Histopathologic and Clinical Features of Medullary
Microcarcinoma and C-Cell Hyperplasia in Prophylactic
Thyroidectomies for Medullary Carcinoma
A Study of 42 Cases
Demet Etit, MD; William C. Faquin, MD, PhD; Randall Gaz, MD; Gregory Randolph, MD;
Ronald A. DeLellis, MD; Ben Z. Pilch, MD
Context.Prophylactic thyroidectomies are increasingly
performed on patients at risk for developing medullary thy-
roid carcinoma (MTC); consequently, pathologists are
more commonly encountering these specimens in routine
practice.
Objective.To describe the detailed clinicopathologic
features of prophylactic thyroidectomies for medullary car-
cinoma.
Design.We present a retrospective series of 42 pro-
phylactic thyroidectomies for MTC performed for one or
more of the following: family history of multiple endocrine
neoplasia (MEN) or MTC, elevated serum calcitonin level,
or detection of a RET proto-oncogene mutation.
Results.Patients included 22 men and 20 women
(mean age, 26.2 years). Among those with known RET
proto-oncogene mutations, affected sites included exons
10, 11, 14, and 16. In 93% (n 39) of cases, either
C-cell hyperplasia (n 36), medullary microcarcinoma
M edullary thyroid carcinoma (MTC) is an uncommon
thyroid malignancy of C-cell derivation represent-
ing approximately 3% to 12% of all thyroid cancers.13 It
has a propensity for metastasis to regional lymph nodes,
and the average 10-year survival for all types of MTC
ranges from 61% to 75%.3,4 Although a majority of MTCs
are acquired as sporadic tumors, 25% to 30% of cases are
heritable, being associated with multiple endocrine neo-
plasia (MEN) 2A, MEN 2B, or with the familial medullary
thyroid carcinoma syndrome.1,5,6 Inherited forms of MTC
are due to autosomal dominant mutations of the RET pro-
Accepted for publication April 8, 2008.
From the Departments of Pathology (Drs Etit, Faquin, and Pilch) and
Surgery (Drs Gaz and Randolph), Massachusetts General Hospital, and
the Massachusetts Eye and Ear Infirmary, Harvard Medical School (Drs
Faquin, Gaz, Randolph, and Pilch), Boston; and the Department of
Pathology, Rhode Island Hospital, Brown University Medical School,
Providence (Dr DeLellis). Dr Etit is now with the Department of Pa-
thology, Ataturk Research and Training Hospital, Izmir, Turkey.
The authors have no relevant financial interest in the products or
companies described in this article.
Reprints: Ben Z. Pilch, MD, Department of Pathology, Warren 219,
Massachusetts General Hospital, 55 Fruit St, Boston, MA 02115
(e-mail: bpilch@partners.org).
Arch Pathol Lab MedVol 132, November 2008
(MMC; n 29), or medullary macrocarcinoma (n 1) was
found. C-cell hyperplasia was often multifocal (n 30) and
bilateral (n 23) and included both nonnodular and nod-
ular patterns. A total of 94% of C-cell hyperplasia cases
and all MMC cases were microscopically detectable using
hematoxylin-eosin stains. The MMCs were characterized by
a complex microarchitectural pattern with a desmoplastic
stromal response (n 29) and focal amyloid deposition (n
12). Most MMCs exhibited a solid pattern (n 24) of
round, polygonal, spindled, or plasmacytoid-shaped cells.
Only 1 case of MMC showed evidence of metastatic dis-
ease to a pretracheal lymph node.
Conclusions.Based upon our clinicopathologic find-
ings and review of the literature, we conclude that thy-
roidectomies in at-risk patients are very frequently asso-
ciated with C-cell hyperplasia and/or MMC; however, the
clinical prognosis for these patients is very good.
