies were
significantly fragmented, the exact location of any
one tumor fragment was equivocal. One of the
cases with pagetoid spread also displayed focal tu-
mor necrosis, the only tumor within this series with
such a finding. One of the patients with pagetoid
spread developed recurrent disease but did not
have evidence of disease at last follow-up.
The tumor cells were immunoreactive with a va-
riety of keratin antibodies, including cytokeratin
(CK) cocktail (89.6%), CK7 (89.6%), and CAM 5.2
(81.3%; Table 5). The CK reactivity was usually very
intense and strong (4?). CK20, when present (3 of
48tumors), was only
focally and weakly
Table 4. Microscopic Features of Middle-Ear Adenomas
Number with only a single pattern
Surface origin or pagetoid spread (n)
Pleomorphism, (moderate to severe), n
Other histologic findings (n)
aThe architecture usually included more than one pattern, except for
nine cases that only presented a single histologic pattern.
The CK immunoreactivity was primarily distrib-
uted within glandular structures. Moreover, the
CK7 immunoreactivity specifically highlighted the
inner (luminal) layer of the glandular cells with a
uniform and intense result (Fig. 6), although it was
only variably present with moderate to strong reac-
tivity in the other architectural patterns.
Neuroendocrine marker immunoreactivity in-
enolase (NSE; 50%), synaptophysin (31.3%), and
FIGURE 1. Neuroendocrine adenoma of the middle ear displaying a trabecular growth pattern composed of columnar cells with round-to-oval
nuclei, ‘salt-and-pepper’ chromatin pattern, and eosinophilic, finely granular cytoplasm.
FIGURE 2. Multiple architectural patterns are present in neuroendocrine adenomas of the middle ear. Upper left, solid growth pattern with
plasmacytoid cells. Upper right, trabecular growth pattern with artifactual clefting. Lower left, infiltrative pattern. Lower right, organoid pattern.
Adenoma of the Middle Ear (K.R. Torske et al.) 547
serotonin (25%). Neuroendocrine markers were
positive within the basal cell layer of the glandular
elements while more diffusely positive in the other
architectural patterns. Reactivity, however, was not
uniform and varied both between cases and in level
of intensity. In all but two cases, at least one neu-
roendocrine marker was present to a significant
degree. Both of the nonreactive cases displayed a
predominant glandular pattern but were positive
for HPP in the basal cells.
FIGURE 3. Single tumor displaying multiple growth patterns, to include infiltrative (upper right), organoid (upper central), solid, trabecular, and
FIGURE 4. Glandular pattern with easily identifiable inner, flattened cellular layer, and an outer cuboidal-to-columnar layer. Note the lightly
basophilic amorphous material present within the glandular lumina.
HPP was at least focally positive in nearly all
cases (45/48, 93.8%). Reactivity occurred in the
same distribution as the other neuroendocrine
markers and tended to be of moderate-to-strong
intensity (Fig. 7). The three nonreactive cases dis-
played positive staining for NSE, chromogranin,
synaptophysin, and/or serotonin.
S-100 was positive in the lesional cells in 15% of
cases. Interestingly, strong reactivity was also noted
within the stromal nuclei in 18% of the lesions. The
significance of this finding is unclear but may indi-
cate a stromal dendritic cell reaction to the invad-
ing tumor cells.
