The

human

keratins

biology

and

pathology

The

keratins

are

the

typical

intermediate

filament

proteins

of

epithelia

showing

an

outstanding

degree

of

molecular

diversity

Heteropolymeric

filaments

are

formed

by

pairing

of

type

I

and

type

II

molecules

In

humans

functional

keratin

genes

exist

They

are

expressed

in

highly

specific

patterns

related

to

the

epithelial

type

and

stage

of

cellular

differentiation

About

half

of

all

keratins

including

numerous

keratins

characterized

only

recently

are

restricted

to

the

various

compartments

of

hair

follicles

As

part

of

the

epithelial

cytoskeleton

keratins

are

important

for

the

mechanical

stability

and

integrity

of

epithelial

cells

and

tissues

Moreover

some

keratins

also

have

regulatory

functions

and

are

involved

in

intracellular

signaling

pathways

e.g.

protection

from

stress

wound

healing

and

apoptosis

Applying

the

new

consensus

nomenclature

this

article

summarizes

for

all

human

keratins

their

cell

type

and

tissue

distribution

and

their

functional

significance

in

relation

to

transgenic

mouse

models

and

human

hereditary

keratin

diseases

Furthermore

since

keratins

also

exhibit

characteristic

expression

patterns

in

human

tumors

several

of

them

-LRB-

notably

and

-RRB-

have

great

importance

in

immunohistochemical

tumor

diagnosis

of

carcinomas

in

particular

of

unclear

metastases

and

in

precise

classification

and

subtyping

Future

research

might

open

further

fields

of

clinical

application

for

this

remarkable

protein

family

Introduction

Most

eukaryotic

cells

contain

in

their

cytoplasm

a

more

or

less

elaborated

cytoskeletal

system

consisting

of

intermediate

filaments

-LRB-

IF

-RRB-

which

are

chemically

very

stable

long

and

unbranched

filaments

of

nm

in

diameter

Among

the

various

families

and

subfamilies

of

IF

proteins

that

of

the

keratins

is

outstanding

due

to

its

high

molecular

diversity

The

keratin

gene

family

consists

of

the

highest

number

of

members

in

humans

with

distinct

functional

genes

IF

proteins

are

expressed

in

a

highly

cell

type-specific

manner

and

herein

keratins

represent

the

typical

IF

category

of

epithelial

cells

In

some

but

not

all

epithelia

keratin

filaments

are

conspicuously

bundled

as

tonofilaments

Figure

shows

these

keratin

filament

bundles

at

the

light

microscopical

-LRB-

Fig.

b

-RRB-

and

the

electron

microscopical

level

-LRB-

Fig.

d

-RRB-

Inside

the

cell

they

braid

the

nucleus

-LRB-

Fig.

-RRB-

span

through

the

cytoplasm

and

are

attached

to

the

cytoplasmic

plaques

of

the

typical

epithelial

cell

cell

junctions

the

desmosomes

-LRB-

Fig.

d

for

a

recent

review

see

Waschke

-RRB-

This

feature

already

suggests

that

keratins

play

a

major

functional

role

in

the

integrity

and

mechanical

stability

of

both

the

single

epithelial

cells

and

via

cell

cell

contacts

of

that

of

the

epithelial

tissues

Consequently

they

are

inherent

part

of

the

continuum

of

stability

from

the

single

cell

to

the

tissue

formation

Evidence

for

this

main

function

of

keratin

filaments

has

been

amply

provided

by

the

recognition

of

various

hereditary

keratin

diseases

and

transgenic

mouse

models

In

addition

however

various

regulatory

functions

have

been

discovered

more

recently

-LRB-

for

recent

reviews

see

Magin

et

al.

Oshima

Uitto

et

al.

McLean

and

Irvine

-RRB-

Fig.

of

epithelial

cells

a

Immunofluorescence

staining

of

keratin

-LRB-

red

nuclei

stained

in

blue

by

DAPI

-RRB-

in

PLC

-LRB-

liver

carcinoma

-RRB-

cells

in

vitro

b

Keratin

filaments

-LRB-

in

red

-RRB-

and

the

desmosomal

component

desmoplakin

-LRB-

in

green

-RRB-

are

labeled

in

cultured

keratinocytes

of

line

HaCaT

c

Electron

microscopic

image

of

tonofilament

-LRB-

keratin

-RRB-

bundles

-LRB-

arrowhead

-RRB-

of

HaCaT

keratinocytes

d

Keratin

intermediate

filaments

-LRB-

black

arrowhead

-RRB-

insert

at

desmosomes

-LRB-

white

arrowhead

-RRB-

at

cell

cell

contact

sites

of

keratinocytes

of

the

epidermal

stratum

spinosum

-LRB-

electron

microscopy

-RRB-

Historically

keratin

research

started

with

studies

of

sheep

hair

-LRB-

wool

-RRB-

keratins

-LRB-

Crick

Powell

and

Rogers

Oshima

-RRB-

Several

important

discoveries

were

made

in

the

of

the

last

century

One

was

the

finding

of

the

spontaneous

self-assembly

and

polymerization

of

keratin

filaments

from

denatured

soluble

keratin

proteins

by

dialysis

in

vitro

-LRB-

Steinert

et

al.

-RRB-

Further

milestones

were

the

findings

that

antibodies

against

keratins

from

epidermis-type

epithelia

such

as

the

bovine

muzzle

-LRB-

prekeratin

-RRB-

react

with

tonofilaments

in

various

epithelial

cells

including

non-stratified

simple

epithelia

of

inner

organs

-LRB-

Franke

et

al.

-RRB-

and

that

keratins

of

various

mammalian

species

exhibit

a

high

degree

of

molecular

diversity

with

differentiation-specific

expression

-LRB-

Franke

et

al.

-RRB-

Systematic

protein

biochemical

analyses

of

human

cells

and

tissues

by

one

and

two-dimensional

gel

electrophoresis

Western

blotting

and

peptide

mapping

disclosed

the

diversity

of

human

-LRB-

cyto

-RRB-

keratin

polypeptides

-LRB-

Moll

et

al.

Tseng

et

al.

Wu

et

al.

-RRB-

From

these

data

in

the

catalog

of

human

cytokeratins

including

members

was

proposed

-LRB-

Moll

et

al.

-RRB-

which

although

intended

as

provisional

has

been

widely

accepted

and

used

Along

with

these

studies

and

subsequently

the

principle

of

separation

of

these

proteins

into

type

I

-LRB-

acidic

-RRB-

and

type

II

-LRB-

basic

to

neutral

-RRB-

keratins

-LRB-

see

below

-RRB-

also

emerged

Another

unique

property

of

the

keratins

is

that

in

contrast

to

the

other

IF

proteins

they

only

can

constitute

their

filamentous

stage

by

heteropolymeric

pair

formation

of

type

I

and

type

II

-LRB-

-RRB-

molecules

Later

on

several

new

keratins

were

identified

and

added

to

the

cytokeratin

catalog

the

most

notable

of

these

being

the

simple-epithelial

keratin

-LRB-

Moll

et

al.

-RRB-

and

several

keratins

specific

for

distinct

epithelia

such

as

keratin

in

the

upper

epidermis

-LRB-

appendix

e

now

-RRB-

in

the

upper

hard

palate

epithelium

-LRB-

similar

to

but

with

appendix

p

for

palate

now

-RRB-

-LRB-

Collin

et

al.

b

-RRB-

or

several

keratin

-LRB-

h

-RRB-

isoforms

-LRB-

Takahashi

et

al.

-RRB-

Simultaneously

informations

about

the

keratin

gene

sequences

were

revealed

Moreover

within

the

last

years

a

large

number

of

hair

follicle-specific

epithelial

keratins

were

discovered

This

series

started

with

-LRB-

appendix

hf

stands

for

hair

follicle

expression

now

-RRB-

which

was

expressed

in

the

hair

follicle

companion

layer

-LRB-

Winter

et

al.

-RRB-

was

the

first

epithelial

keratin

specifically

expressed

in

the

hair

follicle

Surprisingly

there

were

much

more

epithelial

keratins

with

hair

follicle

specificity

namely

the

type

II

keratins

and

-LRB-

now

-RRB-

and

type

I

keratins

and

-LRB-

now

-RRB-

all

of

them

specifically

expressed

in

and

closely

restricted

to

the

various

compartments

of

the

hair

follicle

inner

root

sheath

-LRB-

Langbein

et

al.

for

review

see

Langbein

and

Schweizer

-RRB-

Besides

the

variety

of

epithelial

-LRB-

soft

or

cyto

-RRB-

keratins

hairs

and

nails

are

built

up

from

a

somewhat

separate

subfamily

of

hard

or

trichocytic

keratins

commonly

designated

as

hair

keratins

-LRB-

Heid

et

al.

Langbein

et

al.

Langbein

and

Schweizer

Schweizer

et

al.

-RRB-

They

differ

from

the

epithelial

keratins

by

their

considerably

higher

sulfur

content

in

their

non-α-helical

head

and

tail

domains

which

is

mainly

responsible

for

the

extraordinary

high

degree

of

filamentous

cross-linking

by

keratin-associated

proteins

-LRB-

KAPs

-RRB-

-LRB-

for

review

see

Rogers

et

al.

-RRB-

Very

recently

the

Keratin

Nomenclature

Committee

established

the

novel

consensus

nomenclature

for

mammalian

keratin

genes

and

proteins

-LRB-

Schweizer

et

al.

-RRB-

relying

upon

and

systematically

extending

the

aforementioned

catalog

This

nomenclature

is

now

in

accordance

with

the

nomenclature

of

the

Human

Genome

Organization

-LRB-

HUGO

-RRB-

for

both

the

gene

and

protein

names

Following

the

unified

new

principles

several

parts

of

the

former

nomenclature

were

implemented

the

hair

keratins

-LRB-

e.g.

Ha

and

Hb

-RRB-

and

the

special

epithelial

keratin

designations

-LRB-

e.g.

-RRB-

were

equally

integrated

-LRB-

see

Table

-RRB-

and

the

nomenclature

system

although

now

complete

for

humans

is

open

to

application

in

other

mammalian

species

by

following

the

same

principles

Among

human

keratins

the

new

consensus

nomenclature

-LRB-

Table

-RRB-

comprises

the

type

I

keratins

and

-LRB-

including

and

-RRB-

and

the

type

II

keratins

-LRB-

including

and

-RRB-

and

Thus

there

are

type

I

keratin

genes

-LRB-

epithelial

keratins

and

hair

keratins

-RRB-

and

type

II

keratin

genes

-LRB-

epithelial

keratins

and

hair

keratins

-RRB-

All

in

all

out

of

the

human

keratin

genes

at

least

-LRB-

-RRB-

are

specifically

expressed

in

the

hair

follicle

In

the

human

genome

the

keratin

genes

are

clustered

at

two

different

chromosomal

sites

chromosome

-LRB-

type

I

keratins

except

-RRB-

and

chromosome

-LRB-

type

II

keratins

including

-RRB-

The

keratin

genes

are

designated

as

etc.

-LRB-

Schweizer

et

al.

Fig.

-RRB-

Fig.

keratins

a

Organization

of

the

human

keratin

genes

in

the

genome

The

type

I

and

type

II

keratin

gene

subdomains

are

located

on

chromosomes

and

respectively

The

type

I

keratin

is

located

in

the

type

II

cluster

on

chromosome

-LRB-

arrow

-RRB-

b

Two-dimensional

catalog

of

the

human

keratin

proteins

according

to

molecular

weights

-LRB-

MW

-RRB-

and

isoelectric

points

-LRB-

IEP

-RRB-

as

calculated

from

amino

acid

sequences

The

keratin

genes

are

designated

according

to

the

new

keratin

nomenclature

-LRB-

Schweizer

et

al.

-RRB-

Table

new

human

keratin

nomenclature

-LRB-

Schweizer

et

al.

-RRB-

For

-LRB-

in

gray

-RRB-

the

numbering

of

the

original

catalog

-LRB-

Moll

et

al.

-RRB-

has

been

maintained

The

respective

gene

names

-LRB-

KRT

-RRB-

by

the

human

genome

consortium

utilize

the

same

numbers

e.g.

All

these

keratins

belong

to

the

family

of

IF

proteins

and

therefore

share

common

protein-structural

characteristics

They

contain

a

central

rod

domain

of

amino

acids

with

α-helical

conformation

flanked

by

non-helical

head

and

tail

domains

of

variable

length

The

head

domain

consists

of

subdomains

and

The

central

α-helical

rod

domain

is

composed

of

subdomains

and

connected

by

the

linkers

and

The

tail

domain

then

consists

of

subdomains

and

-LRB-

Lane

and

McLean

Parry

et

al.

Geisler

and

Weber

-RRB-

The

molecular

weight

of

human

keratins

ranges

from

to

kDa

-LRB-

Fig.

-RRB-

A

unique

feature

of

keratins

including

the

hair

keratins

is

their

pairing

i.e.

the

obligate

formation

of

heterodimers

between

one

type

I

keratin

and

one

type

II

keratin

This

occurs

by

association

of

the

corresponding

rod

domains

in

α-helical

coiled-coil

conformation

The

resulting

heterodimers

and

tetramers

form

the

basic

building

units

of

the

keratin

filaments

Single

keratin

proteins

deviating

from

equimolar

type

I/type

II

amounts

are

rapidly

degraded

-LRB-

Lu

and

Lane

-RRB-

As

keratin

filaments

are

important

structural

stabilizers

of

epithelial

cells

there

is

unabatedly

high

interest

in

keratins

in

biology

embryology

pathology

and

dermatology

Notably

this

main

cytoskeletal

function

transcends

the

single

cell

level

Typically

keratin

filaments

insert

at

desmosomes

-LRB-

Fig.

d

-RRB-

and

hemidesmosomes

Thus

they

contribute

not

only

to

the

stability

between

epithelial

cells

itself

but

also

to

basement

membrane

attachment

and

insofar

to

the

connective

tissue

compartment

of

a

given

epithelium

In

the

non-stratified

-LRB-

simple

-RRB-

epithelia

of

internal

parenchymatous

organs

which

experience

little

mechanical

stress

only

very

few

keratin

members

form

sparse

and

loosely

distributed

keratin

filaments

in

the

cytoplasm

Otherwise

considerably

more

members

take

part

on

the

IF

cytoskeletal

composition

of

squamous

epithelia

which

increases

in

the

cornified

stratified

epithelia

such

as

in

the

epidermis

lining

the

outer

body

surface

where

they

are

abundant

and

densely

bundled

as

tonofilaments

The

loose

filaments

in

the

former

case

are

composed

of

simple-epithelial

keratins

like

-LRB-

and

-RRB-

while

the

bundled

filaments

-LRB-

tonofilaments

-RRB-

in

the

latter

case

-LRB-

Fig.

d

-RRB-

are

built

up

from

keratinocyte-type

keratins

such

as

in

the

basal

layer

and

with

even

more

pronounced

bundling

in

the

suprabasal

layers

and

in

the

uppermost

ones

The

rule

that

the

stronger/harder

the

epithelial

structure

the

more

keratin

members

are

involved

culminates

in

the

hair

fiber

where

keratins

are

sequentially

expressed

This

clearly

underscores

the

importance

of

the

keratins

for

the

tissue

integrity

and

the

relevance

of

the

molecular

diversity

of

keratin

proteins

The

important

mechanical

function

of

stratified

epithelial

and

epidermis-type

keratins

is

evident

and

proven

not

only

through

knock-out

mouse

models

but

also

through

various

human

hereditary

keratin

diseases

Thus

point

mutations

of

distinct

keratin

genes

now

widely

explain

the

pathogenesis

of

several

autosomal-dominant

familial

diseases

many

of

which

are

blistering

skin

diseases

The

most

well

known

of

these

inherited

skin

fragility

disorders

is

epidermolysis

bullosa

simplex

-LRB-

EBS

-RRB-

the

various

variants

of

which

are

caused

by

a

spectrum

of

point

mutations

of

or

-LRB-

Lane

and

McLean

McLean

and

Irvine

Uitto

et

al.

