Multiple Endocrine Neoplasia Type 2

Slide 1 · Multiple Endocrine Neoplasia, Type 2

Pathology • RET signaling • clinicopathologic phenotypes

Thyroid C cells

Adrenal medulla

Parathyroid (2A)

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Explain why activating germline RET variants create an inherited endocrine-tumor syndrome.

Differentiate MEN2A, MEN2B, and familial medullary thyroid carcinoma.

Recognize medullary carcinoma, pheochromocytoma, and parathyroid manifestations.

Apply genetic testing, presurgical safety, and prevention principles.

Slide 3 · MEN2: An inherited, multi-organ tumor predisposition

MEN syndromes predispose to proliferative lesions in multiple endocrine organs.

MEN2 is an autosomal dominant RET-associated syndrome.

Medullary thyroid carcinoma is the major shared malignancy.

Pheochromocytoma and parathyroid disease vary by phenotype.

Slide 4 · Inherited MEN tumors differ from sporadic tumors

Feature

Inherited MEN phenotype

Typical sporadic counterpart

Presentation

Often younger age

Often later onset

Distribution

Multiple organs or bilateral sites

Commonly one primary site

Within one organ

Multifocal lesions frequent

Often solitary

Precursor change

Cell-type hyperplasia may precede tumor

Syndromic precursor less typical

Slide 5 · Three clinical tissues explain most MEN2 morbidity

THYROID

Thyroid C cells → medullary carcinoma

ADRENAL

Adrenal medulla → pheochromocytoma

PARATHYROID

Parathyroid → primary hyperparathyroidism (MEN2A)

Slide 6 · MEN2 clinical phenotypes

Feature

MEN2A

MEN2B

Familial MTC

Medullary carcinoma

Characteristic

Characteristic; earlier, aggressive

Main manifestation

Pheochromocytoma

Risk present

Risk present

Typically absent in the restricted family phenotype

Parathyroid disease

May occur

Not characteristic

Not typical

Other

—

Mucosal neuromas; marfanoid habitus

MTC-only kindred

Slide 7 · MEN2 is genetically distinct from MEN1

Feature

MEN1

MEN2

Principal gene

MEN1 (menin)

RET (receptor tyrosine kinase)

Genetic mechanism

Tumor-suppressor pathway

Constitutive signaling, gain of function

Signature sites

Parathyroid, pancreatic / duodenal NETs, pituitary

Thyroid C cells; adrenal medulla; parathyroid in 2A

Thyroid malignancy

Not the defining lesion

Medullary thyroid carcinoma

Slide 8 · MEN4 is not a subtype of RET-associated MEN2

Feature

MEN2

MEN4

Germline gene

RET

CDKN1B

Protein affected

RET receptor tyrosine kinase

p27 cell-cycle checkpoint protein

Typical phenotype

Medullary thyroid carcinoma ± pheochromocytoma

MEN1-like; parathyroid / pituitary lesions

Practical distinction

RET-family cascade testing

Separate molecular diagnosis

Slide 9 · Autosomal dominant inheritance: A family-level diagnosis

One parent with a pathogenic germline RET variant

Possible carrier

Possible noncarrier

Possible carrier

Possible noncarrier

Each child has a 50% genetic risk; These illustrative offspring do not represent observed family outcomes.

Slide 10 · RET: A membrane receptor tyrosine kinase

Extracellular ligand engagement

RET kinase signaling

Growth and differentiation programs

Slide 11 · Constitutively active RET removes ligand dependence

A

Physiology: Ligand-dependent receptor signaling

B

MEN2: Activating RET variant sustains signaling without ligand

Slide 12 · The direction of RET dysfunction matters

RET alteration

Functional consequence

Clinical association

Germline gain of function

Constitutive receptor activation

MEN2A / MEN2B

Germline loss of function

Impaired enteric ganglion development

Hirschsprung disease

Slide 13 · Genotype influences clinical phenotype

MEN2A and MEN2B are associated with different activating RET variants.

MEN2B classically involves an alteration in the tyrosine kinase domain.

Variant identity is relevant to clinical risk stratification and timing of thyroid surgery.