(Arch Pathol Lab Med. 2008;132:17671773)
to-oncogene with incomplete penetrance, often presenting
as multifocal disease in a background of C-cell hyperpla-
sia (CCH). With routine testing of family members of af-
fected patients for RET proto-oncogene mutations coupled
with screening of serum calcitonin levels in affected in-
dividuals, patients with inherited forms of MTC are being
detected at earlier stages, often before the development of
clinically detectable MTC.7 Prophylactic thyroidectomies
are increasingly being performed on patients at risk for
MTC, and as a consequence, pathologists are more com-
monly encountering these specimens in routine practice.7,8
To add to our understanding of the range of histopatho-
logic changes within these prophylactic thyroidectomies,
we describe our experience based on the clinicopathologic
features of a series of 42 cases and compare it with results
in the literature.
MATERIALS AND METHODS
The database of the Department of Pathology at Massachusetts
General Hospital, Boston, was searched to retrospectively iden-
tify specimens of thyroidectomies that were performed prophy-
lactically for possible MTC. The search encompassed cases ac-
cessioned during a 30-year period (19772007). To qualify for in-
clusion within the study, the thyroidectomy had to be performed
for one or more of the following reasons: a positive family history
Prophylactic Thyroidectomy for Medullary CarcinomaEtit et al 1767
of MEN 2A, MEN 2B, or familial MTC, an elevated serum cal-
citonin level, or a RET proto-oncogene mutation. In addition, a
member of an affected family was screened for an elevated serum
calcitonin or a RET proto-oncogene mutation in order to have a
prophylactic thyroidectomy. Using these criteria, 42 cases with
available histology slides were identified for inclusion in the
study group. For each case, clinical charts and records were re-
viewed to document patient demographics, ultrasound findings,
family history, including MEN status or history of MTC, serum
calcitonin levels, RET proto-oncogene mutation status, and clin-
ical follow-up. Although the cases in this study came from a 30-
year period, the most current presurgical workup of patients pri-
or to prophylactic thyroidectomy for MTC at Massachusetts Gen-
eral Hospital includes the following: serum calcitonin and carci-
noembryogenic antigen measurements, calcium and parathyroid
hormone determinations to exclude parathyroid hyperplasia, 24-
hour urine for catecholamines, vanillylmandelic acid, and meta-
nephrines to exclude pheochromocytoma, and RET oncogene
analysis to determine the need for family screening. Preoperative
imaging included ultrasound evaluation and neck computed to-
mography for evaluation of cervical lymph nodes. Among the
patients in our series where presurgical ultrasound records were
available, 13 had ultrasonographically visualized nodules rang-
ing from less than 0.5 cm to 2.2 cm; 7 were multifocal and 4 were
bilateral. All of these patients received a prophylactic thyroidec-
tomy for possible MTC or CCH. Although fine-needle aspiration
is typically performed for any thyroid nodule larger than 1.0 cm,
none of the patients in our series, based upon medical records
available for review, had a presurgical fine-needle aspiration eval-
uation.
Serum Calcitonin Measurements
Serum calcitonin measurements were conducted using the
DPC Immulite 2000 Chemiluminescent Method (Siemens Health-
care Diagnostics, Deerfield, Ill) in blood samples.
RET Proto-oncogene Analysis
A total of 32 of 42 patients within our study were evaluated
for mutations of the RET proto-oncogene prior to thyroidectomy
once this test became available for standard screening. Genomic
DNA was obtained from submitted blood samples according to
standard procedures.9,10 Polymerase chain reaction was used to
amplify exons 10, 11, 13, 14, 15, and 16 of the RET gene. Sequenc-
es of primers and polymerase chain reaction protocols were ob-
tained from previously published sources.11
Histochemical and Immunohistochemical Stains
Immunohistochemical stains for calcitonin were performed on
selected paraffin blocks using the avidin-biotin peroxidase meth-
od with an anti-calcitonin antibody at a 1:500 dilution (Dako Cor-
poration, Carpinteria, Calif) and processed using automated im-
munostaining (Ventana Benchmark, Tucson, Ariz). The positive
control tissue was an MTC sample that was not included in the
study. For each case, 1 to 5 blocks were stained for calcitonin
immunoreactivity. In 21 cases where focal amyloid was suspect-
ed based upon hematoxylin-eosin findings, a Congo red stain
was performed using standard methods.
