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angioid streaks caused by degeneration of the Bruch’s membrane, which exists between the retina and choroids and contains
abundant elastic fibers. It is at this point that many patients with
pseudoxanthoma elasticum (PXE) first see a doctor. Fibrosis and
calcinosis occur in the aortic tunica media, leading to constriction
of the blood vessels and bleeding. This results in high blood pressure in renal arteries, claudication in the lower legs, cardiac
attack, cardiac infarction, coldness of the limbs and gastrointestinal bleeding. Women outnumber men by two to one, but male
cases tend to be more severe.
Pathogenesis
Mutation in ABCC6 on chromosome 16, a member of the ATP
binding cassette (ABC), has been associated with the occurrence
of PXE. This gene encodes multidrug-resistant protein MRP6.
Although both dominant and recessive inheritance patterns are
known, recent studies support the leading theory that PXE is
autosomal recessive.
Pathology
Swelling and disruption occur in the elastic fibers in the middle-dermal to deeper-dermal layers, accompanied by calcium
deposition and changes in the vascular walls (Fig. 18.20).
Treatment, Prognosis
The prognosis is good, as long as the cardiovascular symptoms
are not severe. Eye symptoms should be treated.
Fig. 18.20 Histopathology of pseudoxanthoma elasticum (von Kossa stain).
Calcium deposition stains brownish-black with
Kossa.
Disorders of subcutaneous fat
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A. Panniculitis
Inflammatory lesions of the subcutaneous fat can be classified
into three distinct categories.
① Septal panniculitis
② Lobular panniculitis
③ Panniculitis associated with vasculitis
1. Erythema nodosum (EN)
Outline
● Red
nodules accompanied by tenderness occur, most
commonly on the extensor surfaces of the lower extremities. They do not ulcerate.
● It is an inflammatory reaction whose inductive factors
include upper respiratory infection, drug eruption, Behçet’s
disease and sarcoidosis.
● Inflammation is histopathologically found in the subcuta-
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Disorders of the Dermis and Subcutaneous Fat
neous fat tissue septum.
should be differentiated from erythema induratum.
● Conservative therapies such as bed rest and cooling are
the first-line treatments. When induced by an infection,
antibiotics are administered. NSAIDs and potassium iodide
are also useful. Steroids may be used for severe cases.
● It
Clinical images are available in hardcopy only.
Clinical images are available in hardcopy only.
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Fig. 18.21 Erythema nodosum (EN).
Multiple erythema accompanied by severe tenderness on the extensor of the lower legs.
Clinical features
Adult women are most commonly affected. After a precursor
of upper respiratory infection, a few symmetrical, vaguely margined, light pink erythema occur, sometimes accompanied by a
fever. There is arthralgia. The erythema occur predominantly on
the extensor surfaces of the lower legs (Fig. 18.21). The erythemata vary in size from 1 cm to 10 cm. The eruptions are slightly
elevated indurations that are accompanied by heat sensation.
Tenderness and spontaneous pain are present. Ulceration does
not occur. In progressive cases, the same type of eruptions may
develop on the arms and hands. The eruptions change color from
dark red to yellow to blue in 2 to 4 weeks, and heal without scarring.
Pathogenesis
Erythema nodosum (EN) is induced by infectious allergy to
bacteria, fungi or viruses. It often appears secondarily after upper
respiratory or enteric infection caused by hemolytic streptococcus. Hansen’s disease, tuberculosis, toxoplasmosis and chlamydiosis may also cause EN. When the cause is infectious disease,
the condition is called acute EN, because it progresses rapidly
and resolves in several weeks. Drugs such as sulfa drugs and oral
contraceptives can also be causes. Additionally, EN may accompany Behçet’s disease, ulcerative colitis, Crohn’s disease, sarcoidosis or leukemia. However, it may occur sporadically
without any underlying diseases.
Pathology
In the early stages of EN, lymphoid cells and neutrophils infiltrate the dermis and subcutaneous fat tissue (fatty septum in particular); the condition is septal panniculitis. There are no findings
of vasculitis or degeneration of fat cells. Granulomas that contain
giant cells develop in the later stages.
Diagnosis
Clinical features of tenderness, histopathological findings and
precursory infectious disease are diagnostic. EN often occurs as a
symptom of various diseases (Table 18.2); the primary disease
should be identified.