Pathogenic / likely pathogenic status must be distinguished from uncertain variants.

Slide 14 · A germline variant creates a multifocal tissue field

1

All thyroid C cells share inherited RET susceptibility.

2

Multiple foci of C-cell hyperplasia may appear.

3

Separate sites may progress to medullary microcarcinoma and carcinoma.

Slide 15 · C-cell hyperplasia is a key precursor clue

Thyroid topography (schematic)

Separate foci

Multiple clusters of parafollicular C cells may be distributed in the thyroid.

Adjacent C-cell hyperplasia strongly supports syndromic medullary carcinoma.

Carefully assess the contralateral lobe; A dominant nodule need not be solitary disease.

Slide 16 · MEN2A: The classical endocrine triad

THYROID

Medullary thyroid carcinoma

ADRENAL

Pheochromocytoma

PARATHYROID

Parathyroid hyperplasia / hyperparathyroidism

Slide 17 · MEN2A: Medullary carcinoma is the dominant threat

Medullary carcinoma in almost all MEN2A patients.

Tumors are commonly multifocal and associated with adjacent C-cell hyperplasia.

Clinical aggressiveness makes prevention through early detection important.

Secretion of calcitonin provides a biologic and clinical biomarker.

Slide 18 · MEN2A: Pheochromocytoma is often bilateral

Pheochromocytoma in approximately 40%–50% of MEN2A patients.

Tumors may be bilateral; Extra-adrenal chromaffin tumors are also discussed.

Catecholamine excess can produce dangerous cardiovascular episodes.

Excluding an active pheochromocytoma precedes elective thyroid surgery.

Slide 19 · MEN2A: Parathyroid disease is less frequent

Parathyroid hyperplasia / hypercalcemic manifestations in approximately 10%–20% of MEN2A patients.

Excess parathyroid hormone raises serum calcium.

Nephrolithiasis may be a presenting manifestation.

Absence of hypercalcemia does not exclude RET-associated MEN2.

Slide 20 · MEN2A may appear as separate organ presentations

A thyroid mass or elevated calcitonin

Hypertensive attacks with adrenal mass

Hypercalcemia / renal stones

Slide 21 · MEN2B has a distinctive non-endocrine phenotype

Medullary thyroid carcinoma and pheochromocytoma overlap with MEN2A.

Mucosal neuromas / ganglioneuromas are characteristic clues.

Marfanoid skeletal habitus may be present.

Primary hyperparathyroidism is not typical of MEN2B.

Slide 22 · MEN2B-associated MTC is especially aggressive

MEN2B medullary carcinomas as more aggressive than those in MEN2A.

Onset is often in early childhood in authoritative clinical summaries.

A visible thyroid nodule may be a late manifestation of an inherited process.

Recognizing an extracervical phenotype can permit earlier RET testing.

Slide 23 · Mucosal neuromas: A high-value phenotypic clue

Site

Possible manifestation

Lips / oral mucosa

Thickened lips; mucosal neuromas

Tongue

Mucosal neuromas

Eyes

Medullated corneal nerves / neuromatous findings

GI tract

Ganglioneuromatosis; motility symptoms

Slide 24 · Marfanoid habitus is a clue, not a diagnosis

An elongated / asthenic body habitus may accompany MEN2B.

Long skeletal proportions and hyperextensible joints are.

The associated mucosal and endocrine findings create the diagnostic pattern.

Avoid diagnosing a RET syndrome from body proportions alone.

Slide 25 · MEN2B: Parathyroid hyperfunction is not typical

A

MEN2A: Parathyroid hyperplasia is part of the classical triad

B

MEN2B: Primary hyperparathyroidism is generally absent

Slide 26 · MEN2A and MEN2B: Discriminating findings

Feature

MEN2A

MEN2B

RET mechanism

Activating kinase signaling

Activating kinase signaling

Medullary carcinoma

High risk; often multifocal

Early, often more aggressive

Pheochromocytoma

Present in subset

Present in subset

Hyperparathyroidism

Subset affected

Not characteristic

Neuromas / marfanoid

Not typical

Characteristic

Slide 27 · MTC begins in thyroid parafollicular C cells

Parafollicular C cell

Neuroendocrine transformation

Calcitonin-producing medullary carcinoma

Slide 28 · MTC is not a follicular-cell thyroid cancer

Feature

Medullary carcinoma

Papillary / follicular carcinoma

Cell of origin

Parafollicular C cell

Follicular epithelial cell

Functional marker

Calcitonin

Follicular differentiation / thyroglobulin

MEN2 association

Strong with germline RET

Not defining MEN2 lesions

Slide 29 · Gross MTC may be multifocal and bilateral

Thyroid topography (schematic)

Separate foci

Familial lesions are frequently multicentric and bilateral.