Histopathologic Evaluation
All specimens were inspected grossly, and multiple sections
were taken. Thirty-four of the thyroidectomies were entirely sub-
mitted for histologic evaluation, and 8 cases had representative
sections submitted. For these 8 cases, the median number of sec-
tions per centimeter of thyroid was 1.1 sections per cm length of
thyroid (range, 1.01.7 sections per cm length). Glass slides and
special stains from each of the 42 cases were reviewed by 3 pa-
thologists (B.Z.P., W.C.F., and D.E.), and a selected number of
cases were reviewed with a fourth pathologist (R.A.D.). A con-
sensus opinion was reached for the presence of CCH and MTC.
The criterion for CCH was the presence of 50 or more C cells per
low-power field (100). For each case, at least 1 block was stained
1768 Arch Pathol Lab MedVol 132, November 2008
for calcitonin for confirmation. C-cell hyperplasias were histo-
morphologically separated into nodular CCH, that is, C cells fill-
ing a thyroid follicle, or nonnodular CCH, and solitary or mul-
tifocal. Relative to the classification scheme for CCH described
by Perry et al,12 the nodular CCH cases in our series are equiv-
alent to their neoplastic nodular CCH. In addition, the nonno-
dular CCH category presented here encompasses both the focal
and diffuse CCH as described by Perry et al. Medullary micro-
carcinomas (MMCs), as defined by the World Health Organiza-
tion, were less than 1 cm in greatest dimension13,14 and were eval-
uated for the implied invasion through the follicular basement
membrane by assessing the presence of irregular outlines and
sclerosis within solid foci of C cells. In 22 patients, regional
lymph node samplings were evaluated histopathologically, and
the parathyroid tissues of 12 patients were also examined.
Follow-up
Clinical follow-up information was available for 29 of the pa-
tients within our series. The range of follow-up was 1 month to
30 years (average follow-up, 4.7 years), and follow-up data in-
cluded contents of clinical notes, radiologic imaging, and serum
calcitonin levels.
RESULTS
There were 20 female and 22 male patients who ranged
in age from 2 to 73 years (mean age, 26.2 years). The cor-
responding family history, MEN status, and results of
RET proto-oncogene analysis for the 42 patients in our
series are presented in Table 1. A total of 71.4% of patients
(n 30) had MEN 2A, and 95% of patients (n 40) had
a positive family history of MTC. Of 32 patients who had
RET proto-oncogene analysis, 29 (90.6%) had a mutation
detected, 14 in exon 14 codon 804 (V804M), 9 in exon 11
codon 634 (C634A), 5 in exon 10 codon 609 (C609S), and
1 in exon 16 codon 918 (M918T). In 31 (77.5%) of 40 pa-
tients where results of calcitonin screening were available,
the basal and/or stimulated serum calcitonin level was
high (range, 62200 pg/mL) relative to the reported age-
and sex-specific normal reference range.
Histomorphologic Findings
All patients included in the series (n 42) had a pro-
phylactic total thyroidectomy performed. A total of 93%
of patients (n 39) had either CCH and/or MTC; 85.7%
(n 36) had at least a single focus of CCH, and 71.4% of
patients (n 29) had at least 1 focus of MMC. One patient
had a medullary macrocarcinoma (1.1 cm). Among the
MMCs, 62% (n 18) were multifocal, 48% (n 14) were
bilateral, and 38% (n 11) were solitary. Only 3 cases
(7%) showed neither MMC, MTC, nor CCH, and in all 3
cases, the entire thyroid glands had been submitted for
evaluation. The results of the histomorphologic findings
are summarized in Tables 1 and 2. Cases with CCH in-
cluded solitary and multifocal CCH. In 83.3% of cases (n
30), the CCH found on the examined slides was mul-
tifocal, and 77% (n 23) were bilateral. The foci of CCH
were nodular in 33% (n 10), nonnodular in 23% (n
7), and mixed nodular and nonnodular in 43% (n 13)
of cases (Figure 1, A). Although not all foci of CCH were
seen using hematoxylin-eosin staining alone, 94.4% (n
34) were detectable on hematoxylin-eosin. Foci of CCH
were characterized histologically by cells that were slight-
ly larger than adjacent follicular cells with granular cy-
toplasm, round nuclei, and coarse granular chromatin
(Figure 1, B).