Clinical Therapy and Patient Outcome
All tumors were managed by surgery. The surgi-
cal procedures were most often excisional biopsy
via a simple or modified mastoidectomy. Radical
mastoidectomy was performed in cases where tu-
mor encased the ossicles. Secondary reconstructive
procedures were not documented. Radiation ther-
apy or chemotherapy was not used for any of the
Ten patients developed recurrent disease or have
not been disease free. Two patients elected not to
have a definitive or wide excision, and so over the
course of 11.6 and 13.6 years, respectively, these
patients have had multiple “biopsies” to remove the
bulk of the tumor in each case, but have never had
a definitive resection. If these two patients are ex-
cluded from further consideration, eight patients
Table 5. Immunohistochemical Panel Results
Intensity (% of Cells
Reactive): no. of cases
Cytokeratin 43 (89.6)
Keratin 7 43 (89.6)
3 (6.4)1? ? 3? (?75%):3
CAM5.2 39 (81.3)
Chromogranin 42 (87.5)
Serotonin 12 (25.0)
Neuron-specific enolase 24 (50.0)
Human pancreatic polypeptide 45 (93.8)
1? ? 4? (?1–?90%):15
2? ? 4? (?75%):8
48 (100)4? (?90%):48
FIGURE 5. Pagetoid spread within metaplastic middle ear mucosa or external ear canal mucosa.
Adenoma of the Middle Ear (K.R. Torske et al.)549
developed recurrences. These eight patients in-
cluded six men and two women, aged 32–65 years,
with an average age at presentation of 46.9 years.
The symptoms were similar, with an average dura-
tion of 14.0 months. The mean size of the tumor
was 1.0 cm, with seven tumors involving the left
and one the right. Only one tumor extended into
the mastoid bone. Two tumors had moderate nu-
FIGURE 6. Glandular lumen with an inner flattened layer (arrows), surrounded by an outer cuboidal layer. Cytokeratin 7 immunohistochemistry
(bottom left) highlights the inner epithelial layer.
FIGURE 7. Human pancreatic polypeptide (left) and cytokeratin 7 (CK7; right) immunohistochemistry. Note the predominantly basilar staining
pattern of the HPP and the inner, luminal pattern of the CK7.
550 Modern Pathology
clear pleomorphism and two had high cellularity.
All were managed by excisional biopsy (n ? 8 pa-
tients). In all recurrences, the initial excision was
conservative, leaving the ossicular chain intact. At
the time of the recurrence, slightly more aggressive
surgical excisions resulted in a clinical cure, espe-
cially when the involved ossicles were removed
with the tumor.
There were no significant differences in morphol-
ogy, immunohistochemistry, clinical presentation,
or treatment outcomes in the group of patients
analyzed. These findings lead to the conclusion that
only one type of neoplasm was represented in our
clinical series, which displayed numerous different
architectural patterns but similar cytomorphology
and immunohistochemical reactive patterns.
Carcinoid Tumor versus Middle Ear Adenoma
Benign neuroendocrine lesions of the middle ear
have been described by many names, including
carcinoid tumor (CT) (3), middle-ear adenoma
(MEA) (2), adenomatous tumor of the middle ear (1,
5), adenocarcinoid, and amphicrine tumor (6), with
carcinoid tumor and middle-ear adenoma being the
most accepted. There has been much debate in the
literature as to the true nature of these neoplasms
and whether they are similar, related but dissimilar,
or totally separate entities. We feel that they repre-
sent the same tumor with different degrees of glan-
dular and neuroendocrine differentiation.
Review articles of both MEAs and CTs have de-
scribed a similar average age at presentation of
approximately 37 years and a roughly equal gender
distribution (2, 7–10). Clinical presentation has also
been similar, with decreased hearing acuity, full-
ness, and tinnitus being the most frequently ex-
pressed symptoms. These findings are similar to
those of this clinical series, although our average
age (45 y) was slightly older.
At surgery, carcinoid tumors and middle-ear ad-
enomas are both tightly adherent to the middle-ear
cavity, commonly encasing the ossicular chain. Per-
foration of the tympanic membrane with extension
into the external auditory canal was an occasional
feature (2, 7, 9, 11). However, destruction of or
invasion into the surrounding bone has only rarely
been reported (7, 9, 12), is not extensive in nature,
and tended to bony erosion rather than destruc-
tion. Either tumor tended to be avascular, gritty,
fibrous, or rubbery and appeared pale reddish-gray
or yellow-tan (13).