-RRB-

Nineteen

different

keratin

genes

including

hair

keratins

and

hair

follicle-specific

epithelial

keratins

have

up

to

now

been

identified

as

being

involved

in

pathogenic

keratin

mutations

-LRB-

Lane

and

McLean

Schweizer

et

al.

-RRB-

they

will

be

discussed

in

the

descriptions

of

the

individual

keratins

below

Updated

details

may

be

retrieved

from

an

Internet

database

-LRB-

Human

Intermediate

Filament

Database

-RRB-

Notably

the

knock-out

experiments

and

the

genetic

diseases

demonstrated

that

mutations

in

keratin

genes

often

-LRB-

depending

on

the

locus

of

mutation

within

the

keratin

molecule

-RRB-

cause

more

severe

defects

than

the

complete

loss

of

a

keratin

gene

whose

failure

might

be

compensated

if

available

at

this

site

by

another/other

keratin/s

Moreover

it

has

been

recognized

that

keratins

are

not

simply

static

intracellular

skeletal

structures

but

rather

are

highly

dynamic

Along

with

this

view

besides

their

mechanical

function

new

functional

roles

of

keratins

have

been

defined

and

still

emerge

under

special

physiological

conditions

-LRB-

Magin

et

al.

Oshima

-RRB-

These

include

the

protection

of

the

placental

and

trophoblast

barrier

function

-LRB-

Jaquemar

et

al.

Hesse

et

al.

-RRB-

the

protection

from

apoptosis

-LRB-

Caulin

et

al.

Ku

et

al.

Tong

and

Coulombe

-RRB-

the

protection

of

the

liver

against

stress

and

from

injury

-LRB-

Zatloukal

et

al.

Ku

et

al.

-RRB-

and

the

regulation

of

protein

synthesis

and

cell

size

during

wound

healing

involving

intracellular

signaling

pathways

-LRB-

Kim

et

al.

-RRB-

Keratins

may

also

play

a

role

in

epithelial

polarity

and

membrane

traffic

-LRB-

Oriolo

et

al.

-RRB-

Thus

keratins

obviously

exert

widely

varying

signaling

functions

beyond

their

mechanical

roles

Beyond

their

biological

functions

keratin

expression

patterns

not

only

characterize

cells

as

epithelial

they

are

also

characteristic

for

distinct

including

the

terminal

stages

during

cellular

epithelial

differentiation

from

embryonal

to

adult

or

of

the

internal

maturation

program

during

development

Epithelial

tumors

including

metastases

most

widely

retain

the

keratin

patterns

of

their

-LRB-

normal

-RRB-

epithelial

origin

thus

the

determination

of

the

keratin

patterns

of

tumors

are

being

widely

exploited

for

cell

and

tumor

typing

Therefore

keratins

have

evolved

to

be

one

of

the

most

potent

epithelial

differentiation

and

tumor

markers

in

cell

biology

embryology

and

surgical

pathology

Specific

antibodies

against

several

keratins

are

routinely

used

world

wide

in

pathology

laboratories

for

immunohistochemical

typing

of

carcinomas

in

tumor

diagnostics

Numerous

papers

published

since

deal

with

the

application

of

keratins

as

marker

proteins

in

tumor

pathology

-LRB-

Oshima

-RRB-

and

several

previous

review

articles

-LRB-

e.g.

Lane

and

Alexander

Nagle

Schaafsma

and

Ramaekers

Moll

Chu

and

Weiss

-RRB-

cover

this

field

of

application

which

also

will

be

especially

considered

in

this

review

Another

clinical

application

is

the

detection

of

soluble

keratin

protein

fragments

derived

from

and

in

the

circulation

of

cancer

patients

such

fragments

released

by

carcinoma

cells

are

increasingly

used

to

monitor

tumor

load

and

disease

progression

in

the

case

of

certain

carcinomas

such

as

non-small

cell

lung

cancer

-LRB-

Barak

et

al.

Linder

-RRB-

Through

analysis

of

different

fragments

in

the

serum

it

is

also

possible

to

assess

the

type

of

chemotherapy-induced

tumor

cell

death

and

distinguish

between

apoptosis

and

necrosis

due

to

the

fact

that

is

cleaved

at

specific

sites

during

apoptosis

and

a

monoclonal

antibody

-LRB-

-RRB-

specific

for

caspase-cleaved

forms

of

is

available

-LRB-

Leers

et

al.

Linder

et

al.

Linder

-RRB-

Human

keratins

and

their

expression

patterns

In

the

following

the

different

human

keratins

and

keratin

pairs

will

be

discussed

together

with

their

cell

type

and

tissue

distribution

-LRB-

summarized

in

Table

-RRB-

and

their

functional

significance

in

relation

to

transgenic

mouse

models

and

human

hereditary

keratin

diseases

Furthermore

characteristic

expression

patterns

in

human

tumors

-LRB-

summarized

in

Table

-RRB-

and

their

possible

diagnostic

relevance

will

be

considered.Table

expression

patterns

of

typical

keratins

in

selected

human

normal

epithelial

tissuesKeratins

of

simple

epitheliaKeratins

of

stratified

epitheliaType

II

keratins

I

keratins

epitheliaaAll

cellsDuctal

epithelia

of

parenchymatous

organsbAll

and

in

all

cellsSparse

cellsSparse

heterogeneously

in

pancreatic

ductsGastrointestinal

epitheliaAll

in

all

cellsGastric

foveolar

epithelium

intestinal

heterogeneously

in

luminal

cells

in

sparse

luminal

cellsRespiratory

epitheliumPredominantly

luminal

in

luminal

cells

in

all

cellsPredominantly

basal

in

basal

cellsPredominantly

basal

cellsUrotheliumAll

and

in

all

cellsLuminal

-LRB-

umbrella

-RRB-

cellsBasal

cellsFew

basal

in

all

basal

and

intermediate

cellsNon-keratinizing

stratified

squamous

epitheliaSome

basal

in

many

basal

cellsBasal

cell

layer

-LRB-

predominantly

-RRB-

Basal

cells

layerSuprabasal

compartmentAt

some

sites

focal

expression

in

suprabasal

cellsSuprabasal

compartmentEpidermisPredominantly

basal

cell

layerBasal

cell

layerSuprabasal

in

upper

spinous

and

granular

layer

in

palmoplantar

epidermisdNot

included

are

the

corneal

keratins

the

gingival/hard

palate

keratin

the

eccrine

sweat

gland-specific

keratin

and

the

hair

follicle-specific

epithelial

and

hair

keratins

-LRB-

for

keratin

expression

in

eccrine

sweat

glands

and

in

the

hair

follicle

see

the

schematic

drawings

in

Figs.

and

-RRB-

aIncluding

hepatocytes

acinar

cells

of

pancreas

proximal

tubular

cells

of

kidneybBile

ducts

pancreatic

ducts

renal

collecting

ductscMost

villus

and

surface-lining

cells

scattered

cells

in

cryptsdHeterogeneous

expression

in

the

suprabasal

compartmentTable

expression

patterns

of

typical

keratins

in

selected

human

carcinomasOnly

diagnostically

relevant

data

as

detectable

by

monoclonal

antibodies

widely

established

in

clinical

pathology

are

presented

-LRB-

for

references

see

Moll

Chu

and

Weiss

and

text

-RRB-

Explanation

of

symbols

filled

circle

extended

staining

of

most

tumor

cases

open

dotted

circle

focal/heterogeneous

staining

of

some

but

not

all

cases

open

circle

no

stainingaIn

rare

cases

focal

staining

may

be

observedbFocal

or

extended

staining

in

a

subpopulation

of

tumor

cases

corresponding

to

the

basal-like

phenotypecNon-mucinous

typesdPreferentially/more

extended

in

poorly

differentiated

caseseIn

rare

cases

focal

staining

may

be

observed

however

squamous

cell

carcinomas

of

the

cervix

uteri

may

express

extendedly

Simple

-LRB-

one-layered

-RRB-

epithelia

primary

keratins

of

simple

epithelial

cells

The

keratins

and

typically

are

co-expressed

and

constitute

the

primary

keratin

pair

of

simple

epithelial

cells

including

various

parenchymatous

epithelia

-LRB-

Franke

et

al.

Moll

et

al.

Owens

and

Lane

-RRB-

They

are

the

first

keratins

to

appear

in

embryogenesis

as

early

as

in

pre-implantation

embryos

-LRB-

Jackson

et

al.

-RRB-

and

also

seem

to

be

the

oldest

keratins

during

phylogenesis

-LRB-

Blumenberg

-RRB-

In

some

epithelial

cell

types

and

are

the

sole

keratins

present

The

classical

example

is

the

liver

with

representing

the

characteristic

and

only

keratin

pair

of

normal

hepatocytes

The

same

is

true

for

other

highly

specialized

parenchymatous

epithelia

such

as

acinar

cells

of

the

pancreas

proximal

tubular

epithelial

cells

of

the

kidney

and

certain

endocrine

cells

such

as

pancreatic

islet

cells

Ultrastructurally

keratin

filaments

of

this

simple

composition

are

loosely

distributed

within

the

cytoplasm

and

show

little

bundling

In

other

simple

one-layered

epithelia

such

as

duct-lining

cells

intestinal

cells

and

mesothelial

cells

additional

simple-epithelial

keratins

-LRB-

and/or

see

below

-RRB-

are

present

in

addition

to

the

primary

pair

Furthermore

occur

together

with

other

keratins

in

various

pseudostratified

-LRB-

e.g.

respiratory

-RRB-

and

complex

-LRB-

e.g.

glandular

-RRB-

epithelia

and

in

the

urothelium

in

these

composite

epithelial

tissues

and

are

often

most

prominent

in

the

lumen-lining

cells

Even

in

non-keratinizing

stratified

squamous

epithelia

and

may

be

focally

expressed

in

the

basal

cell

layer

together

with

and

the

constitutive

stratified-epithelial

keratins

-LRB-

Bosch

et

al.

Moll

-RRB-

Thus

and

are

widely

distributed

among

normal

epithelial

tissues

although

they

are

absent

in

differentiating

keratinocytes

It

should

be

noted

that

and

are

not

strictly

epithelium-specific

since

expression

of

and

may

occur

in

rare

mesenchymal

cells

-LRB-

more

frequently

in

fetal

stages

-RRB-

such

as

certain

smooth

muscle

cells

and

fibroblastic

reticulum

cells

of

lymph

nodes

as

well

as

various

mesenchymal

tumors

including

rhabdo

and

leiomyosarcomas

-LRB-

Huitfeldt

and

Brandtzaeg

Franke

and

Moll

van

Muijen

et

al.

Jahn

and

Franke

Knapp

and

Franke

Knapp

et

al.

Jahn

et

al.

Gould

et

al.

Kuruc

and

Franke

Langbein

et

al.

-RRB-

where

they

are

co-expressed

with

other

intermediate

filament

types

notably

vimentin

and

desmin

While

highly

specialized

parenchymatous

epithelial

cells

in

their

normal

state

such

as

proximal

tubular

cells

of

the

kidney

only

express

and

this

may

change

in

reactive

conditions

Upon

various

types

of

injury

such

as

inflammation

or

atrophy

these

cells

may

additionally

switch

on

and

sometimes

also

-LRB-

as

well

as

vimentin

-RRB-

and

thus

express

four

to

five

instead

of

two

keratins

-LRB-

Moll

et

al.

-RRB-

This

increased

keratin

expression

appears

to

parallel

the

reduction

in

the

degree

of

differentiation

Thus

the

keratin

pattern

of

a

given

epithelial

tissue

may

be

modulated

to

some

extent

in

the

course

of

reactive

changes

frequently

resulting

in

higher

complexity

of

keratin

composition

Already

the

tissue

distribution

of

mainly

in

internal

epithelia

suggests

that

structural

and

mechanical

functions

are

not

their

key

roles

although

their

absence

or

dysfunction

may

be

associated

with

hepatocyte

and

trophoblast

fragility

-LRB-

for

references

see

Magin

et

al.

-RRB-

Instead

genetic

knock-out

experiments

have

revealed

distinct

regulatory

functions

of

these

keratins

-LRB-

Magin

et

al.

Oshima

-RRB-

They

play

a

role

in

protecting

the

placental

barrier

function

-LRB-

Jaquemar

et

al.

-RRB-

and

protecting

cells

in

particular

liver

cells

from

apoptosis

-LRB-

Caulin

et

al.

Ku

et

al.

-RRB-

against

stress

and

from

injury

-LRB-

Zatloukal

et

al.

Ku

et

al.

-RRB-

possibly

by

functioning

as

a

phosphate

sponge

for

stress-activated

kinases

-LRB-

Ku

and

Omary

-RRB-

Interestingly

and

may

play

a

role

in

the

regulation

of

the

cell

cycle

whereby

phosphorylation

of

these

keratins

and

binding

of

adaptor

proteins

seem

to

be

involved

-LRB-

Toivola

et

al.

Ku

et

al.

Margolis

et

al.

Galarneau

et

al.

Magin

et

al.

-RRB-

In

human

pathology

defects

in

and

may

predispose

to

liver

diseases

in

particular

cryptogenic

liver

cirrhosis

-LRB-

Ku

et

al.

Zatloukal

et

al.

-RRB-

as

well

as

to

chronic

pancreatitis

and

inflammatory

bowel

disease

-LRB-

for

references

see

Owens

and

Lane

-RRB-

Altered

and

proteins

together

with

several

stress

proteins

in

particular

ubiquitin

and

constitute

the

hyaline

protein

aggregates

of

hepatocytes

of

several

-LRB-

e.g.

alcoholic

-RRB-

liver

diseases

now

known

as

Mallory

Denk

bodies

-LRB-

Zatloukal

et

al.

