Peutz Jeghers Syndrome

Slide 1 · Peutz–Jeghers Syndrome

Hamartomatous polyposis · STK11 tumor suppression · cancer predisposition

Pathology lecture

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Define Peutz–Jeghers syndrome and its inherited clinical phenotype.

Explain STK11 function and the tumor-suppressor model.

Recognize characteristic gross and microscopic polyp architecture.

Relate gastrointestinal complications and multiorgan cancer risk to clinical evaluation.

Phenotype

STK11 biology

Arborizing histology

Cancer surveillance

Slide 3 · Three linked components define the syndrome

Multiple gastrointestinal hamartomatous polyps.

Characteristic mucocutaneous pigmented macules.

An inherited predisposition to malignancies at several organ sites.

GI HAMARTOMATOUS

POLYPS

PIGMENTED

MACULES

HEREDITARY

CANCER RISK

Slide 4 · Hamartomatous polyps belong in a broader category

Hamartomatous polyps may occur sporadically or in genetic syndromes.

Some inherited hamartomatous polyposis syndromes carry increased cancer risk.

Histologic appearance alone does not establish the full syndrome.

Hamartomatous polyp

Assess associated syndrome

Determine systemic implications

Slide 5 · Autosomal dominant inheritance is a defining feature

Peutz–Jeghers syndrome is a rare autosomal dominant condition.

A germline alteration can be present in multiple tissue lineages.

A positive family history is diagnostically informative.

AUTOSOMAL DOMINANT

One inherited altered STK11 allele

Familial transmission is possible

Slide 6 · Clinical recognition often begins in childhood

A median age at presentation of approximately 11 years.

The earliest important problem may be a gastrointestinal polyp complication.

The pigmentation phenotype offers an additional clue before or during evaluation.

Birth

Testicular

Sex cord tumors

Late childhood

Gastric / small

Intestinal cancer

2nd–3rd decades

Colorectal and

Multiple extra-GI sites

Teaching timeline; Surveillance windows are discussed separately.

Slide 7 · The syndrome links the skin and the gut

Dark blue-to-brown macules accompany gastrointestinal polyposis.

The pigment pattern is mucocutaneous rather than restricted to sun-exposed skin.

Recognition should prompt integration with symptoms and family history.

GI HAMARTOMATOUS

POLYPS

PIGMENTED

MACULES

HEREDITARY

CANCER RISK

Slide 8 · Typical pigment sites are diagnostically useful

Lips, nostrils, and buccal mucosa are characteristic locations.

Palmar surfaces may also contain pigmented macules.

Genital and perianal sites can be involved.

Perioral / lips

Buccal mucosa

Nostrils

Palms

Genital / perianal

Slide 9 · Buccal pigmentation helps distinguish freckles

The macules may superficially resemble ordinary freckles.

Involvement of the buccal mucosa is an especially useful discriminator.

A mucosal inspection adds information beyond perioral observation.

Perioral / lips

Buccal mucosa

Nostrils

Palms

Genital / perianal

Slide 10 · Pigmentation is a phenotype, not a stand-alone test

Pigmented macules contribute to the diagnostic pattern.

Absence of pigmentation does not rule out Peutz–Jeghers syndrome.

Polyp burden, anatomic location, pedigree, and molecular findings must be considered.

Polyp morphology

GI multiplicity + pigment + pedigree

STK11 testing supports assessment

Slide 11 · Peutz–Jeghers polyps favor the small intestine

The small intestine is the most common polyp location.

Lesions also occur in the stomach and colon.

Site distribution is useful when the pathology resembles a sporadic hamartoma.

Small intestine

Most common

Stomach

Possible

Colon

Possible

Bladder / lung

Much less common

Slide 12 · Extraintestinal polyps are uncommon

The Robbins morphology section also describes much rarer polyps in bladder and lung.

These sites are not the defining distribution of gastrointestinal polyposis.

Distinguish occasional ectopic polyp locations from the spectrum of cancer susceptibility.

Small intestine

Most common

Stomach

Possible

Colon

Possible

Bladder / lung

Much less common

Slide 13 · A polyp has two distinct clinical dimensions

Local mass effect can create acute gastrointestinal complications.

Systemic predisposition creates a separate, long-term oncologic problem.

A benign-appearing individual polyp does not eliminate hereditary cancer risk.

Polyps

Neoplasms

Mechanical consequences

Multiorgan cancer risk

Slide 14 · STK11 is the major molecular link

Heterozygous germline loss-of-function STK11 alterations occur in affected families.