Microscopically, middle-ear adenomas and car-
cinoid tumors have also been described as display-
ing similar, if not indistinguishable morphologies
(2, 7–9, 11). Architecturally, the neoplasms are ar-
ranged in glandular spaces, trabeculae, festoons,
ribbon-like patterns, anastomosing cords, and solid
sheets with variable cohesiveness. The glandular
spaces commonly contained an amorphous secre-
tory product that stained with mucicarmine, peri-
odic acid–Schiff, and Alcian blue. The predominant
architectural pattern tended to vary between tu-
mors and even within the same tumor. In both
neoplasms, the cells are described as cuboidal-to-
columnar, uniform in size, with eosinophilic, finely
granular cytoplasm. The nuclei are round-to-oval
with finely dispersed chromatin and may be cen-
trally or eccentrically placed. A plasmacytoid ap-
pearance may be noted (14). Nucleoli are incon-
spicuous and mitoses are essentially absent. All
these cytomorphologic and architectural features
were observed within this clinical study.
Immunohistochemical staining for both MEAs
and CTs has demonstrated similar results (5, 6, 11,
14–17). Cytokeratin cocktail and vimentin immu-
nostaining have been uniformly positive. Neuroen-
docrine markers such as NSE, chromogranin, and
synaptophysin have been uniformly present, al-
though not necessarily all in the same tumor. Vari-
able positivity for S-100, serotonin, glucagon, Leu-7,
ACTH, and somatostatin has also been noted. Hu-
man pancreatic polypeptide was uniformly positive
within both tumors with only rare exception (two of
our reported cases; 16). Although lysozyme immu-
noreactivity was considered essential for the diag-
nosis of MEA by one author (7), its absence has
been noted by others (5, 11, 14, 16, 17), and we did
not perform this reaction in this clinical series.
The location and degree of positivity of the im-
munohistochemical staining varied with the archi-
tectural pattern. In small series and in this clinical
study, CK was most strongly deposited in the cyto-
plasm of the glandular component and weakest
within the solid component (15, 16). Neuroendo-
crine markers were most strongly identified in the
trabecular, ribbon, and solid components while
Table 6. Overall Patient Outcome (All Follow-up in Years)
Group All Casesa
All cases, n (follow-up in y)
Patients with extension, n (follow-up in y)
Patients with recurrences, n (follow-up in y)
aFollow-up was available in 45 of the 48 patients; NED, no evidence of disease; D, with disease; n/a, nonapplicable.
Adenoma of the Middle Ear (K.R. Torske et al.) 551
only weakly demonstrated in the glandular compo-
nent (16, 17). Keratin 7 demonstrated a distinctly
glandular specificity, especially for the inner lining
cells of the glandular lumina, a finding not reported
before now. These architecturally associated differ-
ences in immunohistochemical staining may have
led different authors to favor either MEA or CT.
Although not performed for this study, middle-
ear adenomas and carcinoid tumors have been ex-
tensively examined by the use of electron micros-
copy, and the results were similar (5, 6, 11, 15,
17–19). Electron microscopy demonstrated two dis-
tinct cell types, so-called Type A and Type B cells.
The Type A cells were noted within the apical as-
pect of the glandular lumina and rarely scattered
within the solid areas. These cells exhibited a flat-
tened apical pole and thin, elongated microvilli.
Most significantly, these cells demonstrated exo-
crine activity with apically oriented 275–600 nm
secretory granules composed of a flocculent dense
core and an electron-lucent rim, representative of
mucus granules. The granules were occasionally
noted to fuse with the apical cellular membrane,
thereby discharging their secretory product.
The Type B cells were noted in the basal aspect of
the glandular structures and were the predominant
cell within the solid, trabecular, and ribbon-like
formations. They were most noteworthy for their
basally located 110–350-nm cytoplasmic dense-
core neurosecretory granules that were surrounded
by a thin halo and distinct limiting membrane.