Differential diagnosis
It is differentiated from erythema induratum, cellulitis, thrombophlebitis, Weber-Christian disease, lupus erythematous profundus and polyarteritis nodosa.
Disorders of subcutaneous fat / A. Panniculitis
Treatment
Bed rest is required. The lower extremities are kept cool and
elevated. In cases with intense inflammation, oral NSAIDs,
potassium iodide and steroids are administered. Any primary diseases are treated. If bacterial infection is identified, antibiotics are
used.
Prognosis
When induced by drugs or infection, EN does not recur as long
as it is appropriately treated. When the cause is any of the chronic underlying diseases listed above or is unknown, there may be
recurrence.
Table 18.2 Primary diseases that cause erythema nodosum (EN).
Disease
Findings and check points
Allergy caused
by bacterial,
fungal or viral
infection
Symptoms of various infectious
diseases
Behçet’s
disease
Findings of other diseases (oral
aphtha, uveitis, genital ulcers),
needle reaction test positivity
Tuberculosis
Tuberculin skin test positive,
tuberculous granuloma in
tissue, nodules by chest X-ray
Sarcoidosis
Bilateral hilar lymphadenopathy
(BHL) by chest X-ray, uveitis,
high concentration in serum of
Ca2+/ACE/lysozyme, negative
tuberculin skin test
Drug eruption
History-taking and investigation
of oral drugs is needed.
Ulcerative
colitis, Crohn’s
disease
Occult blood in stool,
gastrointestinal endoscopy
2. Erythema induratum
Synonyms: Erythema induratum Bazin, Nodular vasculitis
Outline
● Painless
subcutaneous nodules occur most frequently on
the lower legs of women. The primary disease is lobular
cellulitis.
● It is clinically similar to EN; however, acute inflammatory
findings are not present. The nodules are firm and often
accompanied by ulceration with scarring.
● When tubercle bacillus allergy (tuberculid) is identified,
therapy for tuberculosis should be given.
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Myelodysplastic Atypical hemocytes in bone
syndrome
marrow and peripheral blood,
chromosomal abnormality
Leprosy
Histological findings, lepromin
test positive, neurological
findings
Clinical features
Symmetrical, diffuse, elevated, dark red infiltrative erythema
and subcutaneous induration occur on both the extensor and flexor surfaces of the lower legs of middle-aged and elderly adults
(Fig. 18.22). Women are more commonly affected than men. The
induration disappears in 1 to 2 months; however, it may ulcerate
or coalesce to become plate-like, and scarring may be present.
The skin lesion may occur singly or multiply. When multiple,
eruptions from each stage are present at the same time. Nodular
vasculitis is a subtype of erythema induratum.
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Clinical images are available in hardcopy only.
Pathogenesis
Erythema induratum used to be regarded as tuberculid, i.e., an
allergic reaction to tubercle bacilli or to metabolites of such
bacilli. Nevertheless, there were cases in which tuberculosis did
not present, and steroids were effective as a treatment. Therefore,
erythema induratum has come to be thought of as lobular panniculitis that occurs with circulatory failure as the underlying disease. Even so, the tubercle bacillus was recently reported to have
been detected by PCR assay of skin biopsy in about 80% of
cases. In recent years, the theory of tubercle bacillus allergy as
the causative factor has reemerged.
Fig. 18.22 Erythema induratum.
Ulceration and erythema accompanied by induration occurred.
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Disorders of the Dermis and Subcutaneous Fat
Pathology
Necrosis of fat lobular tissue and granuloma are accompanied
by giant cells and epithelioid cellular infiltration. In typical cases
caused by tuberculosis, there are tuberculoid granulomas with
caseous necrotic centers surrounded by epithelioid cells, Langerhans giant cells and lymphocytes. Vasculitis of subcutaneous fat
tissue (most frequently in veins) is present (Fig. 18.23).
Diagnosis, Examination
Tuberculin skin test and chest X-ray are conducted to determine whether there is a tubercle bacillus allergy. Tubercle bacillus DNA is identified by PCR assay of biopsy tissue.
Fig. 18.23 Histopathology of erythema induratum.