STK11 is also known as LKB1.

It encodes a serine/threonine kinase with tumor-suppressive functions.

STK11 / LKB1

Serine/threonine kinase

AMPK-related regulation

Slide 15 · STK11 acts through metabolic regulation

The STK11 kinase regulates AMP-activated protein kinase–related pathways.

These pathways participate in control of cellular growth and anabolic metabolism.

Loss of regulation can favor the metabolic conditions that support neoplasia.

STK11 signaling

Metabolic checkpoint / cell polarity

Constrains growth and anabolism

Slide 16 · Cell polarity is part of the STK11 phenotype

Cell polarization among the cellular processes regulated by STK11–AMPK signaling.

Polarity controls how cells organize their structural axes and tissue architecture.

This connects a molecular tumor suppressor to broader cellular organization.

STK11 signaling

Metabolic checkpoint / cell polarity

Constrains growth and anabolism

Slide 17 · Normal STK11 signaling restrains anabolism

Growth requires energy use and synthesis of proteins, lipids, and other components.

STK11-related signaling acts as a brake on growth and anabolic metabolism.

Loss of a brake is a conceptual mechanism of tumor-suppressor dysfunction.

STK11 signaling

Metabolic checkpoint / cell polarity

Constrains growth and anabolism

Slide 18 · STK11 influences multiple metabolic functions

Chapter 7 identifies roles in glucose uptake and gluconeogenesis.

Protein synthesis and mitochondrial biogenesis are also affected.

Lipid metabolism is another regulated process.

STK11 / LKB1

Serine/threonine kinase

AMPK-related regulation

Slide 19 · A multistep model connects genotype to phenotype

A germline STK11 loss-of-function alteration creates inherited susceptibility.

Abnormal growth regulation is linked to hamartomatous polyposis.

Additional somatic events can contribute to development of an associated cancer.

Inherited STK11 alteration

Growth / polarity dysregulation

Polyposis and cancer susceptibility

Slide 20 · STK11 behaves as a tumor-suppressor gene

A tumor suppressor constrains processes that otherwise permit uncontrolled growth.

Peutz–Jeghers syndrome begins with inherited alteration of one STK11 copy.

A second somatic event may abolish the remaining normal copy in a tumor.

Inherited STK11 alteration

(one allele)

Somatic loss of remaining copy

(in many associated cancers)

Loss of tumor-suppressive function

Slide 21 · The two-hit model applies to associated cancers

A germline variant represents the inherited first alteration.

The second, previously functional allele is often lost somatically in associated cancers.

Not every polyp or tumor is asserted to follow an identical molecular sequence.

Inherited STK11 alteration

(one allele)

Somatic loss of remaining copy

(in many associated cancers)

Loss of tumor-suppressive function

Slide 22 · The detectable mutation fraction is incomplete

Germline STK11 loss-of-function mutations in approximately half of familial cases.

These mutations are also observed in a subset of apparently sporadic cases.

A negative test must therefore be interpreted in the context of phenotype.

STK11 / LKB1

Serine/threonine kinase

AMPK-related regulation

Slide 23 · Negative STK11 testing cannot exclude the syndrome

Not all clinically affected patients have a detectable STK11 alteration in the cited source.

An informative tissue diagnosis and classic pigment phenotype remain relevant.

Molecular testing supports rather than replaces clinicopathologic judgment.

Polyp morphology

GI multiplicity + pigment + pedigree

STK11 testing supports assessment

Slide 24 · STK11 loss also occurs in sporadic malignancies

Somatic STK11 loss-of-function variants are identified in diverse carcinomas.

That finding supports its broader tumor-suppressor role.

Somatic tumor STK11 loss by itself does not establish inherited Peutz–Jeghers syndrome.

Inherited STK11 alteration

(one allele)

Somatic loss of remaining copy

(in many associated cancers)

Loss of tumor-suppressive function

Slide 25 · Grossly, polyps are often large and pedunculated

A prominent stalk connects the lesion to the mucosal surface.

The polyp head may be sizeable.

Gross shape alone cannot establish a specific hereditary syndrome.

Lobulated head

Pedunculated stalk

Slide 26 · A lobulated head is a classic gross feature

The polyp contour is characteristically lobulated.

Lobulation corresponds to the complex internal architecture.

The decisive microscopic feature is the branching stromal framework.

Lobulated head

Pedunculated stalk

Slide 27 · Arborizing architecture is the microscopic hallmark

The stroma branches in a tree-like pattern through the polyp.