The mean size of the MMCs was 0.3 cm, with a size
range of less than 0.1 to 0.8 cm. In every case of MMC
Prophylactic Thyroidectomy for Medullary CarcinomaEtit et al
 Table 1. Clinicopathologic Features of Study Cases
Case MEN Family MTC Foci and Specimen
No. Status* History Age, y/Sex RET Proto-oncogene CCH Foci Size in cm Sampling
1 MEN 2A Positive 37/F Positive (V804M) exon 14 MF nodular MF, up to 0.1 Entirely
2 MEN 2A Positive 19/F Positive (V804M) exon 14 MF nonnodular Absent Entirely
3 MEN 2A Positive 19/F Positive (V804M) exon 14 MF nonnodular Absent Entirely
4 MEN 2A Positive 20/M Positive (V804M) exon 14 MF nodular nonnodular Absent Entirely
5 Non-MEN Positive 9/M Positive (C609S) exon 10 MF nodular nonnodular S, 0.1 Entirely
6 MEN 2A Positive 20/F Positive (C620F) exon 10 S nodular (on recut gone) Absent Entirely
7 MEN 2A Positive 3/F Positive (C634A) exon 11 MF nonnodular nodular S, 0.1 Representative
8 MEN 2A Positive 11/F Positive (C634A) exon 11 MF nonnodular MF, up to 0.3 Entirely
9 MEN 2A Positive 70/F Positive (V804M) exon 14 MF nodular nonnodular MF, up to 0.4 Representative
10 MEN 2A Positive 45/F Positive (V804M) exon 14 Absent S, 0.1 Entirely
11 MEN 2A Positive 2/M Positive (C634A) exon 11 Absent MF, up to 0.2 Entirely
12 MEN 2A Positive 8/M Positive (C634A) exon 11 S nonnodular S, 0.2 Representative
13 MEN 2A Positive 7/M Positive (C634A) exon 11 MF nonnodular MF, up to 0.4 Entirely
14 MEN 2A Negative 30/M Positive (C634A) exon 11 MF nodular nonnodular MF, up to 0.2 Entirely
15 MEN 2A Positive 6/F No workup MF nodular S, 0.2 Entirely
16 Non-MEN Positive 73/F Negative MF nodular nonodular MF, up to 1.1 Entirely
17 MEN 2A Positive 19/M Positive (C609S) exon 10 S nonnodular Absent Entirely
18 MEN 2A Positive 40/M Positive (C609S) exon 10 MF nodular nonnodular MF, up to 0.2 Entirely
19 Non-MEN Positive 38/F Positive (V804M) exon 14 MF nodular MF, up to 0.4 Entirely
20 Non-MEN Positive 32/F Positive (V804M) exon 14 MF nodular MF, up to 0.6 Entirely
21 MEN 2A Positive 9/F No workup MF nodular nonnodular S, 0.2 Entirely
(by report)
22 MEN 2A Positive 15/F No workup MF nonnodular MF, up to 0.6 Entirely
23 MEN 2A Positive 42/M No workup Absent S, 0.2 Entirely
24 Non-MEN Positive 48/M Negative MF nodular MF, up to 0.1 Representative
25 Non-MEN Positive 43/M Negative MF nodular nonnodular MF, up to 0.4 Representative
26 Non-MEN Positive 68/F No workup MF nodular nonnodular MF, up to 0.5 Representative
27 MEN 2A Positive 25/F No workup MF nodular S, 0.2 Entirely
28 Non-MEN Positive 7/M No workup MF nodular Absent Entirely
29 MEN 2B Positive 10/M Positive (M918T) exon 16 S nodular MF, up to 0.6 Entirely
30 MEN 2A Positive 3/M Positive (C634A) exon 11 MF nodular S, 0.3 Entirely
31 MEN 2A Positive 9/F Positive (C634A) exon 11 S nonnodular (on the re- Absent Entirely
port)
32 MEN 2A Positive 11/M Positive (C634A) exon 11 Absent Absent Entirely
33 MEN 2A Positive 17/F No workup MF nonnodular MF, up to 0.5 Entirely