Firm, gray-tan, infiltrative nodules characterize larger tumors.

Larger tumors may show hemorrhage or necrosis.

Slide 30 · Microscopic MTC: Neuroendocrine architecture

Amyloid

Tumor nests

Polygonal or spindle-shaped tumor cells form nests or trabeculae.

Nuclei often show fine stippled neuroendocrine chromatin.

Stromal amyloid is common but not obligatory.

Schematic — not a histologic specimen

Slide 31 · The amyloid of MTC derives from calcitonin

Neoplastic C-cell synthesis of calcitonin peptides

Local deposition of amyloid in tumor stroma

Amorphous extracellular eosinophilic material

Slide 32 · A C-cell hyperplasia–microcarcinoma continuum

1

Hereditary C-cell hyperplasia

2

Small invasive medullary microcarcinoma

3

Larger medullary thyroid carcinoma

Slide 33 · MTC morphology: What the pathologist should report

Unifocal versus multifocal growth; Unilateral versus bilateral distribution.

Relationship to background C-cell hyperplasia.

Tumor extent and evidence of invasion.

Regional nodal involvement and other findings requiring staging.

Slide 34 · Sporadic versus hereditary MTC: Pathology clues

Clue

Hereditary / MEN2

Sporadic

Patient age

Often younger

Typically adult

Distribution

Frequently bilateral / multifocal

Commonly solitary

C-cell hyperplasia

Characteristic precursor

Usually absent

RET germline status

Pathogenic variant

Most cases negative

Slide 35 · Calcitonin: A tumor-produced biochemical marker

MTC retains the C-cell ability to produce calcitonin.

Serum calcitonin assists diagnosis and follow-up.

Tumor production does not usually cause clinically prominent hypocalcemia.

Interpret results in their clinical context; There is no invented universal cutoff on this slide.

Slide 36 · CEA provides a complementary MTC marker

Carcinoembryonic antigen can be secreted by medullary carcinoma.

It contributes to assessment of tumor burden and follow-up.

Calcitonin and CEA are markers of MTC biology, not markers of germline inheritance.

RET testing—not either serum marker—establishes molecular inherited risk.

Slide 37 · Other MTC peptides may cause paraneoplastic effects

Secretory product

Illustrative consequence

Calcitonin

Useful diagnostic / follow-up biomarker

VIP

Secretory diarrhea in some tumors

ACTH

Ectopic Cushing syndrome in some tumors

Other peptides

Variable syndromic presentations

Slide 38 · Biomarker roles must not be conflated

Test

Primary role

Does it establish inherited MEN2?

Germline RET

Molecular predisposition

Yes, if pathogenic / likely pathogenic

Calcitonin

MTC-associated disease marker

No

CEA

MTC-associated disease marker

No

Metanephrines

Pheochromocytoma biochemical testing

No

Slide 39 · Pheochromocytoma arises from chromaffin cells

Adrenal medullary chromaffin cell

Catecholamine-producing neoplasm

Systemic adrenergic manifestations

Slide 40 · Pheochromocytoma: Classic zellballen nests

Capillary-rich intervening stroma

Chromaffin cell nests

Neoplastic chromaffin cells form nests separated by capillaries.

Chief cells have granular cytoplasm; Supporting sustentacular cells lie at the periphery.

Neuroendocrine-type chromatin may be visible; Architecture is variable.

