PATHOLOGY LAB: INFLAMMATORY MYOPATHIES

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Pathology Lab II
-

Inflammatory Myopathies


PATHOLOGY LAB: INFLAMMATORY MYOPATHIES

Dr. Brownlee



CASE OUTLINE

References

Introduction and Epidemiology

Case Presentation: Abigail Adams

Muscle Biopsy

Dermatomyositis

Polymyositis

Inclusion body myositis

Quiz



INTRODUCTION & EPIDEMIOLOGY

The term “myositis” can be used for any disorder associated with skeletal muscle inflammation. The inflammation
may be confined to a single muscle or may be diffuse. Inflammatory myopathies may be subdivided into two maj
or
groups: (1) idiopathic inflammatory myopathies and (2) infectious myopathies. The idiopathic inflammatory
myopathies comprise three major diagnoses: (1) dermatomyositis (DM), (2) polymyositis (PM) and (3) inclusion
-
body myositis (IBM). Although these di
sorders share several common features including muscle weakness and
inflammatory infiltrates on muscle biopsy, they are a heterogeneous group in terms of morphologic findings, clinical
presentation and pathogenesis.

Inflammatory myopathies typically affect

1 per 100,000 population. In all age groups, DM is the most common and
PM is the least common. IBM is the most common myopathy above the age of 50. DM is twice as common in
women as in men. DM affects children and adults equally. In adults, the peak age o
f DM onset is approximately 50
years, and, in children, the peak age is between 5 and 10 years of age.



REFERENCES:

1.


Robbins and Cotran Pathologic Basis of Disease, 8
th

Edition, 2010.

2.


Harrison’s Principles of Internal Medicine

3.


Agamanolis, D.

www.neuropathologyweb.org

4.


Miller ML. Clinical manifestations and diagnosis of adult dermatomyositis and polymyositis. UpToDate
Literature review version 18.2, May 2010.

5.


Dala
kas MC Hohlfeld R. Polymyositis and dermatomyositis. Lancet 2003; 362: 971.



CASE PRESENTATION: ABIGAIL ADAMS

Mrs. Adams is a 45
-
year
-
old woman with a past medical history significant for depression for which she is treated
with an Paxil. She was
hospitalized


4 years ago


for an emergency appendectomy, but otherwise has enjoyed good
health. She presents to her internist today complaining of fatigue and bilateral upper and lower extremity muscle
weakness. She notes that over the past 4 months, she
has been experiencing increasing difficulty with her everyday
tasks at home and at work. She says that she has been having difficulty standing from a sitting position and even has
difficulty stepping onto a curve and climbing a short flight of stairs. She
denies headaches, muscle pain, visual
difficulties, swollen joints, fever, heat and cold intolerance, and dysphagia currently. She has not noted any skin
rashes. She denies tobacco smoking , alcohol and illicit drug use.

Physical examination reveals that M
rs. Adams is in no acute distress, She appears her stated age. Her oral
temperature was measured to be 99.0 F, pulse 70, respiratory rate of 18, and blood pressure of 120/80. Examination
of her upper and lower extremity muscle groups documented bilateral w
eakness and some focal myalgia; however,
her deep tendon reflexes were all intact.


Mrs. Adams had some blue
-
purple discoloration of on her upper eyelids
with mild edema and a rash involving her face and upper trunk. She had knuckle erythema and a raised a
ppearing
scaly rash on the dorsal aspect of her hands.


Similar dermatologic findings were noted on her knees and elbows.

Because of the patient’s constellation of signs and symptoms with physical examination findings, serum muscle
enzymes, EMG and muscle
biopsy were requested. Serum creatine kinase (CK) levels were measured at 2050. A
needle EMG of lower extremity muscles revealed short
-
duration, low amplitude polyphasic units on voluntary
activation and increased spontaneous activity with fibrillations an
d complex repetitive discharges. A surgeon was
consulted to obtain the muscle biopsy. Pathologic examination of the muscle biopsy obtained from the quadriceps
documented a predominantly perivascular


mononuclear (lymphocytic)


inflammatory infiltrate.

THE
SKELETAL MUSCLE BIOPSY

Muscle biopsy work
-
up requires that skeletal muscle biopsies be obtained fresh and placed on a clamp holding the
tissue is a non
-
contracted state. The operating room submits the tissue to the pathology laboratory fresh and on
clamp.