Smooth muscle bundles are integral to the arborizing core.

The appearance is more specific than simple polyp size or pedunculation.

Branching smooth muscle

Slide 28 · Smooth muscle extends among the glands

Bundles of smooth muscle are intermixed with lamina propria.

Branching smooth muscle helps separate Peutz–Jeghers from juvenile polyps.

Recognition should be at the architectural level, not from a single crypt.

Branching smooth muscle

Slide 29 · Lamina propria and connective tissue form the core

The arborizing scaffold includes connective tissue and lamina propria.

Smooth muscle forms a conspicuous branching component.

The glandular structures remain embedded within that framework.

Branching smooth muscle

Slide 30 · The glandular epithelium may look normal

Glands lined by normal-appearing intestinal epithelium.

Architectural complexity need not imply cytologic malignancy.

The polyp is assessed together with the broader cancer-predisposition syndrome.

Branching smooth muscle

Slide 31 · Read a Peutz–Jeghers polyp from low to high power

First identify the overall polyp configuration and its lobules.

Then trace a branching smooth-muscle–stromal axis.

Finally assess the epithelium lining the glands and correlate with the clinical phenotype.

Branching smooth muscle

Slide 32 · The diagnostic feature is an organized branch pattern

The smooth muscle is not merely scattered between unrelated glands.

Arborization creates a coherent branching internal architecture.

This distinction matters when comparing other hamartomatous polyps.

Branching smooth muscle

Slide 33 · Juvenile polyps provide the key histologic contrast

A juvenile polyp typically contains cystically dilated glands.

Those glands often contain mucin and inflammatory debris.

The lamina propria is expanded by an inflammatory infiltrate.

Cystically dilated glands

Slide 34 · Peutz–Jeghers versus juvenile polyp

Feature

Peutz–Jeghers polyp

Juvenile polyp

Core architecture

Arborizing smooth-muscle stroma

Cystically dilated glands

Epithelium

Often normal-appearing intestinal lining

Mucin-filled, dilated glands

Intervening stroma

Smooth muscle plus lamina propria

Inflammation-expanded lamina propria

Most useful clue

Tree-like smooth muscle branching

Cystic gland pattern

Slide 35 · Juvenile polyposis has different genetic drivers

Juvenile polyposis syndrome may involve SMAD4 mutations.

BMPR1A is another established gene in the TGF-β superfamily pathway.

This differs mechanistically from the STK11–AMPK axis of Peutz–Jeghers.

PJS: STK11

Juvenile: SMAD4 / BMPR1A

AMPK-related growth control

TGF-β family signaling

Slide 36 · Hamartomatous syndromes: Pathway comparison

Syndrome

Gene / pathway

Characteristic emphasis

Peutz–Jeghers

STK11; AMPK-related

Arborizing polyps; Pigmented macules

Juvenile polyposis

SMAD4 / BMPR1A; TGF-β

Cystic glands; GI cancer susceptibility

PTEN hamartoma-tumor

PTEN; PI3K/AKT

Mixed polyp phenotypes; Thyroid / breast lesions

Tuberous sclerosis

TSC1 / TSC2; MTOR

Hamartomas with multisystem findings

Slide 37 · Sporadic hamartomatous polyps can overlap

Morphologic overlap exists between Peutz–Jeghers and sporadic hamartomatous lesions.

Multiple small-intestinal polyps increase the clinical suspicion of syndromic disease.

Pigmentation and positive family history add discriminatory information.

Polyp morphology

GI multiplicity + pigment + pedigree

STK11 testing supports assessment

Slide 38 · Pathologic diagnosis benefits from anatomic context

A solitary histologic specimen cannot show the whole gastrointestinal distribution.

Location in the small intestine supports the characteristic syndrome pattern.

The pathology report should be interpreted alongside clinical and family information.

Small intestine

Most common

Stomach

Possible

Colon

Possible

Bladder / lung

Much less common

Slide 39 · An integrated phenotype is more useful than one sign

Multiple gastrointestinal hamartomatous polyps are a major finding.

Mucocutaneous hyperpigmentation is a characteristic associated clue.

A compatible family history and STK11 result can strengthen the assessment.

Polyp morphology

GI multiplicity + pigment + pedigree

STK11 testing supports assessment

Slide 40 · Familial adenomatous polyposis has a different lesion type

Classic familial adenomatous polyposis is characterized by multiple adenomas.

It is linked to APC and Wnt-pathway dysregulation.