34 Non-MEN Positive 2/M Positive (V804M) exon 14 Absent Absent Entirely
35 Non-MEN Positive 2/M Positive (V804M) exon 14 Absent Absent Entirely
36 MEN 2A Positive 18/F No workup MF nodular MF, up to 0.8 Representative
37 Non-MEN Negative 68/M No workup S nonnodular S, 0.7 Representative
38 MEN 2A Positive 42/M Positive (V804M) exon 14 MF nonnodular nodular Absent Entirely
39 MEN 2A Positive 44/M Positive (V804M) exon 14 MF nodular nonnodular MF, up to 0.1 Entirely
40 MEN 2A Positive 39/F Positive (V804M) exon 14 MF nodular nonnodular S, less than 0.1 Entirely
41 MEN 2A Positive 52/M Positive (C620F) exon 10 MF nodular MF, up to 0.2 Entirely
42 MEN 2A Positive 19/M Positive (V804M) exon 14 MF nonnodular Absent Entirely
* MEN indicates multiple endocrine neoplasia; Non-MEN, no evidence of MEN syndrome.
V indicates valine; M, methionine; C, cysteine; S, serine; F, phenylalanine; A, arginine; and T, threonine.
CCH indicates C-cell hyperplasia; MTC, medullary thyroid carcinoma; MF, multifocal; and S, solitary.
Entirely indicates the entire thyroid was submitted for histologic evaluation; Representative, representative sections of the thyroid were sub-
mitted for histologic evaluation.

except for one, the carcinoma was confirmed in at least 1 immunohistochemistry for carcinoembryogenic antigen
slide using immunohistochemical staining for calcitonin. was performed, 100% of CCHs (n 23) and MMCs (n
In the 1 case where the calcitonin-stained slide was un- 20) were positive.
available, it was reported as positive for this stain in the All of the MMCs were recognizable microscopically us-
corresponding pathology report. For those cases where ing hematoxylin-eosin staining.
Although most of the MMCs showed a rounded solid
architectural growth pattern, lobular or irregular patterns
Table 2. Numbers of Cases With or Without C-Cell
were also seen (Figure 2, A and B). Although some were
Hyperplasia (CCH) and Medullary Thyroid Carcinoma well circumscribed, most MMCs appeared histologically
(MTC) nonencapsulated. Unequivocal angiolymphatic invasion
was not identified, and only 1 case (case 29) exhibited mi-
MTC/CCH Combination n
croscopic extrathyroidal extension. Most the MMCs were
No MTC/no CCH 3 composed predominantly of round or polygonal cells, but
No MTC/CCH 9 occasional cases contained spindle-shaped or plasmacy-
MTC/no CCH 3 toid cells (Figure 2, C). The cells were arranged in nests,
MTC/CCH 27
sheetlike, and cordlike patterns. The cytoplasm was typi-
Total 42 cally granular or amphophilic (Figure 2, D), and nuclei
Arch Pathol Lab MedVol 132, November 2008 Prophylactic Thyroidectomy for Medullary CarcinomaEtit et al 1769

Figure 1. C-cell hyperplasia. A, Both nodular and nonnodular forms
of C-cell hyperplasia are present, as highlighted by immunohistochem-
ical staining for calcitonin (calcitonin immunohistochemistry, original
magnification 50). B, The C cells have delicate granular cytoplasm,
round nuclei, and an even chromatin pattern (hematoxylin-eosin, orig-
inal magnification 400).