A biopsy received in formalin alone will not be very useful. The freshly obtained skeletal muscle biopsy
may be divided into several fragments so that the appropriate studies may be conducted. A portion of the tissue is
snap frozen in liquid nitrogen beca
use the tissue is subjected to frozen sections for special histochemical staining.
Secondly, a portion of the skeletal muscle is submitted in formalin fixative for routine processing. Lastly, fragments
of skeletal muscle are sectioned into 1 cubic millimet
er fragments of tissue and submitted into glutaraldehyde
fixative for electron microscopic evaluation. Most importantly, before subjecting a patient to a biopsy, make sure
that the surgeon knows that the tissue must be submitted to the pathology laboratory

fresh and placed onto a clamp.

DERMATOMYOSITIS

1.


Definition and Clinical Manifestations

Dermatomyositis, as its name indicates, is an inflammatory process of the skin and skeletal muscle.

A.

Cutaneous manifestations:


The disease is characterized by a distinctive rash accompanying (or
preceding) muscle weakness. The characteristic heliotrope rash, named for the flower because of the blue
-
purple discoloration of the skin, may involve the upper eyelids. A flat, red rash m
ay involve the face and
upper trunk . Gottron rash, or papules, are raised violaceous scaly eruptions on the skin. These areas of
scaly discoloration may also involve the knees and elbows, malleoli, neck and anterior chest. The skin rash
may worsen upon su
n exposure. Calcinosis cutis, or deposition of calcium with the skin can also be seen in
DM. Calcinosis cutis manifests as firm, yellow, or flesh
-
colored nodules, commonly seen over bony
prominences.


Skin biopsy is oftentimes helpful in establishing the d
iagnosis of DM.

Erythematous cutaneous lesions may occur on exposed skin such as the face, neck, and anterior chest. This
is called the “V” sign of the neck and the shawl sign on the upper back. Periungal telangiectasias involve
the skin of the hands. Tela
ngiectasias are small dilated blood vessels near the surface of the skin, measuring
between 0.5 and 1 millimeter in diameter.



The heliotrope rash is named for the color of the heliotrope flowering plant (left). Prominent blue
-
purple
cutaneous discolorat
ion of the eyelids with accompanying edema may be seen in patients with
dermatomyositis.





Gottron’s papules are erythematous plaques located on the dorsal aspects of the hands especially located over
the proximal and distal joints of the hand.



B.

Skeletal Muscle Manifestations:

Muscle weakness is typically characterized by slow onset, is bilaterally
symmetrical, and sometimes associated with myalgias. DM typically affects the proximal skeletal muscle groups
first. Muscle weakness typically progress
es to the point that it interferes with the activities of daily living including
getting up and down from a chair, for example. Fine motor movements controlled by distal muscles are only
affected late in the course of the disease. When the diseases involve
s skeletal muscle of the oropharynx and
proximal esophagus, dysphagia may occur.


Sensory function (sensation) remains normal. The deep tendon reflexes
are preserved. Myalgia is relatively uncommon in patients with DM, affecting only about 30% of these pat
ients.

C. Other Clinical Findings:

Extracutaneous and extramuscluar manifestations are also seen:

Arthralgias and arthritis may also be seen in 25% of patients. Arthralgias are joint pains or aches without obvious
gross signs of inflammation such as swelli
ng, warmth, or redness. The term arthritis is applied to cases in which
joint pain is associated with obvious gross signs of inflammation. The arthritis of DM is not erosive or deforming, in
contrast to rheumatoid arthritis.

Esophageal disease may be anoth
er manifestation of DM. Dysphagia, or difficulty swallowing, is estimated to be
present in 15
-
50% of patients. The dysphagia of DM patients is caused by involvement of skeletal muscle of the
pharynx and proximal esophagus.

Pulmonary disease occurs in 15
-
30
% of patients. Interstitial pneumonitis is more frequent in patients with
esophageal involvement. There may be clinical, radiologic and pathologic overlap between the findings of DM and
other collagen vascular diseases.

Cardiac disease in DM is associated
with a poor prognosis. Conduction defects and rhythm disturbances are the
most common cardiac manifestations of DM.

DM patients are also more likely to develop visceral cancers. Large population
-
based cohort studies reveal that 20
-
25% of patients with DM
have an associated malignant disease. Malignancies may occur before the onset of DM,
concurrently with DM, or after the onset of DM. The most common forms of malignancy seen in patients with DM
include carcinoma of the lung, breast, ovaries and colon.

D. J
uvenile DM:

Juvenile DM causes a similar cutaneous rash and involves skeletal muscles, but is more
commonly associated with abdominal pain and gastrointestinal tract dysfunction. Vasculopathy within blood vessels
of the gastrointestinal tract can lead to m
ucosal ulceration and perforation.