Peutz–Jeghers instead has characteristic arborizing hamartomatous polyps with STK11 dysfunction.

Peutz–Jeghers

Classic FAP

Hamartomatous arborizing polyps

Multiple epithelial adenomas

Slide 41 · Syndrome-level discriminators in polyposis

Syndrome

Principal GI finding

Associated diagnostic clue

Peutz–Jeghers

Arborizing hamartomatous polyps

Mucocutaneous pigmented macules

Juvenile polyposis

Hamartomatous polyps with cystic glands

Family history; SMAD4/BMPR1A

Classic FAP

Numerous adenomatous polyps

APC-associated Wnt dysregulation

PTEN-associated

Hamartomatous / inflammatory polyps

Benign skin, thyroid, breast lesions

Slide 42 · Intussusception is a polyp-related emergency

A prominent polyp can act as a lead point for bowel telescoping.

One segment of intestine enters the adjacent segment.

This complication can occasionally be fatal.

Bowel segment enters adjacent lumen

Lead-point polyp

Slide 43 · Mechanical effects differ from malignant progression

Intussusception is a mechanical complication of a polyp.

Cancer risk reflects inherited tumor susceptibility at multiple sites.

Both require attention, but their pathophysiology and clinical urgency differ.

Polyps

Neoplasms

Mechanical consequences

Multiorgan cancer risk

Slide 44 · A hamartomatous label does not imply a harmless patient

Histologically bland gland lining may coexist with a strong hereditary cancer predisposition.

Long-term oncologic assessment is required irrespective of one polyp’s appearance.

Avoid equating “hamartomatous” with “no cancer risk”.

Polyps

Neoplasms

Mechanical consequences

Multiorgan cancer risk

Slide 45 · The cancer burden extends beyond the intestine

A markedly increased lifetime malignancy risk.

Gastrointestinal and extraintestinal malignancies both contribute.

Surveillance therefore cannot be limited to the colon.

Gastrointestinal tract

Pancreas

Breast

Lung

Ovary

Uterus

Testis

Slide 46 · Gastrointestinal malignancy sites include several organs

Colon, stomach, and small intestine are relevant to the gastrointestinal spectrum.

Pancreatic cancer is a particularly important extraintestinal-organ cancer.

Site-specific surveillance is a central part of the clinical implications.

Gastrointestinal tract

Pancreas

Breast

Lung

Ovary

Uterus

Testis

Slide 47 · Important extra-GI tumor sites are diverse

Breast and lung cancers are included’s risk spectrum.

Ovarian and uterine cancers also warrant attention.

Sex cord tumors of the testes are relevant to early-life surveillance.

Gastrointestinal tract

Pancreas

Breast

Lung

Ovary

Uterus

Testis

Slide 48 · Interpreting the textbook lifetime-risk estimate

Robbins gives an approximately 40% lifetime cancer risk figure for Peutz–Jeghers syndrome.

The estimate is presented as a textbook summary rather than a site-specific risk model.

Do not distribute this figure across organ systems or infer individual prognosis from it.

Polyps

Neoplasms

Mechanical consequences

Multiorgan cancer risk

Slide 49 · Surveillance spans successive life stages

Surveillance beginning in early life.

Different malignancy types become surveillance priorities at different ages.

Exact tests and intervals are not specified by the source excerpt.

Birth

Testicular

Sex cord tumors

Late childhood

Gastric / small

Intestinal cancer

2nd–3rd decades

Colorectal and

Multiple extra-GI sites

Slide 50 · Testicular sex cord tumors are an early concern

Surveillance for testicular sex cord tumors from birth.

This is a distinctive component of a multisystem predisposition phenotype.

The textbook excerpt does not provide a detailed testicular monitoring protocol.

Birth

Testicular

Sex cord tumors

Late childhood

Gastric / small

Intestinal cancer

2nd–3rd decades

Colorectal and

Multiple extra-GI sites

Slide 51 · Gastric and small-bowel surveillance begins in childhood

Surveillance for gastric and small-intestinal cancers in late childhood.

The small bowel is also the predominant site of hamartomatous polyps.

Clinical plans must address both local polyp complications and malignant risk.

Small intestine

Most common

Stomach

Possible

Colon

Possible

Bladder / lung

Much less common

Slide 52 · Adult surveillance broadens across organ systems

The text places surveillance for colorectal, pancreatic, breast, lung, ovarian, and uterine cancers in the second and third decades.

The affected sites differ by sex and other individual characteristics.

Detailed modalities and frequencies require dedicated clinical guidelines beyond this excerpt.