Furthermore, a transitional form exhibiting features
of both Type A and Type B cells has also been
The immunohistochemical findings support the
electron microscopic features (5, 6, 11, 14–18, 20,
21). The Type A cells found within the glandular
lumens stained with keratins, especially keratin 7.
Cytokeratin staining was still present, although less
intensely, within the Type B cells found within the
solid, trabecular and other components. Con-
versely, the Type A cells were negative for neuroen-
docrine markers, whereas the Type B cells dis-
played intense immunoreactivity in keeping with
their neuroendocrine nature.
The clinical (age, gender predilection), histologic,
immunohistochemical, and electron microscopic
features of these middle-ear neoplasms are similar
to those of carcinoid tumors found within the lung
against the diagnosis of a carcinoid tumor within
the middle ear have stemmed primarily from its
lack of paraneoplastic syndromes (i.e., “carcinoid
syndrome”) and lack of documented metastasis to
regional lymph nodes or distant sites. Paraneoplas-
tic systemic alterations caused by the elaboration of
hormonal products are a well-known feature of car-
cinoid tumors, especially the so-called “carcinoid
syndrome” consisting of flushing, diarrhea, sweat-
ing, wheezing, and abdominal pain. However, lung
carcinoid tumors only present with systemic alter-
ations in less than 5% of cases. When systemic
changes are present, these lung tumors tend to be
large (?3.5 cm; 28). The correlation of large tumor
size to increased levels of hormone elaboration is
logical, although these large tumors also have a
greater frequency of liver metastasis that increases
the chance of a paraneoplastic syndrome. With this
in mind, the lack of systemic changes associated
with those tumors of the middle ear may be more a
function of their relatively small size (average, 0.8
cm in this study) rather than a lack of biologic
potential. This is supported by their immunohisto-
chemical staining for hormone products such as
serotonin, ACTH, glucagon, HPP, and somatostatin.
In fact there is a case of carcinoid tumor of the
middle ear presenting with carcinoid syndrome
(flushing, palpitation, dizziness, and diarrhea; 29).
Unfortunately, no account was given as to the rel-
ative time frame between the disappearance of
symptoms and the removal of the tumor, nor were
the symptoms investigated by additional biochem-
ical analysis because they were not initially thought
to be related to the patient’s complaints.
The metastatic rate for typical carcinoids of the
lung is approximately 23% (28). Those that do me-
tastasize tend to go to regional lymph nodes or the
liver. The lack of documented metastasis of the
tumors of the middle ear may be explained by the
smaller size of the neoplasms in addition to the
relative lack of vascularity of the middle-ear cavity
when compared with the lung. Only a single case of
metastasis to cervical lymph nodes has been docu-
mented (30). This tumor was initially treated with
external beam radiation and developed multiple
recurrences. The metastatic
showed significant pleomorphism and moderate
mitotic activity, both of which were lacking in the
previous biopsies of the middle-ear mass. Although
attributed to the tumors’ inherent biologic poten-
tial for metastasis, we feel that the history of treat-
ment with radiation therapy and the significant
change in cytomorphology more likely represented
a radiation-induced malignant transformation.
Carcinoid tumors of the lung are thought to orig-
inate from enterochromaffin cells (Kulchitsky cells),
which are neuroendocrine cells normally present in
the lung parenchyma. These cells are considered to
originate from an endodermally derived pluripo-
tential stem cell (26, 27). In common with the lung,
the mucosa of the middle ear is also derived from
the endoderm (15, 31, 32). However, epithelial cells
with neuroendocrine characteristics (such as the
Kulchitsky cells of the lung) are not noted within
the middle-ear cavity, either in healthy or inflamed
states (5, 33–35). Therefore, an easily identifiable
progenitor cell is lacking within the middle ear,
endodermal stem cell may still be present within
the surface mucosa of the middle ear that may give
rise to carcinoid neoplasms similar to the cell of
origin hypothesized for the lung (17).