-RRB-

In

regard

to

malignant

tumors

and

are

expressed

in

most

carcinomas

except

for

some

differentiated

squamous

cell

carcinomas

Therefore

and

antibodies

strongly

stain

most

adenocarcinomas

hepatocellular

carcinomas

renal

cell

carcinomas

and

neuroendocrine

carcinomas

Since

highly

sensitive

monoclonal

antibodies

against

these

keratins

are

available

such

as

the

classical

mouse

monoclonal

clone

against

-LRB-

Makin

et

al.

-RRB-

and

clone

against

-LRB-

Bártek

et

al.

-RRB-

these

keratins

may

be

helpful

in

diagnostic

immunohistochemistry

in

cases

of

carcinomas

with

low

keratin

content

such

as

small-cell

lung

cancer

to

prove

their

epithelial

nature

Regarding

carcinoma

subtyping

negative

or

weak/focal

immunostaining

for

and

may

indicate

squamous

cell

differentiation

although

strong

expression

of

these

keratins

can

occur

particularly

in

poorly

differentiated

squamous

cell

carcinomas

-LRB-

see

below

chapter

Keratins

as

diagnostic

markers

in

tumor

pathology

-RRB-

In

the

case

of

breast

carcinomas

certain

publications

have

reported

a

correlation

between

the

level

of

or

immunostaining

and

a

favorable

prognosis

for

the

patients

-LRB-

see

below

chapter

Keratins

as

diagnostic

markers

in

tumor

pathology

-RRB-

Another

clinical

application

of

is

the

monitoring

of

fragments

of

these

keratins

in

the

serum

as

serological

tumor

markers

to

monitor

cancer

load

cancer

progression

and

response

to

therapy

Among

the

oldest

of

these

markers

are

tissue

polypeptide

antigen

-LRB-

TPA

-RRB-

and

tissue

polypeptide-specific

antigen

-LRB-

TPS

-RRB-

which

have

been

recognized

to

correspond

to

a

mixture

of

and

-LRB-

Weber

et

al.

-RRB-

and

to

-LRB-

Rydlander

et

al.

-RRB-

respectively

-LRB-

for

review

see

Linder

-RRB-

More

recently

an

apoptosis-specific

fragment

of

as

detected

by

monoclonal

antibody

-LRB-

Leers

et

al.

-RRB-

has

become

of

increasing

interest

for

distinguishing

between

necrosis

and

apoptosis

and

for

the

evaluation

of

the

chemotherapy

response

of

carcinomas

by

investigation

of

cancer

patient

serum

e.g.

in

prostate

breast

and

lung

cancer

-LRB-

Linder

et

al.

Linder

-RRB-

secondary

keratins

of

simple

epithelial

cells

Apart

from

keratins

and

are

additional

-LRB-

secondary

-RRB-

and

also

widely

distributed

simple-epithelial

keratins

which

are

frequently

but

not

always

co-expressed

They

typically

occur

as

a

keratin

pair

in

simple

ductal

epithelia

such

as

bile

and

pancreatic

ducts

-LRB-

ductal-type

keratins

-RRB-

However

in

several

epithelia

lacking

such

as

intestinal

epithelium

the

type

I

keratin

must

form

a

pair

with

the

sole

type

II

keratin

The

type

I

keratin

is

the

smallest

keratin

and

is

exceptional

since

it

widely

lacks

the

non-α-helical

tail

domain

typical

for

all

other

keratins

-LRB-

Bader

et

al.

-RRB-

It

may

have

evolved

from

keratinocyte

keratins

-LRB-

Stasiak

et

al.

-RRB-

As

detectable

by

several

specific

and

well-tested

monoclonal

antibodies

-LRB-

Karsten

et

al.

Bártek

et

al.

Nagle

et

al.

-RRB-

exhibits

a

rather

broad

tissue

distribution

It

is

expressed

in

most

simple

epithelia

-LRB-

excluding

parenchymatous

cells

such

as

hepatocytes

pancreatic

acinar

cells

and

renal

proximal

tubular

cells

-RRB-

notably

in

various

ductal

epithelia

in

small

and

large

intestinal

epithelium

in

gastric

foveolar

epithelium

and

in

mesothelium

Furthermore

it

is

present

in

most

cells

of

pseudostratified

epithelia

and

urothelium

as

well

as

in

basal

cells

of

non-keratinizing

stratified

squamous

epithelia

Functionally

keratin

is

dispensable

since

knock-out

mice

were

viable

fertile

and

appeared

normal

-LRB-

Harada

et

al.

-RRB-

This

is

apparently

due

to

functional

compensation

by

since

only

mice

double

deficient

for

and

exhibited

a

severe

phenotype

with

trophoblast

fragility

and

early

embryonic

lethality

-LRB-

Hesse

et

al.

-RRB-

No

mutation

of

the

human

gene

causing

a

disease

has

yet

been

found

-LRB-

Owens

and

Lane

-RRB-

The

expression

of

may

be

induced

in

certain

epithelia

that

normally

lack

this

keratin

by

pathological

alterations

One

example

is

damage

to

renal

proximal

tubular

epithelia

by

various

types

of

injury

as

discussed

above

-LRB-

Moll

et

al.

-RRB-

induction

is

also

observed

in

suprabasal

stratified

squamous

epithelial

cells

of

oral

mucosa

with

epithelial

dysplasia

-LRB-

Lindberg

and

Rheinwald

for

further

references

see

Moll

-RRB-

but

also

with

inflammation

-LRB-

Bosch

et

al.

Moll

-RRB-

so

that

can

not

be

used

as

a

specific

marker

for

dysplasia

in

oral

mucosa

In

carcinomas

is

widely

expressed

in

both

adenocarcinomas

and

squamous

cell

carcinomas

and

therefore

is

not

extensively

used

as

an

immunohistochemical

marker

for

carcinoma

subtyping

One

example

for

such

application

may

be

in

liver

tumors

the

distinction

of

hepatocellular

carcinomas

which

show

little

expression

of

from

cholangiocarcinomas

and

adenocarcinoma

metastases

which

strongly

stain

for

this

keratin

-LRB-

Balaton

et

al.

Goldstein

and

Bosler

see

Table

-RRB-

The

detection

of

soluble

fragments

in

the

serum

released

by

carcinoma

cells

by

the

CYFRA

assay

has

found

broad

clinical

application

as

a

marker

to

monitor

treatment

and

evaluate

response

to

therapy

and

has

proven

particularly

useful

in

the

case

of

squamous

cell

carcinomas

of

the

lung

-LRB-

for

review

see

Barak

et

al.

Gu

and

Coulombe

-RRB-

The

type

II

keratin

another

ductal-type

keratin

has

a

basically

similar

but

somewhat

more

restricted

tissue

distribution

as

compared

to

-LRB-

Moll

et

al.

Ramaekers

et

al.

-RRB-

Like

it

is

expressed

in

several

simple

ductal

epithelia

in

mesothelium

in

pseudostratified

epithelia

-LRB-

preferentially

in

luminal

cells

-RRB-

and

in

urothelium

but

absent

in

parenchymatous

cells

such

as

hepatocytes

However

is

sparsely

expressed

or

absent

in

gastric

foveolar

epithelium

intestinal

epithelium

and

stratified

squamous

epithelia

Human

and

mouse

genes

have

been

characterized

-LRB-

Glass

and

Fuchs

Smith

et

al.

-RRB-

but

mutations

or

disease

associations

have

not

yet

been

reported

-LRB-

Owens

and

Lane

-RRB-

Several

monoclonal

antibodies

against

have

been

described

some

of

which

-LRB-

e.g.

-RRB-

are

well

reactive

with

formalin-fixed

paraffin-embedded

tissues

Of

these

clone

-LRB-

van

Niekerk

et

al.

-RRB-

appears

to

elicit

the

broadest

span

of

immunoreactivity

and

has

found

wide

application

in

diagnostic

tumor

pathology

especially

in

cases

where

primary

tumors

or

metastases

are

uncertain

Since

the

majority

of

carcinomas

are

positive

negative

reactions

are

of

particular

diagnostic

significance

One

main

point

of

diagnostic

utility

of

this

keratin

is

the

negative

-LRB-

or

weak/focal

-RRB-

immunostaining

in

colorectal

adenocarcinomas

-LRB-

see

Fig.

-RRB-

in

contrast

to

the

strong

staining

in

most

other

adenocarcinomas

-LRB-

see

Fig.

Moll

et

al.

Chu

et

al.

Chu

and

Weiss

Tot

-RRB-

This

is

especially

valuable

for

classifying

adenocarcinoma

metastases

with

regard

to

their

possible

primary

tumor

Low

expression

-LRB-

negative

or

weak

immunostaining

or

staining

of

a

minor

proportion

of

tumor

cells

-RRB-

is

also

a

characteristic

feature

of

conventional

-LRB-

clear-cell

-RRB-

renal

cell

carcinomas

-LRB-

as

opposed

to

papillary

and

chromophobe

carcinomas

-RRB-

-LRB-

Moll

Skinnider

et

al.

-RRB-

and

of

-LRB-

non-cervical

-RRB-

squamous

cell

carcinomas

The

validity

in

predicting

the

primary

tumor

in

cases

of

unclear

metastases

is

significantly

increased

when

is

used

in

combination

with

-LRB-

see

below

-RRB-

since

many

carcinomas

exhibit

characteristic

phenotypes

-LRB-

Moll

et

al.

Moll

et

al.

Chu

et

al.

Chu

and

Weiss

Tot

Dabbs

-RRB-

Fig.

in

simple

epithelia

and

adenocarcinomas

-LRB-

paraffin

sections

of

human

tissues

avidin

biotin

complex

peroxidase

staining

-RRB-

Keratin

is

a

characteristic

and

prominent

keratin

of

the

foveolar

epithelium

of

the

gastric

-LRB-

a

-RRB-

and

colorectal

-LRB-

b

-RRB-

mucosa

The

phenotype

of

the

normal

mucosa

is

mostly

maintained

in

primary

and

metastatic

colorectal

adenocarcinomas

This

is

shown

here

for

a

skin

metastasis

-LRB-

on

the

head

-RRB-

of

a

poorly

differentiated

adenocarcinoma

the

tumor

cells

are

negative

for

-LRB-

c

-RRB-

but

positive

for

-LRB-

d

left

portion

of

the

figure

-RRB-

even

including

a

tumor

cell

cluster

that

has

invaded

a

lymphatic

capillary

-LRB-

d

right

upper

corner

-RRB-

This

phenotype

is

strongly

suggestive

of

colorectal

origin

A

primary

tumor

in

the

right

colon

was

detected

later

Liver

metastasis

of

a

ductal

adenocarcinoma

of

the

pancreas

with

typical

keratin

pattern

showing

extended

expression

of

-LRB-

e

-RRB-

and

staining

of

scattered

tumor

cells

for

-LRB-

f

-RRB-

Magnifications

a

d

b

c

e

f

keratin

of

gastrointestinal

epithelium

urothelium

and

Merkel

cells

is

the

simple-epithelial

keratin

with

the

most

restricted

expression

pattern

Although

it

appeared

in

our

early

cytoskeletal

preparations

of

intestinal

epithelial

cells

as

a

quite

prominent

protein

spot

of

kDa

where

we

tentatively

designated

it

as

IT

protein

-LRB-

from

intestinal

Moll

et

al.

-RRB-

we

succeeded

rather

late

in

identifying

it

as

a

type

I

keratin

-LRB-

Moll

et

al.

-RRB-

For

pair

formation

its

type

II

partner

usually

appears

to

be

The

remarkable

expression

spectrum

of

among

normal

tissues

comprises

gastric

foveolar

epithelium

-LRB-

Fig.

-RRB-

and

small

and

large

intestinal

epithelium

-LRB-

Fig.

gastrointestinal-type

keratin

-RRB-

and

in

addition

the

urothelium

and

certain

neuroendocrine

cells

in

particular

Merkel

cells

of

the

skin

In

human

embryogenesis

it

appears

in

the

small

intestinal

epithelium

at

embryonic

week

-LRB-

Moll

et

al.

-RRB-

Within

the

gastrointestinal

and

urothelial

epithelial

tissues

is

absent

from

the

stem

cell

compartment

and

appears

to

be

switched

on

during

terminal

differentiation

and

thus

is

most

prominent

in

small

intestinal

villus-lining

and

large

intestinal

surface-lining

epithelia

-LRB-

Fig.

-RRB-

and

in

urothelial

umbrella

cells

Although

is

a

keratin

typically

expressed

in

simple

epithelia

it

is

also

found

in

the

lone

basally

located

Merkel

cells

of

the

epidermis

and

hair

follicle

outer

root

sheath

-LRB-

Moll

et

al.

-RRB-

Our

knowledge

about

the

function

of

still

is

limited

Mutations

of

human

or

associated

diseases

have

not

yet

been

described

-LRB-

Owens

and

Lane

-RRB-

Transgenic

experiments

suggest

a

role

for

in

maintaining

keratin

filaments

in

intestinal

epithelia

-LRB-

Zhou

et

al.

-RRB-

In

mouse

small

intestinal

epithelium

phosphorylation

on

serine

is

induced

during

apoptosis

and

tissue

injury

and

thus

may

serve

as

stress

marker

-LRB-

Zhou

et

al.

-RRB-

Among

the

monoclonal

antibodies

available

clone

reacts

well

on

routine

paraffin

sections

-LRB-

Moll

et

al.

-RRB-

while

clone

reacts

with

the

homologue

of

rodents

-LRB-

Moll

-RRB-

is

a

potent

immunohistochemical

marker

in

tumor

pathology

since

its

peculiar

expression

spectrum

is

essentially

maintained

in

the

corresponding

primary

and

metastatic

carcinomas

-LRB-

Moll

et

al.

-RRB-

and

the

clone

has

become

part

of

the

routine

antibody

panel

in

most

pathology

laboratories

Most

colorectal

adenocarcinomas

-LRB-

Fig.

-RRB-

the

majority

of

gastric

adenocarcinomas

the

majority

of

transitional

cell

carcinomas

as

well

as

most

Merkel

cell

carcinomas

are

-LRB-

Moll

et

al.

Miettinen

Chu

et

al.

Chu

and

Weiss

Goldstein

and

Bosler

-RRB-

In

a

few

other

carcinoma

types

variable

and

focal

expression

is

seen

notably

in

ductal

adenocarcinomas

of

the

pancreas

-LRB-

Fig.

-RRB-

and

in

adenocarcinomas

of

the

biliary

tract

including

cholangiocarcinomas

of

the

liver

-LRB-

Moll

et

al.

Miettinen

Chu

et

al.