2.


Etiology and Pathogenesis

The cause of inflammatory myopathies is generally unknown. Inflammatory myopathies in general are thought to be
caused by immune
-
mediated insults. Injury to the skeletal muscle in
dermatomyositis is primarily mediated by
immunological mechanisms. The capillaries within muscle tissue appear to be the primary targets for immune
-
mediated injury. Complement mediated injury is thought to be the cause of tissue damage. C5b
-
9 membrane atta
ck
complex is detectable within vessel walls. Myocyte necrosis ensues.


Similar mechanisms of disease are associated
with the cutaneous manifestations of DM.

3.


Morphology

Histopathologic analysis of skeletal muscle biopsies are usually performed by
neuropathologists, pathologists with
additional fellowship training in diseases of the central and peripheral nervous system.


The histopathologic features
of the varying types of myositis are distinctive (see below). Dermatomyositis is characterized by in
flammatory
infiltrate, primarily mononuclear (lymphocytic) in nature, around small blood vessels and within the perimysial
connective tissue. Groups of atrophic muscle fibers are noted particularly within at the periphery of fascicles
(perifascicular distr
ibution of atrophic fibers). Perifascicular atrophy is sufficient for the diagnosis of
dermatomyositis even in the absence of a significant inflammatory infiltrate. Necrotic muscle fibers and
regeneration may also be seen throughout the fascicle. Vasculiti
s may also be seen. The perimysial and endomysial
capillaries show endothelial swelling and necrosis.



Sections of skeletal muscle obtained from the quadriceps muscle demonstrate a significant inflammatory
infiltrate with associated cellular necrosis. Th
e increased space noted between muscle fascicles is indicative of
the atrophy associated with dermatomyositis

Skin biopsies have also proven to be helpful in diagnosing DM, perhaps obviating the need for a skeletal muscle
biopsy. Skin punch biopsies may sh
ow significant epidermal atrophy and a lymphocytic perivascular inflammatory
infiltrate. Correlation with skin biopsy findings and the patient’s clinical findings may be enough to establish a
diagnosis of DM.

4.

Laboratory Studies

Because of the presence of
myocyte necrosis in skeletal muscle tissue, enzymes normally housed within the
myocytes are released into the extracellular space and serum. Elevated erythrocyte sedimentation rates (ESRs) are
often seen in patients with dermatomyositis, as well as other c
onnective tissue diseases. Elevated serum muscle
enzymes including creatine kinase, aldolase, aspartate aminotransferase (AST) and lactic dehydrogenase (LDH) are
often demonstrated in patients as well. Serologic studies may document the presence of Anti
-
Jo
-
1 antibodies,
especially if the patient has lung involvement.


Autoantibodies directed against transfer RNA synthetases seem to be
rather specific for inflammatory myopathies.


Myositis
-
associated autoantibodies and myositis specific
autoantibodies have b
een described, but are not currently routinely used for the diagnosis of DM.



5.

Other Diagnostic Studies

Electromyography (EMG) is a technique for evaluating and recording the electrical activity produced by skeletal
muscles. EMG can be very helpful in the
identification of inflammation and damage to skeletal muscle.


More
recently, magnetic resonance imaging (MRI) has been employed in the evaluation of patients with DM. Based on the
presence of edema, MRI can distinguish between affected and unaffected musc
les. Areas of muscle with
inflammatory edema are hyperintense on T2
-
weighted images, whereas less affected or non
-
affected muscles have a
lower signal on T2 weighted images.

6.


Treatment and Prognosis

Patients with dermatomyositis, as well as other i
nflammatory myopathies are often treated with high dose steroids to
manage the immunologic/inflammatory assault on skeletal muscle microvasculature. For example, high dose
prednisolone (40
-
60 mg) with or without azathioprine and cyclophosphamide may be emp
loyed for its anti
-
inflammatory effects. Long courses (years) of steroid treatment are sometime necessary in the management of these
patients. Prognosis is oftentimes dependent on the presence of an associated neoplasm, particularly carcinoma
primary to th
oracic or abdominal viscera such as lung or colon adenocarcinoma. As you may expect, those patients
with visceral malignancy and dermatomyositis


have significantly reduced survival .



OTHER INFLAMMATORY MYOPATHIES

POLYMYOSITIS

1.


