Thyroid gland
Hyperplasia / goiter
C cell hyperplasia (CCH)

Author: Shahidul Islam, M.D., Ph.D. (see Authors page)

Revised: 19 January 2017, last major update March 2009

Copyright: (c) 2003-2017,, Inc.

PubMed Search: C cell hyperplasia thyroid
Cite this page: C cell hyperplasia (CCH). website. Accessed August 16th, 2017.
Definition / general
  • Associated with MEN2 and medullary thyroid carcinoma
  • Two types (although literature does not always specify):
    • Reactive CCH (physiologic CCH): associated with hypercalcemia, Hashimoto's thyroiditis, prior thyroid surgery, follicular neoplasms, non-Hodgkin's lymphoma; neonates and elderly; not bilateral; usually does NOT evolve into medullary carcinoma (Am J Clin Pathol 1981;75:347)
    • Neoplastic CCH (carcinoma in situ / intraepithelial neoplasia): similar RET mutations as medullary carcinoma, is precursor lesion of familial medullary carcinoma, associated with MEN2A or 2B or sporadic; usually occurs in upper 2/3 of lateral lobes
Clinical features
Case reports
  • Total thyroidectomy, particularly if MEN2A or 2B or RET mutation positive (possibly prophylactic total thyroidectomy or isthmus preserving total bilobectomy, World J Surg 2006;30:860); otherwise, follow with serum calcitonin assays
Gross description
  • May have 1 - 2 mm nodules in mid to upper thyroid lobes
Microscopic (histologic) description
  • Total mass of C cells is increased, C cells have abundant clear cytoplasm and round / oval vesicular nuclei, are located within follicular basement membrane; do not extend through defects in follicular basal lamina, no infiltration of thyroid interstitium and no isolated infiltrating C cells in fibrous stroma (or would be micromedullary thyroid carcinoma)
  • No amyloid deposits

  • Step 1: all H&E slides are screened for microscopic carcinoma or neoplastic CCH
  • Step 2: all calcitonin stained slides are screened for C cells
    • In slides with greatest C cell density (aside from tumor) in each lobe, C cells are counted per 100× (low power field / LPF), and diagnosis of CCH requires one area with > 50 C cells per LPF in both lobes (Am J Surg Pathol 2001;25:1245) or at least 3 LPF with > 50 calcitonin stained cells (J Clin Endocrinol Metab 1997;82:42)

Reactive CCH criteria:
Neoplastic CCH criteria:
  • Neoplastic cells can be identified without calcitonin staining; cells differ from adjacent follicular cells and resemble medullary thyroid carcinoma cells
  • Cells are mild to moderately atypical with nuclear pleomorphism (Mod Pathol 2003;16:756)
  • Progresses from focal to diffuse to nodular hyperplasia to medullary thyroid carcinoma
  • Can use PAS to highlight follicular basement membrane and distinguish cells within follicles (noninvasive) from those outside follicles (invasive)

Patterns of CCH are:
  • Focal: segmental proliferation of C cells within thyroid follicles
  • Diffuse: C cells form circumferential intrafollicular collars or nodular - C cells form clusters completely obliterating follicular lumens (Cancer 1996;77:750, Am J Surg Pathol 2001;25:1245)
Microscopic (histologic) images

Scroll to see all images.

Images hosted on PathOut server:

Contributed by Dr. Mark R. Wick

Calcitonin staining:

C cells highlighted (AFIP)

Nodular CCH

C cells adjacent to follicular carcinoma (AFIP)

Contributed by Dr. Mark R. Wick

MEN2A patients (AFIP):

Circumferential proliferation of C cells around follicular cells

Focal proliferation of C cells (arrow)

C cells form an eccentric intrafollicular proliferation

MEN2A patients with early medullary carcinoma (AFIP):

Group of C cells extends into interstitium

Images hosted on other servers:

Nodular and non-nodular forms

High power

Associated with nodular goiter

MEN2A patient

Calcitonin staining:

C cells form ring around follicle

Sporadic diffuse CCH

Pseudonodular CCH

Cytology description
  • Scant bimodal cell population of benign follicular cells and larger calcitonin positive cells (Acta Cytol 1998;42:963)
Positive stains
Negative stains
Electron microscopy description
  • Proliferation of C cells within follicular basement membrane adjacent to luminal colloid; scattered dense core secretory granules (containing calcitonin)
  • Prominent rough endoplasmic reticulum
Electron microscopy images

Images hosted on PathOut server:

MEN2A patient

Molecular / cytogenetics description
Differential diagnosis
  • Nodular CCH: solid cell nests (keratin+, CEA+, variable calcitonin+, EM shows intermediate filaments and cytoplasmic projections but no dense core secretory granules), squamous metaplasia (associated with thyroiditis), parathyroid nests, thymic remnants, nests of thyroid follicular cells with tangential sectioning (cytoplasm not clear)