were round to oval with coarse granular (salt and pep-
per) chromatin. Binucleated cells were occasionally pres-
ent. In those MMCs with spindle cells, the nuclei were
elongated, but the chromatin pattern was still granular
(Figure 2, E). Regarding other variations in cellular mor-
phology, none of the MMCs in our series exhibited a pre-
dominant clear cell pattern or oncocytic change, and his-
tologic evidence of mucin was not identified. Although
some tumors showed mild nuclear pleomorphism or hy-
perchromasia, the majority were not significantly pleo-
morphic. In 96.5% of MMCs, there was at least focal stro-
mal sclerosis. Even among the smallest recognizable
MMCs that were slightly less than 0.1 cm, stromal scle-
rosis and single cells were present. Necrosis was absent,
and mitotic figures were rare, being found in only 6.9%
(n 2) of cases. A total of 5.7% of cases (n 12) that
were stained using Congo red showed focal positivity for
amyloid.
Associated Lymph Node, Thyroid, and
Parathyroid Findings
A total of 22 cases in the series had at least a limited
regional lymph node dissection accompanying the total
1770 Arch Pathol Lab MedVol 132, November 2008
thyroidectomy. Only case 21, from a 9-year-old girl with
a single 0.2-cm focus of MMC, had a lymph node metas-
tasis of MTC involving a pretracheal lymph node. The
MMC in this case was histomorphologically similar to
those from other cases. It lacked histologic evidence of
angiolymphatic invasion, and it was neither extensively
sclerotic nor amyloid rich. Additional morphologic find-
ings in the thyroidectomy specimens included papillary
thyroid carcinoma (n 3) ranging in size from less than
0.1 to 1.7 cm, the presence of thymic tissue (n 2), and
follicular adenomas or adenomatous nodules (n 5). In-
terestingly, in only 5 cases were definite solid cell nests
identified, and 4 of these were male patients. Parathyroid
exploration was performed in 13 cases, and in 5 cases
(38.5%), hypercellular parathyroids were encountered.
Postoperative follow-up information was available in 29
cases, with a mean clinical follow-up of 4.7 years (range,
1 month to 13 years). In none of the cases was a docu-
mented recurrent MTC encountered. One case had a
3-mm lesion seen on ultrasound in the thyroid bed, with
a serum calcitonin level below the normal reference level
and no change in the lesion on subsequent follow-up. In
the 29 cases with clinical follow-up, serum calcitonin level
tests were performed at regular intervals and the levels
seen were below the age- and sex-dependent normal ref-
erence ranges. Nineteen patients had additional clinical
findings. Two patients had bilateral pheochromocytomas,
and one of these patients developed renal failure and un-
derwent bilateral nephrectomy. Two patients from the
same family had myotonic dystrophy, and one of these
developed renal tubular acidosis. One patient developed
oral mucosal neuromas, and 1 patient, 13 years postop-
eratively, developed hyperparathyroidism, hypercalcemia,
and hypophosphatemia, as well as elevated levels of blood
norepinephrine, epinephrine, dopamine, and urine epi-
nephrine. Two patients had an intestinal tubular adenoma,
and 1 patient developed Alzheimer disease and cardiac
disease.
COMMENT
During the past century, the MEN syndromes have
emerged as an important group of diseases. Among these,
MEN 2A, MEN 2B, and familial medullary thyroid car-
cinoma are associated with the development of MTC, a
potentially lethal malignancy with frequent lymph node
metastases.3,15 The clinical and pathologic features of these
syndromes have been described, laboratory tests to detect
them have been devised, and characteristic genetic abnor-
malities have been identified. As a result, the diagnosis of
these syndromes in asymptomatic patients can today be
accomplished by molecular genetic techniques.16 In an at-
tempt to identify patients with MTC or the precursor le-
sion CCH at a potentially curable stage of the disease,
measurement of serum concentrations of calcitonin and,
more recently, analysis of RET proto-oncogene mutations
have increased in frequency. This has resulted in prophy-
lactic thyroidectomies for such patients being performed
at an early age, especially in patients with mutations in
codons deemed to carry a high risk of development of
MTC (eg, codons 609, 620, 804, 634, and 918). Consequent-
ly, thyroidectomy specimens with earlier and smaller le-
sions are being encountered in surgical pathology practic-
es.