Definition and
Clinical Manifestations

PM is an inflammatory myopathy characterized by symmetric proximal muscle involvement, similar to the
constellation of findings seen in patients with dermatomyositis. There is an overalap in the clinical findings of
polymyositis and

dermatomyositis. Importantly, polymyositis is different from dermatomyositis in that this disease
lacks the cutaneous involvement of dermatomyositis. Polymyositis primarily affects adults. Patients with
polymyositis may also experience concurrent inflamma
tory involvement of blood vessels (vasculitis), heart, and
lungs.

2.


Etiology and Pathogenesis

In contrast to the immune
-
mediated damage of skeletal muscle microvasculature in patients with
dermatomyositis,


polymyositis is caused by direct cytotoxic

T
-
lymphocyte (cell
-
mediated) injury to the myocyte.
Increased serum cytokines like tumor necrosis factor alpha may also be seen in patients with
PM.


Immunosuppressive therapy in patients with polymyositis is generally useless, in contrast to dermatomyosi
tis.

3.

Clinical Manifestations

Unlike patients with DM, patients with PM usually have muscle specific symptoms that are not associated with
some of the clinical findings associated with DM. For example, patients with PM have no associated increased risk
of m
alignancy and the typical dermatologic manifestations of DM are not seen in patients with PM. Heliotrope rash,
shawl sign, and generalized erythroderma, all signs which may be seen in DM patients are not seen in PM. Features
and distribution of muscular we
akness is similar to that seen in DM patients.





4.


Morphology

Polymyositis demonstrates histologic features similar to that seen in dermatomyositis. Lymphocytes are often seen
invading the myocyte
. The lymphocytic infiltrate is predominantly within the muscle fascicle. There are no signs of
vasculopathy in patients with polymyositis.



H&E stained section (left) of muscle biopsy documents myocytic infiltration by lymphocytes.
Immunohistochemical

analysis would confirm that these T
-
lymphocytes are CD8+ cytotoxic lymphocytes.
The image on the right is a lymphocyte penetrating underneath the basement membrane of a myofiber.



5.Laboratory Studies

The laboratory studies for polymyositis are much the
same as for dermatomyositis.

6.Treatment and prognosis

Treatment and prognosis for patients with polymyositis are similar to that of dermatomyositis.



INCLUSION BODY MYOSITIS

1.


Definition

IBM is uncommon. Unlike the other types of inflammatory
myopathy described above, inclusion body myositis is
characterized by an insidious onset with involvement of distal muscles, especially extensors of the knee (quadriceps)
and flexors of the wrists and fingers. Also unlike dermatomyositis and polymyositis,
patients with IBM can show
asymmetric muscle involvement. The disease almost always affects individuals over the age of 50 years. Most cases
of inclusion body myositis are sporadic, but familial cases have also been described.

2.


Etiology and Pathoge
nesis

The pathogenesis of inclusion body myositis is enigmatic. Cytotoxic T lymphocytes are present within the skeletal
muscle, but immunosuppressive treatments are not beneficial to these patients. Interestingly, intracellular deposits of
beta
-
amyloid and

tau proteins have suggested that this myopathy is related to the aging process. There are two forms
of inclusion body myopathy. An autosomal recessive form is caused by mutations of GNE, or UDP
-
acetylglucosamine 2
-
epimerase/N
-
acetylmannosamine kinase, whe
reas the autosomal dominant form of the disease
is caused by mutation of the myosin heavy chain IIa gene.

3.

Clinical Manifestations

IBM is associated with an insidious onset. Sporadic IBM is more common in the sixth and seventh decades than in
younger patien
ts. It is the most common skeletal muscle disease in elderly population. The disease is not
uncommonly confused with refractory PM. The distinction between the two diagnoses in important because it has
prognostic import. The disease causes progressive prox
imal and distal muscle weakness. More prominent distal
muscle weakness tends to be a more common finding in IBM as compared to PM which has a more prominent
proximal distribution of muscle weakness. Affected patients have significant difficulty with ambula
tion and
activities of daily care.

4.


Morphology

The pathological changes of IBM are highly characteristic. Light microscopic examination of skeletal muscle tissue
shows myofibers with vacuoles or cracks some of which are lined by basophilic granules
. Light microscopic features
are best seen in frozen section slides prepared by cryostat and stained with a modified Gomori trichrome. By
electron microscopy, the abnormal fibers contain paired helical filaments similar to those of Alzheimer's disease,
str
aight filaments, myelinoid membranous bodies, increased glycogen, and abnormal mitochondria. The filamentous
inclusions of IBM have the optical properties of amyloid and contain

beta amyloid,hyperphosphorylated tau protein,
apolipoprotein E, presenillin

1, prion protein, and other proteins, similar to protein accumulations seen in patients
with Alzheimer’s disease. The inflamatory component of IBM consists of cytotoxic T cells and macrophages,
similar to polymyositis. The pathogenesis of IBM is not known

but probably involves ageing of myofibers,
oxidative damage, and an unknown trigger that initiates inflammation.