Hyams and Michaels (2) were the first to hypoth-
esize that middle-ear adenomas originated from
the mucosal epithelium of the middle ear. This was
due in part to the perception of tumor cells within
the surface epithelium with invasion of the under-
lying stroma. We were unable to confirm this find-
ing, either in this clinical series or in a review of the
literature. In addition, critical analysis of the pho-
tomicrograph within the article used to document
surface derivation (Fig. 5 on pg. 20) shows it to be
more in keeping with a ceruminal adenoma with a
thick, apparently bilayered epithelium forming
ductal structures with many papillations and de-
capitation apocrine secretions. This is in contrast to
the thin, non-papillated glandular pattern found in
the rest of their cases (specifically Fig. 1) and in this
clinical series. Mills and Fechner (7) are attributed
with observing actual derivation from the surface
mucosa. However, not only is this feature not doc-
umented by a photomicrograph, but it is also de-
scribed as tumor cells “replacing” the overlying ep-
ithelium as opposed to originating from it. This is
similar to our observation of pagetoid-like spread
noted within two of the neoplasms in this series.
The lack of evidence for surface epithelial deriva-
tion leads to the consideration of a stromal precursor.
The stroma of the middle ear is derived from meso-
derm and the neural crest (31, 32, 36). The neural
crest gives rise to parts of the ossicular chain and the
three primary paraganglia (tympanic glomus, jugular
glomus, and satellite glomus of Curveilhier-Arnold)
(37, 38) The glomus cells normally display neuroen-
docrine characteristics with neuroendocrine dense
core granules and positive immunohistochemical
staining for NSE, chromogranin, and/or synaptophy-
sin. Epithelial or exocrine characteristics are not nor-
mal features of these cells. However, rare paragangli-
omas have been noted to show CK positivity
indicative of epithelial expression or perhaps even
transformation (6, 39, 40). Therefore, it is plausible
that a neuroendocrine neoplasm of the middle ear
may originate from a neural crest–derived stem cell.
In either event, a metaplastic alteration would be
required within resident cells of the middle ear to
account for the dual population noted within these
tumors. Either uncommitted epithelial (endoder-
mal) cells would develop neuroendocrine features
or uncommitted neural crest cells would acquire
exocrine and epithelial characteristics. Despite the
lack of evidence for a surface mucosal origin, their
close histologic and clinical relationship to carci-
noid tumors of the lung favors an origin from an
uncommitted endodermal stem cell. It is plausible
that endodermally derived stem cells may have be-
come sequestered within the stroma of the middle
ear during embryogenesis, thereby explaining the
predominant stromal location of these tumors.
Benign or Malignant?
Most authors consider typical carcinoid tumors
of the lung to behave as low-grade malignant tu-
mors. This is supported by their low, but still sig-
nificant metastatic potential (?23%; 28). An alter-
ation in nomenclature
neuroendocrine tumor” has been proposed to bet-
ter define the histologic, morphologic, and clinical
characteristics of typical carcinoid tumors (25). Al-
though not yet adopted by the World Health Orga-
nization, the nomenclature of well-differentiated
neuroendocrine tumor, well-differentiated neuroen-
docrine carcinoma, and poorly differentiated neu-
roendocrine carcinoma are logical replacements for
typical carcinoid, atypical carcinoid, and small cell
carcinoma of the lung, respectively.