Schematic — not a histologic specimen

Slide 41 · Useful stains in pheochromocytoma

Target / component

Supportive immunophenotypic finding

Chief cells

Chromogranin and synaptophysin expression

Sustentacular cells

S-100 highlights supporting cells

Interpretation

Morphology + context; immunostaining alone does not define hereditary status

Slide 42 · Histologic atypia cannot alone prove metastasis

Pheochromocytoma may show pleomorphism without metastatic behavior.

Necrosis, mitoses, invasion, and spindle morphology do not individually settle biologic behavior.

That metastasis is the definitive evidence of malignant behavior.

Modern risk stratification adds contextual factors, not a single reliable histologic switch.

Slide 43 · Catecholamine release explains episodic symptoms

Tumor catecholamine secretion

Peripheral adrenergic stimulation

Headache, sweating, palpitations, hypertension

Slide 44 · A pheochromocytoma crisis can be life-threatening

Hypertension may be sustained, episodic, or both.

Palpitations, sweating, tremor, and apprehension may accompany attacks.

Acute catecholamine surges can precipitate cardiac arrhythmia or pulmonary edema.

Unrecognized disease creates major perioperative risk.

Slide 45 · Pheochromocytoma: First establish biochemistry

Plasma free metanephrines or 24-hour urinary fractionated metanephrines are recommended tests.

Cross-sectional localization follows a supported biochemical suspicion.

Biochemical investigation is appropriate even without classic episodic hypertension.

Screen for functioning pheochromocytoma before any planned operation in an MEN2 patient.

Slide 46 · Other inherited pheochromocytoma syndromes

Syndrome

Typical gene

Distinguishing association

MEN2

RET

Medullary thyroid carcinoma

VHL

VHL

Renal cell carcinoma; hemangioblastoma

NF1

NF1

Neurofibromatosis phenotype

Hereditary PGL/PCC

SDHx

Paraganglioma predisposition

Slide 47 · The operative sequence prevents a catecholamine crisis

Known or suspected MEN2

Biochemical pheochromocytoma assessment

If positive: Stabilize / treat pheochromocytoma before thyroid surgery

Slide 48 · PTH overproduction explains MEN2A hypercalcemia

Parathyroid hyperplasia

Increased parathyroid hormone

Serum calcium elevation / renal stone risk

Slide 49 · MEN2A parathyroid disease is not universal

Only a subset develops parathyroid proliferative lesions.

Hypercalcemia or nephrolithiasis may signal functional hyperparathyroidism.

Serum calcium is the key accessible biochemical screen.

The clinical pattern differs from MEN1, in which parathyroid disease dominates.

Slide 50 · When to suspect hereditary MEN2

Medullary thyroid carcinoma at any age warrants consideration of inherited RET risk.

Multifocal or bilateral medullary lesions strengthen clinical suspicion.

Pheochromocytoma combined with medullary carcinoma is strongly suggestive.

Mucosal neuromas or a positive family history may identify MEN2B risk.

Slide 51 · Germline RET testing is central to diagnosis

A pathogenic / likely pathogenic germline RET variant establishes molecular MEN2.

The result clarifies phenotype and cascade-testing eligibility.

Apparently sporadic medullary carcinoma may still carry a germline variant.

Somatic-only RET tumor changes should not be equated with inherited disease.

Slide 52 · An uncertain RET variant is not a diagnosis

Molecular result

Interpretive principle

Pathogenic / likely pathogenic germline RET

Clinically actionable hereditary predisposition

Variant of uncertain significance

Does not establish or exclude MEN2

Tumor-only somatic RET

Does not prove heritable susceptibility

Negative germline study

Interpret in clinical and family context

Slide 53 · Cascade testing changes the family risk map

One parent with a pathogenic germline RET variant

Possible carrier

Possible noncarrier

Possible carrier

Possible noncarrier

Each child has a 50% genetic risk; These illustrative offspring do not represent observed family outcomes.

Slide 54 · Early thyroidectomy is preventive, not reactive

The rationale is intervention before C-cell neoplasia becomes invasive and advanced.

Germline RET genotype and clinical evaluation inform the recommended timing.

Children with high-risk variants may require very early specialist assessment.

Surgical planning also requires evaluation for coexisting pheochromocytoma.