Microcarcinomas of the thyroid are defined as tumors
measuring less than 1.0 cm in greatest dimension. Most
Prophylactic Thyroidectomy for Medullary CarcinomaEtit et al
Figure 2. Medullary microcarcinoma. A, Some microcarcinomas are very well demarcated with a smooth interface between the outer thyroid
parenchyma and tumor (hematoxylin-eosin, original magnification 50). B, Irregularly shaped focus of microcarcinoma with associated stromal
fibrosis and nodular C-cell hyperplasia (hematoxylin-eosin, original magnification 100). C, A combination of spindled and round cells is present
(hematoxylin-eosin, original magnification 100). D, The cells have amphophilic cytoplasm and round uniform nuclei with granular salt and
pepper chromatin (hematoxylin-eosin, original magnification 400). E, Some microcarcinomas have a predominance of spindled cells (hematox-
ylin-eosin, original magnification 400).

Arch Pathol Lab MedVol 132, November 2008 Prophylactic Thyroidectomy for Medullary CarcinomaEtit et al 1771
of these tumors are papillary thyroid microcarcinomas,
whereas MMCs are uncommonly encountered in thyroid-
ectomy specimens.13,14,17 In one study, MMCs have been
described in autopsy findings with an incidence of
0.15%.17 Medullary microcarcinomas are most commonly
found in thyroids removed prophylactically,14 and a num-
ber of recent studies have addressed the morphology of
prophylactic thyroidectomy specimens.2,58,1822
We present our experience with a retrospective series of
42 patients who had prophylactic thyroidectomy speci-
mens examined for the prevention or early cure of MTC.
Currently, an assay for serum calcitonin is typically per-
formed at Massachusetts General Hospital for patients
presenting with nodular thyroid disease.6,2123 In a series
of 667 cases reported by Kaserer et al,6 routine screening
of serum calcitonin levels in patients with nodular goiter
demonstrated abnormal values in 4.5%, and in all of the
abnormal cases, either MTC or CCH was found. In a study
of patients with primary hereditary MTC, a serum calci-
tonin test was abnormal in 28 (87.5%) of 32 cases,19 and
in our series, preoperative serum calcitonin was abnormal
in 31 patients (73.8%).
The mean patient age in our study was 24.5 years: 18
patients (42.8%) were children or adolescents (218 years
old), and 24 patients (57.2%) were adults (1973 years old).
This correlates well with the findings of a young patient
age in other series of hereditary MTC. In a study by Ka-
serer et al,5 the mean age of familial cases of MTC was 32
years, as opposed to 58 years for sporadic cases where
MTC was found. In other series, the mean ages of patients
with MTC following RET proto-oncogene screening were
18.9 years19 and 16 years,18 although the latter study in-
volved only 14 patients from 2 families. The mean age at
diagnosis for cases of sporadic MTC, by contrast, is re-
ported as between 44 and 50 years.24
Germline and somatic mutations in the RET proto-on-
cogene are associated with inherited and sporadic MTC,
respectively. The various RET proto-oncogene mutations
are reported to occur in different frequencies at various
codons.2,6,2537 According to our study, the most commonly
affected codon was V804M in exon 14, although 4 other
codons were involved (Table 1). Eleven patients in our se-
ries were non-MEN cases. Ten of these had an associated
family history of MTC and are considered examples of
familial MTC. Three of these patients when tested in 1996
were negative for RET mutations, which were reported in
up to 15% of familial MTC cases at that time. Only 1 non-
MEN patient (case 37) had no family history but was
found to have an elevated serum calcitonin level on routine
testing. This case may represent a fortuitous early detec-
tion of a sporadic MMC.