Differential diagnosis
The disorder should be differentiated from EN, thrombophlebitis migrans, cutaneous polyarteritis nodosa and other
vasculitis, and ulceration in the lower extremities. EN is differentiated by its tenderness, its acute, intense inflammatory reaction,
and lesions that do not rupture spontaneously and whose main
pathological component is fat tissue septum.
Treatment
Therapy for tuberculosis should be given. Tubercular lesions
subside with treatment in a few months in most cases. Erythma
induratum that is not caused by tuberculosis is intractable and
progresses slowly. Bed rest for the lower extremities and prevention of stasis are effective. NSAIDs are administered orally.
Steroids are used in severe cases.
3. Weber-Christian disease
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Synonyms: Systemic nodular panniculitis, Relapsing febrile
nonsuppurative nodular panniculitis
Weber-Christian disease MEMO
as a distinct disorder
Weber-Christian disease may display almost
the same clinical course and pathology as the
panniculitis (lupus profundus) that accompanies collagen diseases. Some studies have
questioned whether Weber-Christian disease
is a distinct disorder. While cases of WeberChristian disease with poor prognosis have
been reported, it is likely that those cases are
actually misdiagnosed subcutaneous panniculitis-like T-cell lymphoma (SPTCL).
Weber-Christian disease is subcutaneous inflammation with
unknown cause. Internationally, recent theories have described
Weber-Christian disease as a subtype of EN or T-cell lymphoma
rather than as an independent disease. Weber-Christian disease
was defined in the past as a rare disorder with recurrent subcutaneous nodules and plaques, typically or extremities and buttocks,
and commonly associated with fever. Young and middle-aged
women are most commonly affected. After systemic symptoms
such as fever, fatigue and arthralgia, there are multiple, painful,
subcutaneous nodules or splenial induration of 1 cm to several
centimeters in diameter. The eruptions most frequently occur in
the extremities and trunk. They are light pink and edematous at
the beginning, gradually becoming dark purplish-red and stiff,
with high elasticity. The eruptions chronically recur to cause concavities and pigmentation in the sites.
Systemic symptoms are characterized by the markedly high
fever. Myocarditis and pericarditis are caused by inflammation of
Disorders of subcutaneous fat / A. Panniculitis
pericardial fat tissue. There is also anemia, neurological symptoms from meningitis, and liver enlargement from hyperlipemia
resulting from fat tissue degradation.
Degeneration and necrosis occur in the lobular fat tissue. As
time passes, foamy and other histiocytes are found in the neutrophilic infiltration, giving the appearance of lipid granuloma.
The foamy histiocytes become fibrotic. Blood test shows elevated erythrocyte sedimentation rate, leucopenia and abnormality in
the coagulation-fibrinolytic system. Primary diseases and compounding factors, if found, are treated or removed. As symptomatic therapies, systemic steroids and immunosuppressants are
administered.
Panniculitis caused by
absence of enzyme
309
MEMO
a1-antitrypsin deficiency, a1-antichymotrypsin
deficiency: These are rare diseases. Enhanced
decomposition and Weber-Christian-diseaselike panniculitis may be caused by decrease
of proteolytic enzyme inhibiting substances.
Enzymic panniculitis: Increase of lipase and
amylase in serum may lead to panniculitis in
patients with pancreatitis. Pancreatitis is an
important underlying disease in patients with
panniculitis.
4. Poststeroid panniculitis
It occurs a few days after large doses of steroids are reduced or
stopped. Multiple subcutaneous nodules 5 mm to 50 mm in
diameter suddenly occur on the whole body. They are sometimes
accompanied by tenderness, spontaneous pain and itching. They
are normal skin color or light pink. The pathological findings are
necrosis and degradation of the fat tissue, fat cells and foreignbody giant cells. They subside spontaneously; however, readministration of steroids may be necessary in severe cases.
5. Cold panniculitis
Subcutaneous nodules accompanied by erythema occur on
skin (mainly the cheeks and extremities) that is exposed to the
cold, such as ice and cold air. Newborns and infants are most
commonly affected. The skin lesion heals spontaneously in a few
days to a few weeks.
6. Traumatic panniculitis
It is an inflammatory reaction caused by damage to fat cells
after injury. A painful erythematous plaque or nodule accompanied by palpable infiltration forms, most frequently in the breasts
or lower legs of obese women.
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