Slide 55 · Surveillance targets three separate organ risks

Target

Typical biochemical assessment

Purpose

MTC

Calcitonin; CEA after thyroidectomy

Detect persistent or recurrent disease

Pheochromocytoma

Plasma or urinary metanephrines

Identify potentially dangerous catecholamine-producing tumors

MEN2A parathyroid

Corrected / ionized calcium

Detect primary hyperparathyroidism

Slide 56 · Long-term follow-up persists after thyroidectomy

Thyroid removal reduces the risk of future primary medullary carcinoma when appropriately timed.

Calcitonin and CEA are monitored to evaluate persistent / recurrent disease as relevant.

RET carriers still require phenotype-appropriate adrenal screening.

Family cascade testing remains a separate prevention task.

Slide 57 · Diagnostic sequence for a newly identified MTC

Histologic / cytologic medullary carcinoma

Germline RET testing and family assessment

Phenotype-specific adrenal / parathyroid workup

Slide 58 · Clinical case: Oral neuromas and a thyroid lesion

CASE STEM

A child has thickened lips, tongue mucosal nodules, and a thyroid lesion.

The body habitus is elongated; A family history is unavailable.

What inherited syndrome and molecular mechanism should be prioritized?

Apply phenotype → mechanism → immediate clinical priority

Slide 59 · Case interpretation: A MEN2B clinical pattern

The combined neuroma and body-habitus phenotype is more specific than either alone.

Early medullary carcinoma makes urgent specialist evaluation appropriate.

Confirm with germline RET testing; Phenotype alone does not specify the sequence variant.

Evaluate the adrenal catecholamine risk before invasive procedures.

Slide 60 · Clinical case: Thyroid carcinoma plus adrenal tumors

CASE STEM

A young adult has medullary thyroid carcinoma and bilateral adrenal masses.

Episodes of palpitations, sweating, and labile blood pressure are reported.

What immediate presurgical investigation has priority, and why?

Apply phenotype → mechanism → immediate clinical priority

Slide 61 · Case interpretation: Sequence governs safety

The endocrine tumor combination strongly suggests RET-associated MEN2.

Adrenal masses plus adrenergic symptoms raise concern for pheochromocytoma.

Catecholamine excess can provoke perioperative cardiovascular crisis.

Secure adrenal assessment and appropriate management before thyroid intervention.

Slide 62 · Clinical case: Multiple medullary foci in one thyroid

CASE STEM

Thyroid histology shows several separate medullary carcinoma nodules.

Adjacent nonneoplastic thyroid contains clusters of proliferating C cells.

How does this change the etiologic assessment and family discussion?

Apply phenotype → mechanism → immediate clinical priority

Slide 63 · Case interpretation: Precursor morphology matters

Multifocal medullary growth and C-cell hyperplasia are characteristic of syndromic tumors.

A negative family history does not rule out MEN2.

Germline RET testing may have major implications for asymptomatic relatives.

Calcitonin is a disease biomarker, not the inheritance test.

Slide 64 · Integrating MEN2: From gene to prevention

Germline activating RET variant

C-cell / chromaffin tumor susceptibility

Genetic diagnosis and organ-specific prevention

Slide 65 · MEN2: The five essential distinctions

MEN2 is an activating RET syndrome; MEN1 and MEN4 involve other genes.

MEN2A may include parathyroid disease; MEN2B has neuromas and marfanoid features.

Medullary carcinoma is the defining cancer; C-cell hyperplasia is a hereditary clue.

Assess pheochromocytoma before surgery to avoid catecholamine crisis.

Genotype-informed thyroid prevention and family testing improve risk detection.

Slide 66 · Selected references

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th ed. 2026; Ch 24, pp. 992–993 and 1023–1026.

Eng C, Plitt G. Multiple Endocrine Neoplasia Type 2. GeneReviews. Updated August 10, 2023. NCBI Bookshelf NBK1257.

Brock P, Kirschner L. Multiple Endocrine Neoplasia Type 4. GeneReviews. September 21, 2023. NCBI Bookshelf NBK594826.

Note: current molecular-taxonomy distinctions on MEN4 and clinical surveillance are externally verified supplements, not unmarked quotations from Robbins.