A total of 26 (89.6%) of 29 patients with a positive RET
proto-oncogene mutation had either CCH, MMC, or both.
In the 3 patients with negative pathology, surgery had
been performed on the basis of a positive test for a RET
proto-oncogene mutation. They were boys aged 2, 2, and
11 years. This is slightly less than the 100% of hereditary
cases in other series that had CCH.7,18,19 This small differ-
ence may possibly represent more extensive histopatho-
logic sampling in the other series. None of our patients
with MMC has died as a result of the tumor, and only 1
had a lymph node metastasis of MTC at the time of sur-
gery. Interestingly, the single case in our series (a 9-year-
old girl) with a metastasis to a pretracheal lymph node
had a small, 0.2-cm primary tumor. Our follow-up results
1772 Arch Pathol Lab MedVol 132, November 2008
support the findings of Krueger et al,8 who noted no mor-
tality in patients with MMCs after an observation period
of up to 70 months, and of Bergholm et al,38 who found
no excess in mortality compared with the general popu-
lation of familial MTC patients detected by screening for
a period of up to 20 years. It is noteworthy that 13 of our
patients had mutations at codons considered to be at high
risk for the development of MTC: 9 at codon 634, 3 at
codon 609, and 1 at codon 918.
In contrast to Kruegers series,8 separation of MMCs
from nodular CCHs was not easy in every case if there
were no obvious invasion by tumor. In this situation, the
most helpful finding to differentiate MMC from CCH was
stromal sclerosis within the nodule of C cells. There was
a high incidence (96.5%) of stromal sclerosis in the micro-
carcinoma group of patients in our series. CCH was easily
identified in hematoxylin-eosinstained slides because of
its similar cytomorphologic features to MMC. Most of the
microcarcinomas had morphologic features of convention-
al medullary carcinoma: round and polygonal cells with
granular to amphophyllic cytoplasm, and nuclei with salt
and pepper chromatin. Most MMCs in our study were 0.1
to 0.2 cm in size (51.7%), and the presence of amyloid did
not seem to be related to tumor size. Although the small-
est MMC showed a positive reaction by Congo red stain,
some larger MMCs were negative.
Our findings in prophylactic thyroidectomies of small
MMCs, often multiple and bilateral and often with mul-
tifocal CCH but only 1 macrocarcinoma, are in concert
with the findings of others of small, often multifocal early
C-cell proliferative lesions in these cases.5,8 However, al-
though the study of Kaserer et al6 found that 11 males but
no females had CCH only, in our study we found 9 pa-
tients with CCH but not MTC, of which 5 were male and
4 were female. In addition, we found very few solid cell
nests associated with our C-cell lesions. It would be inter-
esting to note the density of solid cell nests in association
with C-cell lesions in other prophylactic thyroidectomies.
In 3 cases from our series, there was concomitant papillary
thyroid carcinoma present, and 1 was metastatic. This as-
sociation has been reported previously and may be the
result of oncogenic activation of RET in thyroid tumors.3941
From our study and review of the literature, it is clear
that RET proto-oncogene analysis is a valuable test to de-
tect early MTC. Our findings, together with those of oth-
ers, support performing prophylactic thyroidectomy to
give the best chance of cure to the family members of
patients with MEN 2 or hereditary MTC with high calci-
tonin levels or RET proto-oncogene mutations. As MMC
or CCH were found in almost every case in our series,
prophylactic total thyroidectomy may indeed be a lifesav-
ing procedure in many of these cases.
This study was partially supported by a grant
(B.02.1.TBT.0.06.01-219.01-880-5768) from The Scientific
and Technological Research Council of Turkey (TUBITAK).
The authors thank Lisa Gallagher, MD, for her valuable
support collecting multiple previous cases.
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