Birth

Testicular

Sex cord tumors

Late childhood

Gastric / small

Intestinal cancer

2nd–3rd decades

Colorectal and

Multiple extra-GI sites

Slide 53 · Surveillance advice requires source specificity

The Robbins overview establishes the importance of routine surveillance.

It supplies broad life-stage windows, not a prescriptive procedure-by-procedure schedule.

No additional intervals or modality-specific recommendations are implied by this lecture.

Polyp morphology

GI multiplicity + pigment + pedigree

STK11 testing supports assessment

Slide 54 · Family history is integral to diagnostic reasoning

Autosomal dominant inheritance makes affected relatives clinically informative.

A family history may add confidence when polyp morphology is not specific.

A negative molecular test should not automatically erase a strong phenotype or pedigree.

Index patient: Clinical phenotype

Ask about relatives with polyps / pigmentation

Family history informs clinical interpretation

Slide 55 · Case 1: Intestinal obstruction in a child

A child has a small-intestinal polyp and an episode suggestive of intussusception.

The lesion is pedunculated with a lobulated head.

What additional tissue and clinical features would support Peutz–Jeghers syndrome?

Clinical vignette

What is the most discriminating microscopic feature?

What other systems should be examined?

Slide 56 · Case 1: Connect morphology and phenotype

Search for branching smooth-muscle bundles and normal-appearing glandular lining.

Inspect for characteristic mucocutaneous pigmentation, especially oral mucosa.

Ask about additional polyps and an affected family member.

Branching smooth muscle

Slide 57 · Case 2: A juvenile-type polyp differential

A hamartomatous intestinal polyp contains large mucin-filled dilated glands.

Inflammatory debris is present within cystic spaces.

How does this morphology differ from a typical Peutz–Jeghers lesion?

Clinical vignette

Cystically dilated glands with inflammatory debris: Which polyp family is favored?

Slide 58 · Case 2: Resolve the histologic differential

A juvenile polyp favors cystic gland dilatation with inflamed lamina propria.

A Peutz–Jeghers polyp favors arborizing smooth-muscle architecture.

The associated syndromic diagnosis still needs clinical correlation.

Juvenile type

Peutz–Jeghers

Cystic glands + inflammation

Branching smooth-muscle scaffold

Slide 59 · Case 3: A negative molecular result

A patient has multiple small-intestinal polyps with arborizing smooth muscle.

Buccal macules and a relevant family history are also present.

A clinical STK11 test is negative: Is the diagnosis excluded?

Clinical vignette

Would a negative STK11 result invalidate a strong clinicopathologic pattern?

Slide 60 · Case 3: Integrate molecular limitations

No: Detectable STK11 variants are absent in some affected individuals.

The phenotype remains clinically important.

A negative result should be interpreted rather than equated with absence of the syndrome.

Polyp morphology

GI multiplicity + pigment + pedigree

STK11 testing supports assessment

Slide 61 · A practical pathology assessment pathway

Recognize a hamartomatous polyp and define its architecture.

Assess extent and distribution of polyposis.

Integrate mucocutaneous findings and family history.

Use molecular findings as supportive, not infallible, evidence.

Polyp morphology

GI multiplicity + pigment + pedigree

STK11 testing supports assessment

Slide 62 · Four mechanisms unify the clinical picture

Inherited STK11 dysfunction connects the disorder to growth regulation.

Arborizing polyps explain the characteristic intestinal histology.

Polyp mass effect explains intussusception risk.

Multiorgan tumor susceptibility explains lifelong surveillance.

Phenotype

STK11 biology

Arborizing histology

Cancer surveillance

Slide 63 · High-yield take-home summary

Autosomal dominant STK11-associated hamartomatous polyposis.

Dark mucocutaneous macules, particularly oral, are useful clues.

Pedunculated polyps show a characteristic arborizing smooth-muscle core.

Intussusception and multiorgan malignancy risk are separate essential outcomes.

GI HAMARTOMATOUS

POLYPS

PIGMENTED

MACULES

HEREDITARY

CANCER RISK

Slide 64 · Source and scope of this lecture

Primary text: Robbins, Cotran & Kumar: Pathologic Basis of Disease, 11th edition (2026).

Source sections: Peutz–Jeghers syndrome and adjacent juvenile/hamartomatous polyps; STK11 tumor suppressor.

Conceptual tissue drawings are original schematics, not actual photomicrographs.

This source-based lecture does not substitute for updated clinical surveillance guidelines.