-RRB-

Among

ovarian

carcinomas

is

mainly

detected

in

the

mucinous

type

Most

other

carcinomas

including

adenocarcinomas

irrespective

of

their

morphology

are

essentially

negative

for

Thus

significant

positivity

of

a

metastatic

adenocarcinoma

is

predictive

of

a

primary

tumor

in

the

gastrointestinal

or

pancreaticobiliary

tract

It

should

be

noted

that

the

diagnostic

value

is

increased

when

the

markers

and

are

applied

in

combination

For

example

a

phenotype

of

an

adenocarcinoma

metastasis

-LRB-

Fig.

d

-RRB-

strongly

favors

a

colorectal

origin

Some

colorectal

adenocarcinomas

co-express

in

addition

to

but

as

a

general

rule

the

level

of

immunostaining

exceeds

that

of

-LRB-

see

below

chapter

Keratins

as

diagnostic

markers

in

tumor

pathology

-RRB-

Using

RT-PCR

analyses

mRNA

can

be

detected

in

cell

preparations

from

bone

marrow

and

peripheral

blood

from

some

colorectal

cancer

patients

indicating

the

presence

of

disseminated

tumor

cells

that

maintain

expression

and

a

number

of

clinical

studies

have

shown

that

this

is

correlated

with

a

worse

prognosis

-LRB-

Soeth

et

al.

Funaki

et

al.

Wyld

et

al.

Koch

et

al.

Katsumata

et

al.

Friederichs

et

al.

-RRB-

In

addition

to

patients

with

metastatic

colorectal

carcinoma

expression

in

the

peripheral

blood

was

also

detected

in

patients

with

metastatic

gastric

and

pancreatic

adenocarcinoma

but

hardly

in

patients

with

metastatic

lung

carcinoma

-LRB-

Chausovsky

et

al.

-RRB-

underlining

the

tumor

type-specific

expression

of

this

keratin

Stratified

epithelia

major

keratins

of

basal

keratinocytes

The

type-II

keratin

and

the

type-I

keratin

form

the

primary

keratin

pair

of

the

keratinocytes

of

stratified

squamous

epithelia

including

the

epidermis

as

well

as

mucosal

non-keratinizing

stratified

squamous

epithelia

-LRB-

Moll

et

al.

-RRB-

They

are

strongly

expressed

in

the

undifferentiated

basal

cell

layer

containing

the

stem

cells

and

are

down-regulated

in

the

differentiating

suprabasal

cell

layers

-LRB-

Fig.

Fuchs

and

Green

-RRB-

Otherwise

in

the

widely

well

stratified

follicular

outer

root

sheath

and

are

uniformly

expressed

throughout

all

layers

Moreover

the

follicular

companion

layer

which

is

directly

adjacent

to

the

outer

root

sheath

-LRB-

and

formerly

considered

as

innermost

layer

of

the

outer

root

sheath

-RRB-

is

completely

negative

for

both

of

these

keratins

and

expresses

an

own

special

keratin

-LRB-

see

below

-RRB-

Ultrastructurally

keratin

filaments

are

bundled

as

tonofilaments

and

attached

to

desmosomes

and

hemidesmosomes

The

mouse

promoter

is

frequently

used

in

transgenic

experiments

to

promote

epidermis-specific

expression

of

transgenes

-LRB-

e.g.

Oki-Idouchi

and

Lorenzo

-RRB-

In

addition

to

their

occurrence

in

keratinocytes

and

are

expressed

in

basal

and

myoepithelial

cells

of

complex

and

glandular

epithelial

tissues

-LRB-

Purkis

et

al.

-RRB-

On

the

other

hand

these

keratins

are

absent

from

most

simple/one-layered

epithelia

with

very

few

exceptions

notably

the

mesothelium

lining

serous

cavities

-LRB-

Moll

et

al.

-RRB-

and

the

amnion

epithelium.Fig

in

stratified

squamous

epithelia

and

squamous

cell

carcinomas

-LRB-

paraffin

sections

of

human

tissues

avidin

biotin

complex

peroxidase

staining

-RRB-

In

the

epidermis

as

an

example

of

a

normal

stratified

squamous

epithelium

the

basal

cell

layer

contains

abundant

keratin

-LRB-

a

-RRB-

whereas

the

differentiating

suprabasal

compartment

strongly

stains

for

-LRB-

b

note

the

negative

basal

cell

layer

-RRB-

Lymph

node

metastasis

of

a

squamous

cell

carcinoma

of

the

head

and

neck

region

expressing

-LRB-

c

more

intensely

in

the

peripheral

tumor

cell

layers

-RRB-

as

well

as

-LRB-

d

particularly

strongly

in

central

tumor

cells

-RRB-

as

signs

of

their

keratinocyte

origin

Keratin

is

also

maintained

in

a

lymph

node

micrometastasis

of

a

squamous

cell

carcinoma

of

the

head

and

neck

region

-LRB-

e

-RRB-

and

in

a

lymph

node

metastasis

of

an

undifferentiated

nasopharyngeal

carcinoma

with

dissociated

growth

pattern

of

the

tumor

cells

-LRB-

f

-RRB-

in

these

examples

being

a

diagnostically

helpful

feature

Magnifications

a

b

c

e

f

Several

monoclonal

antibodies

-LRB-

MAbs

-RRB-

specific

for

and

have

been

described

that

helped

to

reveal

their

exact

tissue

distribution

These

antibodies

include

MAb

-LRB-

Moll

et

al.

-RRB-

against

and

MAbs

and

against

-LRB-

Purkis

et

al.

-RRB-

The

best

performance

on

paraffin

sections

is

displayed

by

MAb

-LRB-

Lobeck

et

al.

Demirkesen

et

al.

-RRB-

which

although

being

often

regarded

as

antibody

specifically

recognizes

-LRB-

Böcker

et

al.

-RRB-

The

functional

importance

of

and

for

the

physical

stability

of

the

epidermis

has

become

clearly

evident

by

the

recognition

that

dominant-negative

mutations

of

the

or

the

gene

cause

the

hereditary

blistering

skin

disease

epidermolysis

bullosa

simplex

-LRB-

EBS

-RRB-

-LRB-

for

reviews

see

Omary

et

al.

Lane

and

McLean

-RRB-

Most

of

these

mutations

are

missense

or

small

in-frame

deletion

mutations

primarily

affecting

the

keratin

rod

domain

The

presence

of

mutated

or

results

in

increased

fragility

of

the

basal

keratinocytes

so

that

even

mild

physical

trauma

leads

to

intraepidermal

cytolysis

of

basal

cells

and

the

formation

of

fluid-filled

blisters

These

patient-related

findings

were

preceded

by

the

experimental

demonstration

that

expression

of

mutant

in

transgenic

mice

causes

abnormalities

similar

to

EBS

-LRB-

Vassar

et

al.

-RRB-

The

expression

spectrum

of

and

in

tumors

corresponds

well

to

the

patterns

in

normal

epithelia

Thus

most

squamous

cell

carcinomas

-LRB-

Fig.

e

-RRB-

as

well

as

malignant

mesotheliomas

strongly

express

these

keratins

whereas

little

focal

or

no

expression

is

found

in

adenocarcinomas

-LRB-

Moll

et

al.

Moll

Chu

and

Weiss

b

-RRB-

Hence

these

keratins

in

particular

have

found

several

lines

of

diagnostic

application

in

pathology

which

has

been

aided

by

the

availability

of

a

highly

sensitive

and

specific

robust

paraffin-suited

MAb

-LRB-

see

above

-RRB-

Pertinent

examples

are

the

recognition

and

diagnosis

of

poorly

differentiated

squamous

cell

carcinomas

including

micrometastases

in

lymph

nodes

-LRB-

Fig.

-RRB-

of

undifferentiated

nasopharyngeal

carcinomas

which

may

be

diagnostically

difficult

due

to

their

dissociated

growth

pattern

-LRB-

Fig.

-RRB-

and

of

malignant

mesotheliomas

Thus

immunostaining

allows

the

distinction

of

the

small

cell

type

of

squamous

cell

carcinoma

of

the

lung

which

is

from

a

small

cell

carcinoma

or

a

poorly

differentiated

adenocarcinoma

both

of

which

are

-LRB-

Moll

Chu

and

Weiss

-RRB-

and

the

distinction

of

a

malignant

mesothelioma

of

the

pleura

-LRB-

-RRB-

from

a

pulmonary

adenocarcinoma

with

pleural

involvement

-LRB-

-RRB-

-LRB-

Moll

et

al.

Ordonez

Yaziji

et

al.

-RRB-

In

well

and

moderately

differentiated

squamous

cell

carcinomas

is

preferentially

localized

in

the

peripheral

layers

of

the

tumor

cell

formations

-LRB-

Fig.

-RRB-

corresponding

to

the

expression

in

the

basal

cell

layer

of

normal

stratified

squamous

epithelia

Focal

expression

may

be

observed

in

certain

adenocarcinoma

types

notably

in

adenocarcinomas

of

the

endometrium

the

ovary

and

the

pancreas

which

seems

to

be

related

to

their

potency

for

focal

squamous

differentiation

-LRB-

Moll

Chu

and

Weiss

-RRB-

Much

interest

has

evolved

regarding

the

role

of

in

breast

pathology

in

several

aspects

including

the

identification

of

myoepithelial

cells

the

classification

of

proliferative

lesions

-LRB-

Otterbach

et

al.

-RRB-

and

the

recognition

of

a

certain

subtype

of

invasive

ductal

breast

carcinoma

-LRB-

see

below

chapter

Keratins

as

diagnostic

markers

in

tumor

pathology

-RRB-

In

prostate

pathology

the

diagnosis

of

prostatic

adenocarcinoma

is

supported

by

the

immunohistochemical

demonstration

of

absence

of

basal

cells

-LRB-

Abrahams

et

al.

-RRB-

basal

keratinocyte

keratin

and

hair

follicle

stem

cell

marker

was

first

identified

as

a

minor

keratin

of

human

epidermis

by

gel

electrophoresis

of

cytoskeletal

preparations

-LRB-

Moll

et

al.

c

-RRB-

Its

sequence

demonstrated

its

assignment

to

the

type

I

keratins

-LRB-

Leube

et

al.

-RRB-

Only

later

its

cellular

distribution

was

recognized

and

it

was

uncovered

that

is

a

specific

basal

cell

component

of

the

epidermis

-LRB-

Moll

et

al.

Lloyd

et

al.

-RRB-

and

other

stratified

squamous

epithelia

-LRB-

Waseem

et

al.

-RRB-

-LRB-

see

below

for

its

significance

in

the

hair

follicle

-RRB-

Frequently

and

can

also

be

detected

in

the

lower

suprabasal

cell

layers

-LRB-

see

above

and

Fig.

-RRB-

Whereas

the

mRNA

synthesis

of

these

keratins

is

restricted

to

the

basal

layer

the

and

proteins

remain

integrated

in

the

complex

keratin

cytoskeleton

for

some

time

when

cells

leave

the

basal

compartment

Thus

they

may

be

stained

by

immunohistochemistry

in

more

or

less

suprabasal

layers

depending

on

the

epitope

of

the

antibody

used

In

comparison

seems

completely

restricted

to

the

basal

cell

layer

of

stratified

squamous

epithelia

-LRB-

Lloyd

et

al.

Waseem

et

al.

-RRB-

where

it

can

form

heteropolymeric

filaments

with

-LRB-

Lloyd

et

al.

-RRB-

MAbs

recognizing

include

clone

-LRB-

Waseem

et

al.

-RRB-

and

clone

-LRB-

Lyle

et

al.

-RRB-

The

latter

in

fact

is

a

surprising

and

exciting

MAb

originally

made

against

the

lymphocyte

antigen

which

cross-reacts

with

especially

in

the

basal

keratinocytes

of

the

hair

follicle

bulge

region

where

the

respective

stem

cells

are

assumed

Also

polyclonal

antibodies

have

furthermore

been

described

-LRB-

Moll

et

al.

Kurzen

et

al.

Langbein

et

al.

-RRB-

expression

in

basal

cells

is

downregulated

in

activated

epidermal

keratinocytes

such

as

in

organotypic

cultures

and

in

hyperproliferation

-LRB-

Waseem

et

al.

-RRB-

or

upon

wounding

-LRB-

Porter

et

al.

-RRB-

Human

mutations

or

knock-out

mice

for

have

not

yet

been

described

As

to

the

occurrence

of

in

tumors

the

literature

is

inconclusive

as

to

whether

there

is

differential

expression

of

among

cutaneous

tumors

-LRB-

benign

follicular

tumors

versus

basal

cell

carcinomas

-RRB-

possibly

due

to

the

use

of

different

-LRB-

see

also

above

-RRB-

and

thus

a

putative

diagnostic

application

of

immunohistochemistry

in

dermatopathology

is

still

open

-LRB-

Kanitakis

et

al.

Jih

et

al.

Porter

et

al.

Kurzen

et

al.

-RRB-

Currently

the

most

interesting

feature

with

is

the

discovery

that

within

the

hair

follicle

at

least

one

antibody

against

this

keratin

detects

putative

stem

cells

residing

in

the

hair

follicle

bulge

and

thus

might

be

used

as

a

stem

cell

marker

in

hair

follicle

biology

-LRB-

Lyle

et

al.

-RRB-

keratins

of

hyperproliferative

keratinocytes

inducible

in

activated

epidermis

By

gel

electrophoresis

the

type-II

keratin

and

the

type-I

keratin

have

been

identified

in

epidermis

only

in

samples

from

plantar

glabrous

skin

while

in

hairy

skin

these

keratins

appeared

to

be

absent

in

interfollicular

epidermis

but

were

clearly

present

in

hair

follicle

outer

root

sheath

-LRB-

Moll

et

al.

c

Langbein

and

Schweizer

-RRB-

and

companion

layer

-LRB-

Winter

et

al.

Langbein

and

Schweizer

Gu

and

Coulombe

-RRB-

In

nail

epithelia

and

are

constitutive

components

-LRB-

Heid

et

al.

Lane

and

McLean

Perrin

et

al.

-RRB-

and

are

also

consistently

expressed

in

non-keratinizing

stratified

squamous

epithelia

-LRB-

Moll

et

al.

-RRB-

They

are

often

but

not

always

co-expressed

as

a

keratin

pair

-LRB-

Moll

et

al.

Langbein

et

al.

-RRB-

Molecular

genetic

studies

have

revealed

that

in

humans

three

isoforms

of

exist

and

encoded

by

distinct

genes

-LRB-

Rogers

et

al.

Schweizer

et

al.

-RRB-

MAb

is

an

antibody

which

most

probably

stains

at

least

keratin

isoform

and

reacts

well

with

paraffin

sections

-LRB-

Demirkesen

et

al.

Langbein

et

al.

Schmelz

et

al.