Carcinoid tumors of the middle ear, unlike their
relatives in the lung, have not shown metastatic
potential. Whether because of a difference in bio-
logic potential between the middle ear neoplasms
and their supposed pulmonary counterparts or be-
cause of the anatomic constraints of the middle ear
and its relative lack of vascularity, these tumors
clinically behave as benign entities. Bone invasion
and destruction is highly uncommon with these
lesions and, when present, is more in keeping with
low-grade adenocarcinomas of endolymphatic sac
origin (endolymphatic sac tumors; 31) or metastatic
neoplasms to the middle ear. The recurrence rate
for these neuroendocrine neoplasms of the middle
ear is also quite small (see below). When they do
recur, it is usually related to regrowth of an incom-
pletely excised tumor as opposed to an inherent
biologic aggressiveness. Case reports have been
presented of unilateral facial paralysis associated
with this tumor (17, 41–43). Indeed, three of the
cases in this clinical series also displayed nerve-
related symptoms. Nevertheless, facial paralysis
does not seem to portend an adverse clinical out-
come as all patients in this series, and those within
the literature with adequate follow-up had these
symptoms resolve after complete tumor removal.
These findings suggest mass-related compression
of the facial nerve rather than direct neural inva-
sion. In summary, if one defines “malignancy” by
clinical aggressiveness and potential for metastatic
spread, then the tumors of the middle ear should be
regarded as benign.
Adenoma of the Middle Ear (K.R. Torske et al.) 553
Typical carcinoid tumor, by definition, is a low-
grade malignant neoplasm. Although the tumors
within the middle ear are histologically (by light
and electron microscopy) and immunohistochemi-
cally similar to carcinoid tumors, their benign clin-
ical nature precludes including them within this
group. Although the neuroendocrine features of
this tumor are not adequately conveyed by middle-
ear adenoma, it is a correct description of the be-
nign nature of the tumor and its location. Neuroen-
docrine adenoma of the middle ear may be an
excellent alternative as it suggests a correct mor-
phologic and behavioral moniker of this rare
Treatment and Prognosis
Complete surgical removal of the neoplasm, to
include encased ossicles (if present), should be the
treatment of choice (7, 11, 35, 44). When the ossic-
ular chain is involved but not removed, recurrence
(regrowth) of the lesion is much more likely. With
this said, two of the patients within our study were
being treated with repeated debulking procedures
to preserve the ossicular chain and thereby main-
tain hearing. This practice, although not supported
nor discouraged by the authors, would require ex-
cellent continued long term clinical follow-up and
patient compliance. In addition, the biologic poten-
tial for true malignant transformation of longstand-
ing tumors has not been studied, although must be
exceedingly uncommon given the scarcity of re-
ported cases and no transformations identified in
this large clinical study.
Radiation therapy is not required for these tu-
mors (45). In fact, secondary malignant transforma-
tion of these tumors is a possible outcome if our
hypothesis for the one reported case of metastatic
spread is correct (30).
This clinical study uncovered an approximate
18% recurrence rate (not including those two pa-
tients who elected to forgo complete surgical exci-
sion). All recurrences developed when the ossicular
chain was not excised during initial surgery,
thereby potentially leaving the patient with residual
tumor. Subsequent surgical procedures to thor-
oughly remove all involved structures resulted in a
good clinical outcome. Although we did not docu-
ment recurrences in patients who had initial com-
plete removal of the tumor, other investigators have
reported recurrence in isolated patients (7, 45).
Carcinoid tumor and middle-ear adenoma are
two well-documented, albeit rare, neoplasms of the
middle ear. Despite considerable debate over the
perceived similarities and differences between
these two tumors, we believe that they actually
represent the same tumor. We draw this conclusion
based on similarities in clinical, histologic (by light
and electron microscopy), and immunohistochem-
ical results, both within our study and in the review
of the literature. Although akin to that of typical
carcinoid tumors of the lung, the middle-ear neo-
plasms’ clinical behavior merits a benign designa-
tion. We favor middle-ear adenoma as it correctly
describes the benign clinical nature of this neo-
plasm, although neuroendocrine adenoma of the
middle ear may be an even better designation.
Treatment consists of complete surgical excision
with removal of the ossicular chain, if involved.
Recurrence is rare with initial complete excision.
Acknowledgment: The authors thank Dr. Dennis
Heffner for his critical analysis of the manuscript,
insight, and support.
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