Controversies in Thyroid Pathology
Moderators: Dr. Thomas Giordano and Dr. Paul Komminoth
Section 4 -
The Importance of Subclassifying C-Cell Hyperplasia: A Critical Analysis
Ronald A. DeLellis
Department of Pathology and Laboratory Medicine
Brown Medical School and Rhode Island Hospital
Providence , Rhode Island
C-cell proliferative disease in the type 2 multiple endocrine neoplasia (MEN2) syndromes
encompasses a series of abnormalities ranging from mild C-cell hyperplasia (CCH) to frankly invasive
medullary thyroid carcinoma (MTC). Although these disorders were identified originally on the basis of
elevated plasma calcitonin levels, their diagnosis now rests on the demonstration of germline mutations
in the RET proto-oncogene. The histological classification of C-cell proliferative disorders,
particularly the identification and subclassification of CCH, has engendered considerable debate and
controversy. In this presentation, the following questions will be considered:
C-cell hyperplasia was first recognized in asymptomatic individuals with family histories of MEN2 on
the basis of abnormal calcitonin secretory reserves, as determined by calcium gluconate and pentagastrin
provocative testing. Subsequent studies established the concept that CCH represented the precursor of
the bilateral and multicentric MTCs that occurred not only in MEN2A but also in MEN2B and familial MTC
(FMTC). Detailed immunohistochemical and ultrastructural studies demonstrated that C-cells in normal
individuals occupied an exclusive intrafollicular location and that the earliest phases of CCH were
characterized by gradual obliteration of the follicular space by proliferating and focally atypical
C-cells. Transition of this phase of C-cell growth to MTC was characterized ultrastructurally by the
extension of C-cells through the follicular basement membrane into the interstitium of the thyroid
gland. These findings were subsequently confirmed by McDermott et al with immunoperoxidase techniques
for the demonstration of type IV collagen, a constituent of the follicular basement membrane.
- Can the upper limit of normal C-cell
distribution be defined and is it constant among different individuals?
secondary/physiologic CCH be distinguished reliably from MEN2A-associated CCH by histological
- Is MEN2A-associated CCH a preinvasive carcinoma?
- Does secondary/physiologic CCH have a preneoplastic potential?
The precise definition of CCH, however, has remained elusive. Early studies indicated that C-cells
could occur singly or as groups of 3-5 cells in normal adult thyroid glands and that greater than 10
C-cells per 100X field was indicative of CCH. Subsequent studies, however, established that up to 50-
C-cells per 100X field could be present in areas of the highest C-cell density (eg. region of solid cell
nests) in some normal individuals. In a recent quantitative image analysis study, Guyetant and
colleagues demonstrated that C-cells were more numerous in male subjects than in females. This
observation correlates with the known higher plasma calcitonin levels in men than in women. Moreover,
this study demonstrated that 33% of the adult population, including 15% of women and 41% of men, had
evidence of CCH as defined by having at least 3 microscopic fields (100X) with greater than 50 C-cells.
These findings suggest that either a substantial portion of the population has CCH or that the criteria
for the definition of this entity are inaccurate. Interestingly, abnormal pentagastrin tests are found
in approximately 5% of the normal population as compared to the 30% frequency of CCH, as defined
histologically. These observations suggest that there may be considerable variation in C-cell
distribution among normal individuals and that these variations may not be accompanied by
In addition to its presence in MEN2 syndromes, CCH has been reported in a number of other conditions
including hypercalcemia, hypergastrinemia, Hashimoto's thyroiditis and adjacent to a variety of
follicular cell tumors, including follicular adenomas and carcinomas and papillary carcinomas
(peritumoral C-cell hyperplasia). This type of hyperplasia has been referred to as physiologic or
secondary C-cell hyperplasia, in contrast to MEN2-associated CCH, which has been referred to as primary
or "neoplastic" hyperplasia. Perry and coworkers have reported that physiologic CCH is primarily a
diffuse process characterized by increased numbers of normal C-cells and can be diagnosed with confidence
only on the basis of calcitonin immunostains. "Neoplastic" CCH, on the other hand, involves the
proliferation of dysplastic C-cells and can be diagnosed frequently on the basis of H&E stains
alone. While "neoplastic"/MEN2-associated CCH is generally regarded as a precursor of MTC, the
neoplastic potential of physiologic CCH remains unknown, notwithstanding the rare cases of MTC reported
in patients with chronic hypercalcemia.
Carney and coworkers in 1978 proposed that CCH associated with MEN2 syndromes represents a preinvasive
carcinoma or carcinoma in situ. Further evidence for the neoplastic nature of CCH has come from
Diaz-Cano's molecular studies of microdissected foci of thyroid glands from patients with MEN2A. These
studies have shown that foci of CCH are monoclonal with inactivation of the same allele in both thyroid
lobes. Moreover, the foci have different secondary alterations involving the tumor suppressor genes p53,
RB1, WT1 and NF1. These findings, together with the downregulation of apoptosis, are consistent with an
intraepithelial neoplasia and suggest that early clonal expansions precede migration of C-cell precursors
into each thyroid lobe.
Although CCH has been regarded as a precursor and marker of MEN2 associated medullary carcinoma, this
view has been challenged by several recent reports. In a series of 30 patients with nodular thyroid
disease and abnormal pentagastrin stimulated calcitonin levels, Kaserer et al reported 9 patients
(F:M;14:5) with MTC and 11 males but no females with CCH only, as defined by greater than 50 C-cells per
low power field. Six of 16 patients with sporadic MTC had concomitant CCH and 3 of these patients proved
to be new MEN2 index cases, as proven by genetic studies. On the basis of these studies, Kaserer et al
concluded that CCH was an unreliable marker for heritable MTC and that CCH had a preneoplastic potential
in the absence of RET germline mutations.
In a second study of 16 familial and 34 sporadic MTCs, Kaserer et al noted CCH in 16/16 (100%) of
familial cases and in 24/34 (71%) of sporadic cases. Among familial cases, CCH was of neoplastic type in
85% (14/16), nodular type in 6% (1/14), and focal type in 6% (1/14). In sporadic cases, on the other
hand, neoplastic CCH was present in 18% (6/34), nodular hyperplasia in 21% (7/34), diffuse hyperplasia in
18% (6/34) and focal hyperplasia in 14% (5/34). There was no evidence of CCH in 29% (10/34) of the
sporadic cases. On the basis of this study, Kaserer et al concluded that many sporadic MTCs develop on a
background of CCH.
Since there is such a wide variation in C-cell counts in normal thyroid glands, two possible
interpretations of these studies are that the observed "CCH" in sporadic tumor cases represents the upper
limit of normal C-cell distribution or that it is analogous to the secondary CCH found adjacent to
follicular and papillary tumors. Indeed, Mears and Diaz-Cano have reanalyzed the data in the Kaserer
study. They concluded that multifocal and bilateral invasive MTCs associated with expansile
intraepithelial neoplasia (nodular and neoplastic hyperplasia) represent familial disease in 98% of
cases. The probability of sporadic disease associated with nodular and neoplastic C-cell hyperplasia was
calculated as 1.87%.
In summary, C-cell distribution has a remarkably wide variation in normal individuals. The current
criterion of 50 C-cells per 100X microscopic field is, in all likelihood, an underestimate since up to
30% of normal males would have CCH according to this definition. MEN2-associated CCH has characteristic
topographic, cytological and molecular features, which permits its distinction from secondary C-cell
hyperplasia in most cases, and this can be confirmed by the presence of germline RET mutations. Whether
physiologic/secondary CCH has a significant preneoplastic potential remains an unanswered question.
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