-RRB-

although

isoform-specific

antibodies

against

or

will

hardly

be

made

because

of

their

extremely

high

peptide

sequence

homology

Using

this

MAb

plantar

epidermis

shows

extended

albeit

heterogeneous

expression

of

while

interfollicular

epidermis

is

negative

or

exhibits

only

some

positive

suprabasal

cell

groups

-LRB-

Demirkesen

et

al.

Swensson

et

al.

-RRB-

Non-keratinizing

stratified

squamous

epithelia

express

uniformly

in

all

suprabasal

cell

layers

A

MAb

against

has

also

been

described

-LRB-

Leigh

et

al.

-RRB-

In

early

immunohistochemical

studies

using

keratin

group-specific

MAbs

Weiss

et

al.

-LRB-

-RRB-

demonstrated

the

induction

of

-LRB-

keratin

-RRB-

and

-LRB-

keratin

-RRB-

in

various

hyperproliferative

epidermal

disorders

suggesting

that

these

keratins

may

be

molecular

markers

for

hyperproliferative

keratinocytes

More

recent

experimental

studies

showed

that

after

skin

wounding

and

are

rapidly

induced

within

h

in

human

keratinocytes

at

the

wound

edge

before

migration

and

regeneration

begins

-LRB-

Paladini

et

al.

-RRB-

The

particular

cell

biological

properties

of

these

keratins

may

confer

to

activated

keratinocytes

on

the

one

hand

a

moderate

level

of

mechanical

scaffolding

and

on

the

other

hand

sufficient

plasticity

required

during

migration

and

re-epithelialization

-LRB-

Wawersik

et

al.

-RRB-

knockout

mice

showed

delayed

re-epithelialization

after

skin

wounding

-LRB-

Wojcik

et

al.

-RRB-

Upon

double

knock-out

mice

exhibit

epithelial

disintegration

and

white

plaques

in

the

dorsal

tongue

epithelium

-LRB-

Wong

et

al.

Wojcik

et

al.

-RRB-

The

absence

of

a

hair

and

nail

phenotype

in

these

mice

as

might

be

expected

from

the

occurrence

of

in

these

appendages

has

been

shown

to

be

due

to

the

presence

and

compensatory

function

of

other

keratins

in

hair

follicles

and

nails

such

as

-LRB-

Wojcik

et

al.

now

-RRB-

or

-LRB-

now

cf.

Langbein

et

al.

-RRB-

In

man

mutations

in

or

have

been

proven

to

give

rise

to

the

hereditary

disorder

pachyonychia

congenita

type

-LRB-

Jadassohn

Lewandowsky

form

-RRB-

that

manifests

with

thickened

nails

palmoplantar

hyperkeratosis

and

oral

leukoplakias

-LRB-

McLean

et

al.

for

further

references

see

Lane

and

McLean

-RRB-

Notably

the

pathologic

changes

affect

those

tissues

that

constitutively

express

and

-LRB-

see

above

-RRB-

but

not

the

interfollicular

epidermis

Thus

are

constitutive

keratins

of

stratified

epithelia

built

up

by

keratinocytes

of

relatively

high

proliferative

state

such

as

mucosal

tissues

palmoplantar

epidermis

and

certain

skin

appendages

On

the

other

hand

they

are

stress-inducible

keratins

in

interfollicular

epidermis

being

rapidly

switched

on

e.g.

after

injury

and

UV-irradiation

or

being

present

also

in

inflammation

and

in

hyperproliferative

disorders

Expression

of

these

keratins

is

not

restricted

to

stratified

squamous

epithelia

but

may

also

be

observed

in

certain

glandular

structures

Thus

-LRB-

most

probably

-RRB-

and

are

expressed

in

ductal

luminal

cells

as

well

as

in

some

secretory

cells

of

human

eccrine

sweat

glands

-LRB-

Fig.

Demirkesen

et

al.

Langbein

et

al.

-RRB-

has

been

detected

in

subpopulations

of

luminal

cells

of

the

mouse

mammary

gland

-LRB-

Grimm

et

al.

-RRB-

and

the

human

mammary

gland

in

the

latter

also

in

ductal

myoepithelial

cells

-LRB-

Hesse

Langbein

et

al.

-RRB-

Recently

a

population

of

cells

in

the

prostate

gland

with

high

potential

for

proliferation

and

differentiation

has

been

described

-LRB-

Schmelz

et

al.

-RRB-

Fig.

in

eccrine

sweat

glands

and

adnexal

tumors

mRNA

and

protein

by

in

situ

hybridization

-LRB-

ISH

a

a

-RRB-

and

indirect

immunofluorescence

-LRB-

IIF

b-b

-RRB-

microscopy

This

keratin

is

specifically

expressed

in

the

luminal

cells

-LRB-

lc

-RRB-

of

the

intraglandular

-LRB-

igd

-RRB-

the

intradermal

-LRB-

idd

-RRB-

the

sweat

duct

ridge

-LRB-

sdr

-RRB-

and

the

intraepidermal/acrosyringial

-LRB-

ied/ac

-RRB-

duct

of

eccrine

sweat

glands

of

plantar

skin

Peripheral

duct

cells

are

negative

The

secretory

portions

-LRB-

asterisks

-RRB-

are

sb

str

basale

ss

str

spinosum

sg

str

granulosum

sc

str

corneum

gl

glandular

region

with

secretory

and

intraglandular

duct

portions

c

Expression

scheme

of

keratins

of

the

eccrine

sweat

gland

d-d

Immunoperoxidase

staining

of

in

the

luminal

cells

of

the

eccrine

sweat

gland

duct

of

the

foot

sole

epidermis

is

also

expressed

in

the

tubular

structures

-LRB-

arrows

-RRB-

of

eccrine

tumors

such

as

syringoma

-LRB-

e

-RRB-

and

cylindroma

-LRB-

f

-RRB-

Bars

μm

In

the

pseudostratified

epithelia

of

respiratory

mucosal

tissues

and

are

highly

upregulated

in

squamous

metaplasia

-LRB-

Leube

and

Rustad

Stosiek

et

al.

-RRB-

Among

tumors

and

are

typically

and

strongly

expressed

in

squamous

cell

carcinomas

of

different

sites

-LRB-

Moll

et

al.

Moll

-RRB-

preferentially

in

inner

maturing

layers

of

the

tumor

cell

nests

-LRB-

Fig.

-RRB-

Although

low

expression

of

these

keratins

may

be

found

in

adenocarcinomas

such

as

occasionally

in

adenocarcinomas

of

the

uterine

cervix

-LRB-

Smedts

et

al.

-RRB-

and

in

less

than

of

invasive

breast

carcinomas

-LRB-

Wetzels

et

al.

-RRB-

as

detected

by

MAb

may

be

suitable

in

addition

to

as

another

immunohistochemical

marker

of

squamous

differentiation

in

poorly

differentiated

squamous

cell

carcinomas

-LRB-

Moll

-RRB-

keratin

of

basal/myoepithelial

cells

and

inducible

in

activated

keratinocytes

The

type

I

keratin

was

identified

in

our

early

gel

electrophoretic

studies

as

a

major

keratin

of

basal

cell

carcinomas

of

the

skin

which

was

also

present

in

the

normal

pilosebaceous

tract

but

not

in

normal

epidermis

-LRB-

Moll

et

al.

-RRB-

Further

protein

analyses

showed

its

presence

in

squamous

cell

carcinomas

of

various

origins

as

well

as

in

normal

glandular

tissues

-LRB-

such

as

sweat

glands

and

breast

-RRB-

but

its

apparent

absence

also

from

non-keratinizing

stratified

squamous

epithelia

-LRB-

Moll

et

al.

-RRB-

The

unique

cell

type

distribution

of

this

keratin

became

apparent

after

establishment

of

a

specific

MAb

clone

-LRB-

Troyanovsky

et

al.

-RRB-

Broad

tissue

screening

revealed

its

selective

expression

in

basal

and

myoepithelial

cells

of

complex

tissues

including

various

glands

respiratory

epithelium

and

urothelium

-LRB-

Troyanovsky

et

al.

-RRB-

Thus

may

be

regarded

as

a

basal

myoepithelial

cell

keratin

In

the

hair

follicle

confirming

and

extending

previous

biochemical

findings

-LRB-

Moll

et

al.

-RRB-

has

been

localized

as

a

prominent

component

of

the

suprabasal

cell

layers

of

the

outer

follicular

root

sheath

-LRB-

Winter

et

al.

Langbein

and

Schweizer

Langbein

et

al.

Tong

and

Coulombe

-RRB-

It

is

also

present

in

nail

bed

and

nail

matrix

epithelia

-LRB-

McGowan

and

Coulombe

Perrin

et

al.

-RRB-

Immunohistochemistry

also

confirmed

the

essential

absence

of

from

adult

interfollicular

epidermis

but

interestingly

revealed

its

specific

expression

in

the

specialized

epidermal

keratinocytes

of

the

sensory

Merkel

cell-associated

haarscheiben

organs

-LRB-

Moll

et

al.

-RRB-

this

keratin

thus

may

be

applied

as

a

sensitive

haarscheiben

marker

in

studies

of

cutaneous

neurobiology

In

contrast

to

the

adult

is

a

prominent

component

of

fetal

epidermis

-LRB-

Moll

et

al.

-RRB-

as

well

as

of

cultured

epidermal

cells

-LRB-

Weiss

et

al.

-RRB-

Another

interesting

feature

of

is

its

inducibility

after

skin

injury

after

-LRB-

see

above

-RRB-

is

switched

on

in

regenerating

and

migrating

epidermal

keratinocytes

upon

wound

healing

-LRB-

Paladini

et

al.

-RRB-

Its

functional

importance

in

wound

healing

is

suggested

by

the

observation

that

knockout

mouse

embryos

show

a

delay

in

the

closure

of

surface

ectoderm

wounds

-LRB-

Mazzalupo

et

al.

-RRB-

Recent

transgenic

experiments

have

shown

that

can

bind

to

the

adaptor

protein

and

influences

cell

growth

and

size

of

mouse

keratinocytes

by

regulating

protein

synthesis

-LRB-

Kim

et

al.

-RRB-

The

aforementioned

expression

of

in

the

pilosebaceous

tract

-LRB-

in

the

follicular

outer

root

sheath

companion

layer

medulla

and

sebaceous

gland

for

review

see

Langbein

and

Schweizer

-RRB-

has

also

proven

to

be

functionally

relevant

mice

develop

transient

severe

alopecia

in

early

postnatal

life

correlating

with

hair

fragility

and

apoptosis

in

hair

matrix

cells

-LRB-

McGowan

et

al.

-RRB-

The

same

group

later

showed

that

modulates

hair

follicle

cycling

by

delaying

apoptosis

whereby

is

functionally

linked

with

TNFα

signaling

-LRB-

Tong

and

Coulombe

-RRB-

Hereditary

human

diseases

due

to

mutations

have

been

identified

-LRB-

for

references

see

Lane

and

McLean

-RRB-

most

notably

pachyonychia

congenita

type

-LRB-

Jackson

Lawler

form

-RRB-

The

phenotype

of

this

genodermatosis

includes

thickened

nails

and

pilosebaceous

cysts

Another

condition

related

to

mutations

is

steatocystoma

multiplex

in

which

patients

present

with

multiple

hair

follicle-associated

cysts

These

genodermatoses

obviously

are

related

to

the

expression

and

functional

importance

of

in

pilosebaceous

and

nail

-LRB-

Perrin

et

al.

Langbein

and

Schweizer

-RRB-

epithelia

Since

in

keratinocytes

is

like

and

-LRB-

see

above

-RRB-

an

inducible

keratin

upon

stress

injury

or

inflammation

it

is

not

surprising

that

squamous

cell

carcinomas

consistently

express

these

three

keratins

-LRB-

Moll

et

al.

Chu

and

Weiss

-RRB-

As

most

normal

stratified

squamous

epithelia

lack

its

presence

in

the

corresponding

tumors

may

be

regarded

as

neo-expression

during

tumorigenesis

In

the

uterine

cervix

is

expressed

in

cervical

intraepithelial

neoplasia

but

since

it

is

already

present

in

endocervical

reserve

cells

-LRB-

Weikel

et

al.

-RRB-

and

immature

squamous

metaplasia

it

has

not

yet

become

a

routine

diagnostic

marker

-LRB-

Martens

et

al.

-RRB-

Among

adenocarcinomas

focal

expression

seems

to

be

particularly

characteristic

of

pancreatic

ductal

adenocarcinomas

-LRB-

Real

et

al.

Moll

-RRB-

which

may

become

useful

for

their

distinction

from

other

adenocarcinomas

-LRB-

Chu

and

Weiss

-RRB-

In

ductal

breast

carcinomas

is

expressed

in

a

minor

subset

of

tumor

cases

-LRB-

Malzahn

et

al.

-RRB-

now

recognized

to

correspond

to

the

basal-like

subtype

as

defined

by

global

gene

expression

data

-LRB-

see

below

chapter

Keratins

as

diagnostic

markers

in

tumor

pathology

-RRB-

major

keratins

of

keratinocyte

differentiation

and

keratinization

In

the

epidermis

the

transition

of

keratinocytes

from

the

proliferative

basal

cell

layer

to

the

postmitotic

suprabasal

spinous

cell

layers

in

the

process

of

terminal

differentiation

and

keratinization

is

characterized

by

a

profound

change

in

keratin

expression

This

involves

a

switch

from

expression

of

the

basal

cell

keratins

-LRB-

-RRB-

to

the

suprabasal

epidermal

keratins

the

type

II

keratin

and

subsequently

the

type

I

keratin

-LRB-

Fig.

Fuchs

and

Green

Moll

et

al.

Tseng

et

al.

Weiss

et

al.

Roop

Stoler

et

al.

-RRB-

This

is

one

of

the

classical

examples

for

the

carefully

regulated

differentiation-specific

expression

of

keratin

proteins

Ultrastructurally

keratin

filaments

composed

of

the

pair

form

particularly

dense

bundles

which

are

so

characteristic

of

suprabasal

epidermal

keratinocytes

-LRB-

Fig.

-RRB-

Clearly

this

imparts

mechanical

integrity

to

the

cells

and

the

whole

epidermis

In

addition

however

there

seem

to

exist

further

functional

roles

as

experimental

data

have

demonstrated

that

specifically

inhibits

proliferation

and

cell

cycle

progression

of

keratinocytes

-LRB-

Paramio

et

al.

Koch

and

Roop

-RRB-

and

loss

of

leads

to

increased

keratinocyte

turnover

-LRB-

Reichelt

et

al.

for

review

see

Magin

et

al.

