Non infectious&necrobiotic granulomatous diseases of the skin by M.Y.Abdel-Mawla
OF THE SKIN
► Granulomatous reactions in the skin develop as an immune system response to
an antigen, in which epithelioid macrophages and various inflammatory and
immune cells congregate, often surrounded by fibrosis or a lymphocyte cuff
► They are classified as infectious or non-infectious
► There is a poor understanding of the inciting antigen, which may range from
infectious (including live or dead microorganisms) to drugs (and/or their
metabolites), or result from innate host pathology (e.g. connective tissue
disease, vasculitis, or cancerous antigens).
► , it is important to acknowledge the proposed role for infection in the etiology
of several of these conditions that are regarded as 'non-infectious'
granulomatous disorders, such as a slow-growing infection, a post-infectious
immunologic response, or presentation of granulomatous disease in the setting
NON-INFECTIOUS GRANULOMATOUS DISORDERS ENCOMPASS
A CHALLENGING GROUP OF DISEASES BOTH IN TERMS OF
THEIR DIAGNOSIS AND IN COUNSELING PATIENTS REGARDING
IN ADDITION TO THE POSSIBLE SYSTEMIC CO-MORBIDITIES
THEY MAY SUBSEQUENTLY ENCOUNTER. AN IMPORTANT
SOURCE OF THIS CHALLENGE IS THE CLINICAL AND
HISTOLOGIC OVERLAP AMONG THESE CONDITIONS (ALONG
WITH THE POTENTIAL FOR MISDIAGNOSIS DUE TO THIS
NECROBIOSIS IS DEFINED AS THE PHYSIOLOGICAL
DEATH OF A CELL .
IT IS ASSOCIATED WITH ALTERATION OF COLLAGEN
AND OR ELASTIC FIBRES
IT IS IDENTIFIED BOTH WITH AND WITHOUT NECROSIS
IT IS ASSOCIATED WITH NECROBIOSIS
LIPOIDICA AND GRANULOMA ANNULARE
►Necrobiosis refers to the degeneration of collagen
►Although this is easily noted in most necrobiotic
dermatitides, it can be very subtle at times or even
absent depending on the necrobiotic entity and
the timing of the biopsy.
STAINS HELPHUL IN NECROBIOSIS
It is advisable to obtain three H&E levels and colloidal iron (Hale‟s
stain for mucin).
► Elastochrome (elastic trichrome) could also be helpful in
examining the vascular component of the lesion
► Special stains in granulomatous skin diseases, including
necrobiotic dermatitides, to try to visualize any possible infectious
► These stains include: periodic acid-Schiff (PAS) and Gomori
methenamine silver (GMS) for fungal organisms, Zeil-Neilson (ZN)
stain for acid-fast bacilli and Warthin-Starry silver stain for
ACCUMULATION OF BASOPHILIC
FIBERS IN DERMIS, REFERRED TO AS
1. DEGENERATIVE CHANGE IN ELASTIC TISSUE.
2. DEGENERATION OF COLLAGEN FIBERS, WITH
ALTERED STAINING PROPERTIES RESEMBLING
3-FORMATION BY FIBROBLAST-ACTIVATED
ULTRAVIOLET OR MAST CELL MEDIATORS OF
► First of all either collagen fibres split into microfibrils and
granular material, with subsequent appearance of the
► Amorphous mass is formed directly through the gradual loss
of the matrix and membrane with subsequent confluence
into future 'elastotic fibres'. At the amorphous stage, optically
denser material appears..These are acquiring elastic stain
► The elastic fibres were also often altered. When amorphous,
their smaller size was helpful in distinguishing them from
similarly altered collagen bundles.
Non-infectious granulomatous diseases of the skin are a broad group of distinct reactive
inflammatory conditions that share important similarities.
Many of these disorders have significant associations with systemic diseases that impact the
patient's overall prognosis
Ten(10) non-infectious granulomatous conditions with implications for systemic disease:
1. granuloma annulare,
2. annular elastolytic giant cell granuloma,
3. necrobiosis lipoidica,
4. methotrexate induced accelerated rheumatoid nodulosis,
5. necrobiotic xanthogranuloma,
6. interstitial granulomatous dermatitis,
7. interstitial granulomatous drug reaction,
8. palisaded neutrophilic granulomatous dermatitis,
10. metastatic Crohn disease.
BLUE VS RED COLLAGENOLYTIC
► A collagenolytic or necrobiotic non-infectious granuloma is one in which a
granulomatous infiltrate develops around a central area of altered collagen
and elastic fibers
► The altered fibers lose their distinct boundaries and exhibit new staining
patterns, becoming either more basophilic or eosinophilic.