Histologic sections of muscle biopsy show intracellular vacuolization (white areas within the eosinophilc

cytoplasm on the right) and peripheral basophilic stippling.

5.


Laboratory Studies

Mild creatine kinase (CK) elevations are seen in patients with IBM. CK and other skeletal muscle enzyme
elevations are generally higher in patients with DM and PM com
pared to the lower level in patients with IBM.

6.


Treatment and Prognosis




Patients with IBM are often refractory to treatment with corticosteroids and other immunosuppressant agents
such as azathioprine; however, inclusion of these agents may be b
eneficial in some patients. Randomized
controlled studies have also documented little clinical benefit in patients treated with intravenous
immunoglobulin (IVIG). The difficulty with adequate treatment is that patients often present after they have
been ex
periencing symptoms for years. In this scenario, significant skeletal muscle damage has already been
sustained and adequate treatment is more difficult to achieve.




1.

A 40
-
year
-
old male was diagnosed with an inflammatory
myopathy

based upon review of history, physical
examination and a variety of laboratory studies. Based
upon these findings, a diagnosis of dermatomyositis is
made. Which of the following descriptions of the muscle
biopsy findings would you most likely expect to se
e in this
patient?


Prominent intracellular inclusions associated with chronic inflammation


No diagnostic histopathologic findings are associated with dermatomyositis


Absence of dystrophin protein on immunohistochemical

staining of muscle
tissue


Perifascicular atrophy with evidence of vasculitis


Significant lymphocytic inflammatory infiltrate involving myocytes

2.

A 51
-
year
-
old female presented with progressive muscle
weakness in the lower extremities. She had a generalized
eythroderma and demonstrated features suggestive of a
heliotrope rash on her face. No Gottron’s papules were
seen on examination. She has no his
tory of skeletal
muscle disease in her family. To make the diagnosis, the
clinician requested a punch biopsy of the patients skin on
her lower extremity. The morphologic findings one would
expect to see are_________________. Based on this
patient’s diagnos
is of dermatomyositis, she is at increased
risk for developing __________________.


Squamous cell carcinoma of the skin; visceral cancer and heart disease


Squamous cell carcinoma of the skin; heart disease


Squamous

cell carcinoma of the skin; visceral cancer


Epidermal atrophy and lymphocytic perivascular inflammatory infiltrate;
visceral cancer


Epidermal atrophy and lymphocytic perivascular inflammatory infiltrate; heart
disease

3.

Which of the

following findings would you not expect to
see in a patient with polymyositis?


a.

Gottron’s papules and heliotrope rash


b.

Progressive muscle weakness


c.

Lymphocytic inflammatory infiltrate in skeletal muscle biopsy


d.

Elevated serum creatine kinase levels


e.

All of the above findings may be seen in patients with polymyositis

4.

A 57
-
year
-
old female with no significant past medical
history presents to her primary care physician complaining
of increasing difficulty maneuvering her hands and lower
extremities. On examination, she has difficulty flexing her
hands as well as flexing h
er knees. Her family history is
significant for having a mother, grandmother, and great
-
grandfather who experienced similar symptoms. A skeletal
muscle biopsy demonstrated morphologic features
suggesting inclusion body myositis. Based upon the
patient’s cl
inical findings, family history and muscle biopsy
results, which of the following genetic abnormalities would
you suspect?


a.

Dystrophin mutation


b.

Acetylcholinesterase deletion


c.

Myosin heavy chain mutation


d.

UDP
-
acetylglucosamine 2
-
epimerase/N
-
acetylmannosamine kinase
mutation


e.

None of the above

5.

A 56
-
year
-
old woman presented to her family practitioner
complaining of 3 months worsening fatigue. She
complains that she has difficulty climbing stairs and raising
her hands above her head. The patient further relates that
she is a 40 pack
-
year smoker of

cigarettes. Your review of
her chart reminds you that you are currently treating this
patient for hypercholesterolemia and hyptension. Which of
the following laboratory serologic studies may be helpful in
your work
-
up of this patient?


a.

anti
-
SSA antibodies


b.

anti
-
Jo
-
1 antibodies

anti
-

Ro antibodies


c.


d.

anti
-
SSA


e.

none of the above