-RRB-

The

importance

for

epidermal

integrity

is

underscored

by

the

fact

that

point

mutations

in

and

are

associated

with

the

blistering

disorder

epidermolytic

hyperkeratosis/bullous

congenital

ichthyosiform

erythroderma

-LRB-

BCIE

-RRB-

initially

presenting

with

skin

blisters

but

later

with

thickened

ichthyotic

skin

-LRB-

for

reviews

see

Lane

and

McLean

Omary

et

al.

-RRB-

As

expected

the

suprabasal

cells

become

fragmented

easily

and

in

addition

the

epidermis

becomes

hyperproliferative

and

hyperkeratotic

mutations

are

notably

heterogeneous

and

may

result

in

diverse

overlapping

often

relatively

mild

phenotypes

-LRB-

Lane

and

McLean

-RRB-

In

transgenic

mouse

experiments

mutation

or

knock-out

of

results

in

a

phenotype

similar

to

human

epidermolytic

hyperkeratosis

-LRB-

Fuchs

et

al.

Porter

et

al.

-RRB-

Despite

their

association

with

terminal

epidermal

differentiation

and

keratinization

and

may

be

focally

expressed

in

suprabasal

cells

of

internal

noncornifying

stratified

squamous

epithelia

-LRB-

for

references

see

Moll

-RRB-

They

are

also

a

typical

component

of

cells

of

eccrine

sweat

gland

ducts

-LRB-

Fig.

Langbein

et

al.

-RRB-

Surprisingly

although

the

differentiated

parts

of

the

hair

follicle

such

as

suprabasal

outer

root

sheath

upper

companion

layer

upper

inner

root

sheath

or

the

hair

fiber

are

heavily

keratinized

structures

all

of

them

are

free

of

Both

typical

epidermal

keratins

are

completely

lost

in

the

infundibulum

Among

various

antibodies

against

and

described

in

the

literature

MAb

against

is

particularly

suitable

for

application

with

paraffin-embedded

tissues

-LRB-

Ivanyi

et

al.

-RRB-

In

squamous

cell

carcinomas

focal

expression

of

and

usually

in

relation

to

maturation

and

keratinization

can

be

observed

regardless

of

whether

they

are

derived

from

the

skin

or

from

internal

organs

-LRB-

for

references

see

Moll

-RRB-

They

are

more

sparse

in

poorly

differentiated

tumors

but

may

still

be

detected

in

about

of

cases

of

oral

and

pharyngeal

squamous

cell

carcinomas

-LRB-

Moll

-RRB-

However

quantitatively

squamous

cell

carcinomas

rather

embark

on

an

alternative

maturation

pathway

characterized

by

abundant

expression

of

and

-LRB-

see

above

Fig.

-RRB-

Overall

and

can

be

regarded

as

keratinization

markers

of

keratinocytes

These

keratins

have

not

yet

been

routinely

applied

to

tumor

diagnosis

except

for

some

special

aspects

of

skin

tumors

-LRB-

Yuspa

et

al.

-RRB-

palmoplantar

epidermal

differentiation

keratin

The

type

I

keratin

is

a

highly

specific

keratin

of

terminally

differentiating

keratinocytes

of

palmoplantar

epidermis

where

it

is

abundantly

albeit

heterogeneously

expressed

-LRB-

Moll

et

al.

Langbein

et

al.

-RRB-

At

other

body

sites

there

may

be

extremely

sparse

and

focal

expression

in

upper

epidermal

layers

-LRB-

Moll

et

al.

-RRB-

Thus

forming

a

pair

with

appears

to

reflect

a

special

program

of

keratinocyte

differentiation

associated

with

particular

mechanical

reinforcement

-LRB-

Swensson

et

al.

-RRB-

Therefore

it

is

not

surprising

that

mutations

in

the

gene

are

associated

with

a

disorder

of

the

skin

of

the

palms

and

soles

epidermolytic

palmoplantar

keratoderma

which

manifests

itself

as

cytolysis

and

epidermal

thickening

-LRB-

Reis

et

al.

Torchard

et

al.

for

review

see

Lane

and

McLean

-RRB-

In

its

sequence

is

most

closely

related

to

-LRB-

Langbein

et

al.

-RRB-

MAbs

against

-LRB-

clones

PROGEN

Heidelberg

Germany

-RRB-

are

available

-LRB-

Langbein

et

al.

-RRB-

Immunostaining

for

has

significance

for

characterization

of

palmoplantar

keratinocyte

direction

of

transplants

-LRB-

Compton

et

al.

Stoner

and

Wood

-RRB-

and

of

special

genodermatoses

-LRB-

McLean

and

Irvine

-RRB-

but

there

is

no

relevance

of

in

tumor

diagnosis

It

should

be

noted

that

the

occurrence

of

keratin

-LRB-

and

and

-RRB-

may

give

rise

to

problems

in

biochemical

practice

as

biochemicals

or

buffers

are

sometimes

contaminated

with

these

keratins

derived

from

abraded

horny

particles

i.e.

terminally

differentiated

skin

keratinocytes

-LRB-

laboratory

dust

Clark

et

al.

Fox

et

al.

-RRB-

keratin

of

highly

differentiated

advanced

epidermal

keratinocytes

-LRB-

formerly

see

before

and

Table

-RRB-

is

another

keratin

specific

for

the

advanced

terminal

differentiation

process

of

epidermal

keratinocytes

Being

widely

distributed

over

most

body

sites

this

type

II

keratin

is

expressed

late

at

an

advanced

stage

of

differentiation

in

the

uppermost

epidermal

layers

-LRB-

upper

stratum

spinosum

stratum

granulosum

-RRB-

to

a

variable

extent

-LRB-

Collin

et

al.

-RRB-

is

not

expressed

in

follicular

skin

adnexal

structures

like

the

late

compartments

of

outer

or

inner

root

sheath

Correspondingly

mutations

in

have

been

associated

with

ichthyosis

bullosa

of

Siemens

a

blistering

disease

showing

cytolysis

in

superficial

epidermal

layers

-LRB-

for

references

see

Lane

and

McLean

-RRB-

MAbs

specific

for

-LRB-

clones

PROGEN

Heidelberg

Germany

-RRB-

have

been

described

-LRB-

Langbein

et

al.

-RRB-

keratins

of

the

corneal

epithelium

The

-LRB-

type

II

-RRB-

-LRB-

type

I

-RRB-

pair

is

the

cell

type-specific

and

differentiation-related

keratin

pair

of

the

corneal

epithelium

These

keratins

are

expressed

in

all

corneal

epithelial

cell

layers

whereas

in

the

limbus

corneae

only

suprabasal

cells

are

positive

and

the

basally

located

corneal

stem

cells

are

negative

-LRB-

Schermer

et

al.

Pitz

and

Moll

-RRB-

Mutations

in

these

keratins

give

rise

to

Meesmann

's

corneal

dystrophy

characterized

by

intraepithelial

microcysts

in

the

corneal

epithelium

-LRB-

Irvine

et

al.

for

further

references

see

Lane

and

McLean

-RRB-

knock-out

mice

have

a

mechanically

fragile

easily

detachable

corneal

epithelium

-LRB-

Kao

et

al.

-RRB-

Antibodies

against

these

corneal

keratins

described

include

MAb

-LRB-

PROGEN

Heidelberg

Germany

-RRB-

which

reacts

with

and

additionally

with

the

related

-LRB-

formerly

see

below

Collin

et

al.

-RRB-

and

MAb

which

recognizes

-LRB-

Chaloin-Dufau

et

al.

-RRB-

keratins

of

mucosal

stratified

squamous

epithelial

cells

In

internal

stratified

squamous

epithelia

which

mostly

are

non-keratinizing

a

highly

characteristic

keratin

pair

indicates

the

mucosal

path

of

keratinocyte

differentiation

i.e.

the

type

II

keratin

and

the

type

I

keratin

-LRB-

Moll

et

al.

Cooper

et

al.

-RRB-

Immunohistochemical

studies

using

specific

MAbs

such

as

MAb

against

-LRB-

van

Muijen

et

al.

-RRB-

and

MAbs

-LRB-

van

Muijen

et

al.

-RRB-

and

-LRB-

Moll

et

al.

-RRB-

against

revealed

the

presence

of

and

in

the

entire

suprabasal

compartment

of

mucosal

stratified

squamous

epithelia

whereas

the

basal

compartment

is

positive

for

Interestingly

is

completely

absent

in

the

epidermis

and

adnexal

structures

Keratin

is

also

expressed

in

the

urothelium

as

a

major

component

of

the

basal

and

intermediate

cells

whereas

it

is

lost

in

the

superficial

umbrella

cells

-LRB-

that

switch

on

expression

see

above

-RRB-

Keratin

is

also

heterogeneously

expressed

in

columnar

luminal

cells

of

the

pseudostratified

respiratory

epithelium

and

in

the

non-stratified

simple

epithelial

cells

of

e.g.

pancreatic

ducts

-LRB-

van

Muijen

et

al.

Moll

-RRB-

Functionally

and

appear

to

be

important

particularly

as

components

of

mucosal

stratified

squamous

epithelia

Mutations

in

these

keratins

lying

in

the

helix

initiation

or

termination

motifs

-LRB-

HIM

or

HTM

respectively

-RRB-

have

been

shown

to

cause

the

hereditary

disorder

white

sponge

nevus

of

Cannon

-LRB-

for

references

see

Lane

and

McLean

-RRB-

This

mucosal

disorder

presents

with

white

plaques

mainly

on

the

buccal

mucosa

histologically

showing

thickened

spongy

epithelium

with

hydropic

swelling

of

suprabasal

epithelial

cells

Here

again

the

clinical

manifestation

of

pathological

alterations

of

keratins

well

reflects

their

tissue

distribution

It

is

not

surprising

that

squamous

cell

carcinomas

derived

from

the

epidermis

essentially

lack

and

-LRB-

Kuruc

et

al.

for

further

references

see

Moll

-RRB-

However

in

contrast

to

what

might

be

expected

they

are

not

major

components

of

but

are

only

focally

and

variably

expressed

in

squamous

cell

carcinomas

of

the

head

and

neck

with

more

pronounced

expression

in

poorly

differentiated

cases

-LRB-

Moll

-RRB-

Instead

the

predominant

maturation-associated

keratins

expressed

by

these

tumors

are

the

hyperproliferative

keratins

and

-LRB-

see

below

chapter

Keratins

as

diagnostic

markers

in

tumor

pathology

-RRB-

Corresponding

to

its

characteristic

expression

in

normal

urothelium

is

maintained

at

least

focally

in

most

transitional

cell

carcinomas

of

the

urinary

tract

-LRB-

Moll

et

al.

for

further

references

see

Moll

-RRB-

may

be

part

of

a

panel

of

markers

-LRB-

which

also

includes

-RRB-

useful

in

the

histological

diagnosis

of

metastatic

transitional

cell

carcinomas

-LRB-

see

below

chapter

Keratins

as

diagnostic

markers

in

tumor

pathology

-RRB-

As

to

adenocarcinomas

it

is

noteworthy

to

mention

the

frequent

expression

of

in

ductal

adenocarcinomas

of

the

pancreas

-LRB-

Schüssler

et

al.

Real

et

al.

Moll

-RRB-

and

in

a

subpopulation

of

poorly

differentiated

invasive

ductal

breast

carcinomas

-LRB-

Malzahn

et

al.

-RRB-

keratins

with

very

special

expression

sites

-LRB-

previously

designated

-RRB-

is

specifically

expressed

in

suprabasal

cell

layers

of

oral

masticatory

epithelium

i.e.

the

slightly

orthokeratinized

stratified

squamous

epithelium

lining

the

gingiva

and

the

hard

palate

-LRB-

Collin

et

al.

-RRB-

Because

of

the

failure

of

specific

antibodies

for

long

time

which

are

now

available

-LRB-

PROGEN

Heidelberg

made

by

L.L.

-RRB-

no

tumor

studies

have

been

done

yet

The

expression

pattern

of

keratin

-LRB-

previously

designated

-RRB-

was

very

surprising

and

extremely

restricted

This

keratin

is

exclusively

expressed

in

and

restricted

to

the

luminal

cells

of

eccrine

sweat

gland

ducts

-LRB-

Fig.

d

-RRB-

All

other

epithelia

and

glands

tested

so

far

including

apocrine

sweat

gland

were

negative

-LRB-

Langbein

et

al.

-RRB-

Based

on

the

extensive

investigation

of

the

keratin

pattern

new

aspects

of

eccrine

sweat

gland

differentiation

could

be

achieved

-LRB-

Langbein

et

al.

and

supplemental

data

therein

-RRB-

The

high

specificity

of

expression

makes

this

keratin

recommendable

for

using

as

an

eccrine

duct

marker

in

tumor

diagnostics

In

a

first

study

this

assumption

could

be

confirmed

by

the

investigation

of

eccrine

adnexal

tumors

such

as

syringoma

-LRB-

Fig.

-RRB-

poroma

-LRB-

Langbein

et

al.

-RRB-

and

cylindroma

-LRB-

Fig.

-RRB-

hair

follicle-specific

epithelial

keratins

Only

recently

it

has

become

clear

that

some

of

the

epithelial

root

sheaths

of

the

hair

follicle

the

inner

root

sheath

and

the

companion

layer

are

unique

by

their

expression

of

a

number

of

very

special

keratins

-LRB-

for

review

see

Langbein

and

Schweizer

Langbein

et

al.

Schweizer

et

al.

-RRB-

Over

the

years

these

keratins

were

not

detected

before

by

biochemical

methods

because

of

their

quantitative

under-representation

when

compared

to

the

masses

of

hair

or

epidermal

keratins

in

the

tissue

The

first

of

these

new

special

keratins

described

was

This

keratin

was

originally

called

with

hf

indicating

its

expression

site

in

the

hair

follicle

not

knowing

that

this

aspect

of

designation

would

be

unfeasible

later

-LRB-

-RRB-

is

a

type

II

keratin

and

was

although

closely

related

in

its

peptide

sequence

to

following

the

principles

of

the

former

keratin

designation

-LRB-

cf.

Collin

et

al.

b

-RRB-

by

using

the

electrophoretic

properties

designated

as

a

keratin

-LRB-

Winter

et

al.

-RRB-

is

specifically

expressed

in

the

companion

layer

of

the

hair

follicle

-LRB-

Fig.

h

i

-RRB-

a

thin

layer

between

the

outer

and

the

inner

epithelial

root

sheath

-LRB-

Winter

et

al.

-RRB-

As

the

expression

of

this

keratin

as

monitored

by

its

mRNA

synthesis

using

in

situ

hybridization

starts

from

the

bulbar

matricial

compartment

of

the

hair

follicle

and

the

protein

is

still

existent

in

the

upper

differentiated

part

where

the

mRNA

is

no

longer

synthesized

it

was

one

first

but

doubtless

indication

that

this

structure

is

an

own

individual

compartment

of

the

hair

follicle

and

not

the

innermost

layer

of

the

outer

root

sheath

-LRB-

see

Winter

et

al.

Langbein

and

Schweizer

-RRB-

The

only

further

structures

in

which

has

been

detected

are

the

hair

medulla

of

e.g.

beard

hairs

the

nail

bed

and

fungiform

papillae

of

the

tongue

-LRB-

Wang

et

al.

Perrin

Langbein

and

Schweizer

-RRB-

A

mutation

in

appears

to

predispose

to

the

common

hair

disorder

pseudofolliculitis

barbae

which

is

characterized

by

ingrown

beard

hairs

with

inflammation

induced

by

shaving

-LRB-

Winter

et

al.

Schweizer

et

al.

-RRB-

and

to

the

loose

anagen

hair

syndrome

-LRB-

Chapalain

et

al.

-RRB-

Immunostaining

for

has

been

reported

in

trichoblastomas

and

basal

cell

carcinomas

-LRB-

Kurzen

et

al.

-RRB-

and

has

recently

been

observed

in

some

squamoid

cells

of

pilomatricomas

-LRB-

M.

Divo

L.

Langbein

and

R.

Moll

in

preparation

-RRB-

indicating

special

focal

differentiation

in

these

diverse

cutaneous

tumors

We

have

recently

found

sparse

and

focal

expression

of

in

certain

squamous

cell

carcinomas

of

inner

organs

-LRB-

M.

Divo

L.

Langbein

and

R.

Moll

in

preparation

-RRB-

Fig.

labeling

of

hair

follicle-specific

and

hair

keratins

The

hair

follicle-specific

epithelial

keratin

-LRB-

a

-RRB-

is

specifically

found

in

the

hair

companion

layer

-LRB-

cl

-RRB-

and

in

the

medulla

-LRB-

med

-RRB-

of

sexual

-LRB-

e.g.

beard

-RRB-

hairs

-LRB-

b

-RRB-

is

expressed

in

all

compartments

and

-LRB-

c

-RRB-

in

the

cuticle

-LRB-

icu

-RRB-

of

the

hair

inner

root

sheath

-LRB-

IRS

-RRB-

The

hair

keratin

-LRB-

d

-RRB-

expression

is

found

from

the

hair

matrix

to

the

upper

cortex

and

the

hair

cuticle

-LRB-

cu

-RRB-

whereas

-LRB-

e

-RRB-

is

restricted

to

the

hair

cuticle

-LRB-

f

-RRB-

is

an

example

for

hair

keratins

expressed

in

the

mid-to-upper

hair

cortex

-LRB-

co

-RRB-

g

Hair

keratin

is

also

expressed

in

the

upper

transitional

cells

of

pilomatricoma

co

cortex

dp

dermal

papilla

ORS

outer

root

sheath

h

i

Summary

schemes

of

the

expression

of

all

hair

and

hair

follicle-specific

keratins

in

the

human

hair

follicle

is

found

in

the

cortex

of

vellus

hairs

and

medulla

of

sexual

hairs

is

heterogeneously

expressed

in

the

cortex

The

keratin

genes

are

designated

according

to

the

new

keratin

nomenclature

-LRB-

Schweizer

et

al.

-RRB-

A

set

of

four

type

I

keratins

-LRB-

previous

designations

see

Table

-RRB-

and

four

type

II

keratins

-LRB-

previous

designations

see

Table

-RRB-

is

highly

specific

for

the

inner

root

sheath

-LRB-

IRS

-RRB-

of

the

hair

follicle

-LRB-

Fig.

i

-RRB-

These

IRS

keratins

are

differentially

and

partially

sequentially

expressed

in

the

various

IRS

compartments

the

Henle

layer

the

Huxley

layer

and

the

IRS

cuticle

The

keratinocytes

of

all

three

compartments

synthesize

the

IRS

keratins

-LRB-

Fig.

h

i

-RRB-

and

is

restricted

to

the

Huxley

layer

whereas

-LRB-

Fig.

h

i

-RRB-

and

are

sequentially

expressed

in

the

IRS

cuticle

-LRB-

Langbein

et

al.

Langbein

and

Schweizer

Fig.

i

-RRB-

Otherwise

no

classical

epithelial

keratins

were

evidenced

without

any

doubts

in

the

IRS

and

earlier

reports

most

probably

showed

-LRB-

at

that

time

not

expected

-RRB-

cross-reaction

of

antibodies

with

at

least

one

of

these

IRS

keratins

-LRB-

cf.

Langbein

et

al.

-RRB-

Some

of

the

IRS

keratins

together

with

many

others

have

also

been

found

in

the

hair

medulla

-LRB-

see

Schweizer

et

al.

and

Langbein

et

al.

in

preparation

-RRB-

In

mice

spontaneous

hair

disorders

due

to

mutations

in

have

been

identified

-LRB-

for

references

see

Schweizer

et

al.

-RRB-

Human

hair

disorders

related

to

the

IRS

keratins

have

not

yet

been

discovered

Monospecific

antisera

against

all

of

these

keratins

are

available

-LRB-

PROGEN

Heidelberg

Germany

Langbein

et

al.

-RRB-

keratins

of

the

hair

fiber

-LRB-

hair

keratins

-RRB-

It

is

long

known

since

the

early

period

of

keratin

research

that

in

the

-LRB-

hard

-RRB-

material

of

hairs

wool

nails

claws

and

feathers

the

tremendous

masses

of

keratin

filaments

-LRB-

selection

of

the

early

literature

Odland

Fraser

et

al.

Rogers

and

Clarke

Orfanos

and

Ruska

-RRB-

are

embedded

in

a

matrix

of

cross-linking

specialized

keratin

associated

proteins

-LRB-

KAPs

-RRB-

with

more

than

genes

in

humans

-LRB-

for

review

see

Rogers

et

al.

-RRB-

The

special

more

sulfur-rich

keratin

proteins

constituting

these

filaments

are

the

hard

or

trichocytic

keratins

Originally

eight

major

-LRB-

type

I

type

II

-RRB-

and

two

minor

-LRB-

Hax

Hbx

-RRB-

keratins

were

distinguished

-LRB-

Heid

et

al.

b

-RRB-

In

the

last

years

many

more

namely

members

of

this

keratin

subfamily

have

been

identified

first

at

their

gene

level

-LRB-

Rogers

et

al.

and

references

therein

-RRB-

which

are

now

generally

referred

to

as

the

hair

keratins

-LRB-

Langbein

et

al.

Langbein

and

Schweizer

Schweizer

et

al.

see

also

Table

-RRB-

The

conspicuous

abundance

of

these

proteins

comprises

eleven

type

I

hair

keratins

-LRB-

previous

designations

Langbein

et

al.

Langbein

and

Schweizer

Schweizer

et

al.

see

also

Table

-RRB-

and

six

type

II

hair

keratins

-LRB-

previous

designations

Langbein

et

al.

Schweizer

et

al.

see

also

Table

Fig.

i

-RRB-

In

the

hair

they

exhibit

differential

complex

and

in

many

cases

sequential

expression

patterns

within

the

cuticle

and

the

cortex

-LRB-

Langbein

et

al.

Langbein

and

Schweizer

Schweizer

et

al.

for

medulla

Langbein

et

al.

in

preparation

-RRB-

and

-LRB-

Fig.

h

i

-RRB-

are

already

expressed

in

the

hair-forming

matrix

of

the

cortex

and

the

hair

cuticle

The

other

hair

keratins

-LSB-

type

I

-LRB-

focally

-RRB-

and

-LRB-

including

hair

cuticle

-RRB-

type

II

and

-RSB-

are

sequentially

switched

on

upon

differentiation

in

the

lower

hair

cortex

and

in

particular

the

large

bulk

of

hair

keratins

are

expressed

in

the

middle

cortex

-LRB-

keratinizing

zone

-RRB-

of

the

ascending

hair

fiber

-LRB-

Fig.

h

i

-RRB-

Furthermore

-LRB-

Fig.

h

i

-RRB-

and

are

sequentially

expressed

and

restricted

in

the

hair

cuticle

-LRB-

Langbein

and

Schweizer

Langbein

et

al.

-RRB-

As

exceptions

was

only

found

in

the

cortex

of

vellus

hairs

and

although

a

typical

hair

keratin

was

not

detected

in

the

hairs

but

specifically

in

the

filiform

papillae

of

the

tongue

-LRB-

Langbein

and

Schweizer

-RRB-

One

has

to

keep

in

mind

that

out

of

the

human

keratins

at

least

-LRB-

-RRB-

are

expressed

in

the

hair

follicle

Therefore

it

is

most

amazing

that

this

extraordinary

complex

structure

built

up

by

a

stratified

outer

root

sheath

the

companion

layer

the

inner

root

sheath

comprising

Henle

Huxley

and

IRS-cuticle

layers

the

hair

cuticle

cortex

and

sometimes

a

medulla

differentiate

from

cells

of

an

undifferentiated

and

pluripotent

germinative

cell

pool

-LRB-

Fig.

h

i

-RRB-

There

must

exist

an

incredible

fine-tuning

in

the

regulation

of

gene

expression

when

e.g.

one

cell

differentiates

into

the

IRS-cuticle

and

the

directly

neighboring

cell

builds

up

the

hair

cuticle

both

structures

being

only

one

cell

wide

Unfortunately

up

to

now

our

knowledge

on

this

most

complex

regulation

of

hair

keratin

gene

expression

is

rather

fragmentary

Hair

keratins

are

also

prominently

expressed

in

the

nail

matrix

and

nail

bed

and

contribute

to

the

formation

of

the

hard

tissue

of

the

nail

plate

-LRB-

Perrin

et

al.

Perrin

-RRB-

Moreover

in

the

hair

keratins

have

been

additionally

detected

by

immunohistochemistry

in

filiform

papillae

of

the

tongue

and

intriguingly

in

reticulum

cells

and

Hassall

's

corpuscles

of

the

thymus

-LRB-

Heid

et

al.

-RRB-

Some

human

mutations

affecting

hair

keratin

genes

have

been

recognized

The

most

well-known

of

these

is

the

congenital

hair

disease

monilethrix

characterized

by

deformed

hair

shafts

with

a

beaded

appearance

Causative

mutations

for

this

disorder

have

been

identified

in

the

hair

keratins

and

rarely

in

-LRB-

Winter

et

al.

for

further

references

see

Schweizer

et

al.

-RRB-

all

of

which

are

expressed

in

the

cortex

of

hair

shafts

and

thus

indicating

that

monilethrix

is

a

disease

of

the

hair

cortex

A

further

rare

disease

recently

found

to

be

related

to

a

distinct

mutation

in

the

type

II

hair

keratin

is

ectodermal

dysplasia

of

hair

and

nail

type

characterized

by

total

alopecia

and

severe

nail

dystrophy

-LRB-

Naeem

et

al.

-RRB-

The

expression

of

already

in

the

hair

matrix

from

which

hair

fiber

formation

starts

-LRB-

Schweizer

et

al.

-RRB-

may

explain

the

severe

hair

phenotype

of

these

patients

As

to

tumors

hair

keratins

have

up

to

now

only

been

detected

in

pilomatricomas

-LRB-

Moll

et

al.

Régnier

et

al.

-RRB-

which

are

regarded

as

originating

from

hair

matrix

and

undergoing

true

hair

differentiation

The

complex

hair

keratin

expression

in

benign

and

malignant

pilomatricoma

-LRB-

Cribier

et

al.

-RRB-

confirms

this

notion

at

the

molecular

level

Monospecific

antisera

against

all

of

these

keratins

are

available

-LRB-

PROGEN

Heidelberg

Germany

Langbein

et

al.

-RRB-

keratins

with

still

unknown

expression

pattern

These

five

very

different

keratins

complete

the

family

of

human

keratin

proteins

In

principle

mainly

the

gene

and

cDNA

sequences

for

the

type

I

keratins

-LRB-

Zhang

et

al.

-RRB-

and

and

the

type

II

keratins

-LRB-

formerly

-RRB-

-LRB-

formerly

-RRB-

and

-LRB-

formerly

-RRB-

-LRB-

Rogers

et

al.

-RRB-

are

known

up

to

now

Unfortunately

only

very

vague

and

preliminary

-LRB-

or

no

-RRB-

expression

data

are

available

from

Northern

blot

analyses

suggesting

their

expression

in

tongue

-LRB-

-RRB-

and

skin

-LRB-

-RRB-

respectively

-LRB-

Rogers

et

al.

-RRB-

As

they

were

obviously

overlooked

in

former

studies

their

expression

might

be

restricted

to

very

special

epithelia

distinct

cellular

differentiation

stages

or

even

transient

expression

phases

The

investigation

of

the

detailed

expression

pattern

of

these

keratins

will

be

one

of

the

most

urgent

studies

in

this

field

Keratins

as

diagnostic

markers

in

tumor

pathology

One

of

the

important

fields

of

application

of

keratins

-LRB-

making

use

of

the

knowledge

of

their

high

number

of

gene

family

members

combined

with

their

special

and

characteristic

expression

patterns

in

distinct

cell

types

differentiation

stages

or

functional

states

-RRB-

is

their

use

aided

by

specific

antibodies

as

immunohistochemical

markers

in

diagnostic

tumor

pathology

Epithelial

tumors

maintain

at

least

widely

specific

features

of

the

keratin

expression

patterns

of

the

respective

cell

type

of

origin

Thus

in

cases

which

on

the

basis

of

clinical

data

and

conventional

histopathology

remain

unclear

keratin

typing

may

help

to

correctly

identify

and

classify

the

tumor

entity

present

Keratin

profiling

is

especially

valuable

for

carcinomas

of

poorly

differentiated

histology

for

carcinomas

spreading

over

several

organs

and

in

particular

for

metastases

of

an

unknown

primary

tumor

Of

the

human

keratins

only

a

relatively

small

panel

has

attained

diagnostic

importance

up

to

now

which

might

grow

further

with

time

and

respective

studies

by

including

the

keratins

described

within

the

last

years

The

carefully

selected

use

of

diagnostically

relevant

keratin

antibodies

if

appropriate

as

part

of

a

panel

together

with

other

tumor

type

markers

has

become

diagnostic

standard

in

state-of-the-art

clinical

pathology

-LRB-

for

recent

overviews

see

Chu

and

Weiss

Dabbs

-RRB-

In

the

previous

chapter

on

the

individual

keratins

some

data

on

their

expression

patterns

in

tumors

have

already

been

presented

In

the

following

key

diagnostic

features

of

keratin

typing

concerning

important

tumor

entities

will

be

briefly

summarized

Adenocarcinomas

Adenocarcinomas

are

one

of

the

largest

groups

of

human

malignant

tumors

and

may

arise

in

many

organs

and

tissues

They

comprise

more

than

one-half

of

cases

of

cancer

with

unknown

primary

tumor

The

identification

of

the

specific

origin

e.g.

colon

ovary

pancreas

or

lung

has

become

therapeutically

important

since

effective

chemotherapy

schedules

may

be

vastly

different

As

a

group

adenocarcinomas

are

characterized

by

the

predominance

of

simple-epithelial

keratins

notably

and

whereas

and

are

variably

expressed

It

is

this

variability

which

may

be

diagnostically

exploited

and

thus

staining

for

both

and

is

the

current

practice

resulting

in

different

phenotypes

-LRB-

Table

-RRB-

The

highest

diagnostic

significance

of

keratin

typing

is

true

for

colorectal

adenocarcinomas

which

like

the

normal

mucosa

almost

always

remain

-LRB-

Fig.

-RRB-

Most

cases

including

metastases

exhibit

a

phenotype

-LRB-

Fig.

d

-RRB-

or

express

at

lower

level

as

compared

to

-LRB-

Moll

et

al.

Miettinen

for

further

references

see

Moll

Chu

and

Weiss

-RRB-

co-expression

has

been

detected

more

frequently

in

advanced

colorectal

cancers

-LRB-

Hernandez

et

al.

-RRB-

Although

so

characteristic

of

colorectal

tumors

may

in

certain

situations

be

reduced

Thus

reduced

expression

of

has

been

found

in

a

specific

subset

of

colorectal

carcinomas

with

high

levels

of

microsatellite

instability

-LRB-

McGregor

et

al.

-RRB-

notably

expression

remained

low

in

these

tumors

Since

is

a

differentiation

marker

its

reduction

or

even

loss

may

also

be

due

to

dedifferentiation

In

a

large

tissue

microarray

study

reduced

expression

of

and

was

found

to

be

associated

with

shorter

patients

survival

possibly

on

the

basis

of

epithelial-mesenchymal

transition

-LRB-

Knösel

et

al.

-RRB-

Adenocarcinomas

of

the

stomach

usually

show

heterogeneous

expression

of

both

and

the

latter

being

rather

variable

but

yet

expressed

in

the

majority

of

cases

-LRB-

Moll

Chu

and

Weiss

-RRB-

No

systematic

differences

between

intestinal

and

diffuse/signet

ring

cell

carcinomas

have

been

described

In

adenocarcinomas

of

the

pancreas

and

the

biliary

tract

there

is

usually

a

clear

predominance

of

-LRB-

Fig.

-RRB-

together

with

variable

and

focal

-LRB-

often

minor

-RRB-

expression

of

in

up

to

of

cases

-LRB-

Fig.

Moll

Chu

and

Weiss

-RRB-

Ductal

adenocarcinomas

of

the

pancreas

in

addition

often

express

certain

stratified-epithelial

keratins

most

notably

and

-LRB-

Schüssler

et

al.

Real

et

al.

Moll

-RRB-

Finally

a

phenotype

is

characteristic

of

adenocarcinomas

of

the

ovary

-LRB-

except

for

the

mucinous

type

-RRB-

the

endometrium

and

the

lung

Endometrial

adenocarcinomas

often

focally

co-express

certain

stratified-epithelial

keratins

including

reflecting

the

potential

of

the

tumor

cells

for

stratification

to

develop

squamous

metaplasia

Like

other

adenocarcinomas

most

breast

carcinomas

constitutively

express

and

-LRB-

Altmannsberger

et

al.

Malzahn

et

al.

-RRB-

In

some

studies

however

a

high

level

of

or

immunostaining

as

detected

by

certain

monoclonal

antibodies

has

been

correlated

with

favorable

prognosis

and

reduced

or

absent

staining

was

associated

with

unfavorable

outcome

-LRB-

Takei

et

al.

Schaller

et

al.

Woelfle

et

al.

-RRB-

Microarray-based

expression

profiling

of

breast

carcinomas

has

led

to

the

definition

of

distinct

subgroups

One

of

these

has

been

designated

as

basal-like

group

-LRB-

Sørlie

et

al.

-RRB-

which

is

characterized

by

relatively

poor

prognosis

Interestingly

the

typical

expression

profile

of

the

basal-like

cancers

includes

the

basal

cell-typical

keratins

and

Several

older

reports

have

already

described

the

presence

of

such

keratins

in

a

subpopulation

of

breast

carcinomas

-LRB-

Moll

et

al.

Wetzels

et

al.

-RRB-

and

some

did

already

point

to

a

negative

prognostic

significance

of

basal

cell

keratin

expression

in

invasive

ductal

breast

cancers

-LRB-

Dairkee

et

al.

Malzahn

et

al.

-RRB-

This

has

now

been

confirmed

and

extended

by

the

growing

body

of

recent

microarray

data

allowing

to

define

a

subgroup

of

sporadic

breast

cancers

which

exhibit

bad

prognosis

and

association

with

mutation

or

dysfunction

-LRB-

Gusterson

et

al.

Diaz

et

al.

-RRB-

For

the

recognition

of

this

subgroup

immunostaining

for

keratins

such

as

may

achieve

importance

-LRB-

van

de

Rijn

et

al.

for

further

references

see

Gusterson

et

al.

-RRB-

The

different

subtypes

of

renal

cell

carcinomas

-LRB-

RCCs

-RRB-

exhibit

some

characteristic

features

in

keratin

expression

which

may

support

the

precise

classification

of

these

tumors

-LRB-

Thoenes

et

al.

Moll

Chu

and

Weiss

Skinnider

et

al.

Liu

et

al.

-RRB-

Thus

conventional

-LRB-

clear

cell

-RRB-

RCCs

express

a

simple

keratin

pattern

of

mainly

together

with

variable

mostly

minor

expression

of

In

contrast

the

papillary

subtype

of

RCC

is

characterized

by

strong

expression

as

well

as

expression

in

addition

to

the

basic

pair

Chromophobe

RCCs

on

the

other

hand

typically

express

-LRB-

but

little

-RRB-

in

addition

to

-LRB-

Thoenes

et

al.

-RRB-

The

benign

oncocytomas

which

histologically

may

resemble

chromophobe

RCC

are

mostly

-LRB-

Liu

et

al.

-RRB-

The

peculiar

co-expression

together

with

keratins

of

the

mesenchymal

intermediate

filament

protein

vimentin

in

conventional

-LRB-

clear

cell

-RRB-

and

papillary

RCCs

but

not

in

chromophobe

RCCs

and

oncocytomas

is

another

feature

valuable

in

differential

diagnosis

Another

tumor

category

with

characteristic

co-expression

of

keratins

and

vimentin

are

malignant

mesotheliomas

The

epithelial

type

may

be

difficult

to

distinguish

histologically

from

adenocarcinomas

-LRB-

e.g.

pleural

involvement

by

pulmonary

adenocarcinomas

or

pleural/peritoneal

metastases

of

adenocarcinomas

of

various

origins

-RRB-

In

contrast

to

most

adenocarcinomas

epithelial

mesotheliomas

consistently

express

keratinocyte-type

keratins

notably

in

addition

to

keratins

and

typical

for

simple

epithelia

-LRB-

Moll

et

al.

Ordonez

Chu

and

Weiss

Yaziji

et

al.

-RRB-

Thus

in

recent

years

has

been

included

in

the

battery

of

useful

mesothelioma

markers

Neuroendocrine

tumors

Neuroendocrine

tumors

a

large

and

heterogeneous

tumor

group

are

generally

characterized

by

the

expression

of

keratins

typical

of

simple

epithelia

-LRB-

notably

and

more

variably

-RRB-

and

the

complete

lack

of

keratins

typically

found

in

stratified

epithelia

Particularly

interesting

in

a

diagnostic

respect

is

the

well-proven

value

of

as

a

consistent

marker

of

Merkel

cell

carcinomas

of

the

skin

allowing

their

delineation

from

metastatic

small

cell

neuroendocrine

carcinomas

arising

at

other

sites

such

as

small

cell

lung

carcinoma

which

although

morphologically

similar

consistently

lack

-LRB-

Moll

et

al.

Cheuk

et

al.

-RRB-

Another

interesting

recent

issue

concerns

endocrine

tumors

of

the

pancreas

Several

studies

suggest

that

the

expression

of

in

these

tumors

may

be

correlated

with

a

poor

prognosis

-LRB-

Schmitt

et

al.

La

Rosa

et

al.

-RRB-

Transitional

cell

carcinomas

The

urothelium

exhibits

a

unique

complex

pattern

of

keratin

expression

and

are

expressed

in

all

cell

layers

and

are

restricted

to

the

basal

cell

layer

Particularly

characteristic

are

expressed

in

the

basal

and

intermediate

cell

layers

and

specific

for

the

superficial

-LRB-

umbrella

-RRB-

cell

layer

This

urothelial

keratin

pattern

is

relatively

well

conserved

in

noninvasive

and

invasive

transitional

cell

carcinomas

-LRB-

TCCs

-RRB-

-LRB-

for

detailed

reviews

see

Moll

Southgate

et

al.

-RRB-

has

been

found

to

be

retained

in

of

TCCs

-LRB-

Moll

et

al.

-RRB-

Indeed

the

combined

presence

of

keratins

-LRB-

as

well

as

and

-RRB-

typical

for

simple

epithelia

together

with

and

in

a

tumor

is

characteristic

of

urothelial

origin

although

may

be

reduced

or

lost

in

poorly

differentiated

TCCs

Squamous

metaplasia

may

modify

the

keratin

expression

pattern

Particularly

interesting

are

the

recent

prognostically

relevant

findings

that

noninvasive

papillary

TCCs

may

exhibit

a

normal

pattern

-LRB-

predominantly

superficial

-RRB-

or

an

abnormal

pattern

-LRB-

all

cell

layers

or

negative

-RRB-

and

that

the

normal

pattern

is

predictive

of

tumor

non-recurrence

-LRB-

Southgate

et

al.

-RRB-

Squamous

cell

carcinomas

Squamous

cell

carcinomas

of

different

sites

of

origin

are

generally

characterized

by

a

predominance

of

stratified-epithelial/keratinocyte-type

keratins

but

may

co-express

certain

simple-epithelial

keratins

-LRB-

for

details

see

Moll

-RRB-

Most

of

these

tumors

strongly

express

the

keratins

-LRB-

Fig.

e

-RRB-

and

normally

found

in

the

basal

layer

as

well

as

the

keratins

-LRB-

Fig.

-RRB-

and

characteristic

for

hyperproliferative

keratinocytes

Focally

there

may

be

expression

of

-LRB-

particularly

in

higher

differentiated

tumor

cells

which

can

end

in

the

formation

of

horn

pearls

-RRB-

and

to

a

lesser

extent

and

The

co-expression

of

simple

epithelia-typical

keratins

comprises

and

and

different

studies

have

suggested

that

this

co-expression

seems

to

be

more

pronounced

in

poorly

differentiated

squamous

cell

carcinomas

-LRB-

for

references

see

Moll

-RRB-

Recently

it

has

been

demonstrated

that

in

squamous

cell

carcinomas

of

the

oral

cavity

the

expression

of

and

is

an

independent

prognostic

marker

and

indicates

a

decreased

overall

and

progression-free

survival

-LRB-

Fillies

et

al.

-RRB-

In

summary

stratified-epithelial

keratins

in

particular

and

are

useful

as

general

markers

for

squamous

cell

carcinomas

in

histologically

uncertain

poorly

differentiated

or

metastatic

tumor

cases

Although

certain

differences

between

the

keratin

expression

patterns

of

squamous

cell

carcinomas

from

different

sites

of

origin

have

been

noted

it

is

not

yet

possible

to

use

keratins

as

specific

site

markers

in

cases

of

unclear

metastases

-LRB-

Moll

-RRB-

Perspectives

In

the

past

years

our

knowledge

on

keratins

has

tremendously

increased

regarding

their

molecular

and

cell

biology

as

well

as

their

application

as

markers

in

pathological

diagnosis

The

introduction

of

a

new

consensus

nomenclature

-LRB-

Schweizer

et

al.

-RRB-

which

for

the

common

-LRB-

non-hair

follicle

specific

-RRB-

epithelial

keratins

widely

conserves

the

older

names

established

in

the

literature

makes

this

complex

field

much

clearer

than

before

and

will

facilitate

future

research

Today

much

is

known

about

the

structural

functions

of

keratins

as

proven

by

a

wealth

of

human

hereditary

keratin

diseases

and

transgenic

mouse

models

However

numerous

questions

still

need

to

be

answered

particularly

concerning

the

regulatory

functions

of

keratins

As

reviewed

in

this

article

recent

experimental

studies

have

pointed

to

newly

recognized

roles

of

certain

keratins

in

apoptosis

cell

growth

tissue

polarity

wound

response

and

tissue

remodeling

First

specific

signaling

pathways

have

already

been

described

which

seem

to

be

associated

with

distinct

keratins

The

question

of

whether

keratins

might

play

a

role

in

malignant

transformation

is

particularly

exciting

but

at

present

a

causal

role

in

tumorigenesis

has

not

been

established

for

any

keratin

-LRB-

for

review

see

Magin

et

al.

-RRB-

However

keratins

may

in

fact

be

linked

to

the

cell

cycle

machinery

-LRB-

Margolis

et

al.

-RRB-

Future

research

will

hopefully

answer

the

question

why

the

human

organism

actually

needs

different

keratin

proteins

all

of

which

in

the

first

instance

form

the

seemingly

primitive

uniform

structure

of

a

nm

intermediate

filament

although

with

peculiarities

in

the

head

and

tail

domains

of

their

single

molecular

components

One

may

also

expect

for

the

future

that

the

diagnostic

application

of

keratins

although

already

established

in

tumor

pathology

will

be

further

refined

and

extended

Examples

of

very

recent

new

developments

in

tumor

classification

are

the

recognition

of

the

basal-like

subtype

of

breast

cancer

on

the

basis

of

the

expression

of

and

the

prognostic

relevance

of

in

endocrine

pancreatic

tumors

At

the

moment

the

panel

of

keratins

introduced

into

routine

diagnosis

as

histopathological

tumor

markers

is

distinctly

small

essentially

consisting

of

and

Furthermore

the

expression

patterns

of

a

battery

of

special

keratins

were

detected

only

in

the

last

few

years

and

these

keratins

are

just

started

to

be

involved

into

tumor

diagnostic

studies

Not

to

forget

that

at

the

time

out

of

the

human

keratins

are

still

uncharacterized

in

their

expression

sites

and

patterns

and

possibly

their

expression

in

neoplasia

might

have

a

potential

as

diagnostic

markers

Since

all

keratins

have

an

exquisite

cell

type

and

differentiation

stage-specific

regulation

and

expression

pattern

it

might

well

be

that

upon

future

research

further

keratins

will

be

introduced

as

markers

for

certain

diagnostic

questions

in

pathology

to

widen

and

to

refine

the

diagnostic

potential

of

keratins

keratins
differentiation
cytoskeleton
tumor markers