► Within the area of altered collagen, there may be deposition of acellular
substances such as mucin (blue) or fibrin (red), or there may be neutrophils
with nuclear dust (blue), eosinophils (red), or flame figures (red).
BLUE CPLLAGENOLYTIC NECROBIOTIC
►These are the lesions of
granuloma annulare , Wegener‟s
granulomatosis, and rheumatoid
►Human macrophage metalloelastases have
been found in these lesions and may aid in
the macrophage migration to these lesions.
► The activated histiocytes can surround the
altered dermis in a palisading manner,
potentially cordoning off harmful products of
the inflammatory process such as immune
WHY ARE THEY BLUE?
► A non-infectious granuloma can be centrally basophilic either due
to mucin deposition or due to the presence of neutrophils/nuclear
► If increased interstitial mucin is responsible for the blue color, as
confirmed by either an Alcian blue or colloidal iron stain, one should
consider the diagnosis of granuloma annulare (GA).
► If the basophilia of the central zone is due to the presence of
neutrophils/nuclear dust,eitherWegener‟s granulomatosis (WG) or
rheumatoid vasculitis enters the differential.
THE „RED‟ COLLAGENOLYTIC
►The lesions of necrobiosis lipoidica,
necrobiotic xanthogranuloma, rheumatoid
nodules, Churg–Strauss syndrome, and
eosinophilic cellulitis (Well‟s syndrome).
GRANULOMAS:WHY ARE THEY RED?
► Eosinophilic staining of the necrobiotic area within a non-infectious granuloma
can be due to hyalinized collagen, fibrin deposition, or degranulated
► If the collagen is hyalinized, the differential diagnosis of necrobiosis lipoidica
(NL) vs. necrobiotic xanthogranuloma (NXG) exists.
► If the red color is due to fibrin deposition, then a rheumatoid nodule (RN) should
► If degranulated eosinophils are responsible for the color, then the lesions of
Churg– Strauss syndrome (CSS) vs. eosinophilic cellulitis (EC) (Well‟s syndrome)
should be considered.
FEATURES OF NECROBIOTIC GRANULOMAS IN THE
- Located in the superficial and mid dermis.
- Areas of necrobiosis surrounded by peripheral rim of histiocytes and
- Multinucleated giant cells (+/-)
- Intervening areas of dermis between the necrobiotic granulomas is normal.
- Central necrobiotic area contains abundant connective tissue mucins
which is lightly basophilic in apperance. Mucin stains (Colloidal iron and
alcian blue) are useful.
- Small amounts of fibrin may be present as fibrillary eosinophilic material.
- Perivascular infiltrate of lymphocytes in superficial & mid dermis.
- Neutrophils and nuclear dusts are present in some cases.
- Vasculitis may be present near foci of necrobiosis.
necrosis within a
1. GA is a benign inflammatory condition that often presents with a ring of
multiple small, erythematous or flesh-colored, firm papules on the dorsal
surface of the hands and/or feet.
2. Classified according to lesion morphology into subgroups:
• localized, macular or patch, and atypical (consisting of perforating,
subcutaneous, disseminated, palmar, photodistributed, or generalized forms).
• Lesions are generally non-pruritic and self-limited, often resolving without
treatment within 2 years, though a variety of treatments have been attempted.
• A clinically similar, non-infectious granulomatous disease is annular elastolytic
giant cell granuloma (AEGCG), which is often regarded as 'GA in sun-
► Granuloma annulare is a common form of dermatosis in children
and young adults. Lesions are typically found on the hands, the feet
and the extensor surfaces of the limbs, and occasionally on the
trunk. We report a case original in terms of its palpebral localization.
► CASE-REPORT: A 5 year-old girl consulted for papular lesions on the
eyelids. The clinical examination revealed papules on the right
lower eyelid measuring 8 mm, on the left lower eyelid measuring 5
mm and on the right upper eyelid measuring 3 mm. Laboratory tests
including serum glucose, lipids and calcium as well as a complete
blood count proved normal. Biopsy showed granulomatous lesions:
a region of central necrosis surrounded by a palisade of
inflammatory cells confirmed the diagnosis of granuloma annulare.
The lesions disappeared in a few weeks without treatment.
►Histopathologic features OF GRANULOMA ANNULARE
1. “Interstitial GA”
► -May be early changes in other types of GA
► -Lymphocytes around small vessels, histiocytes between collagen bundles
► -Interstitial mucin (Alcian blue, colloidal iron positive, pH 2.5) in areas of histiocytes
► `Differential diagnoses: Morphea, reticular erythematous mucinosis (REM), interstitial
pattern of mycosis fungoides
1. • Palisaded GA
► -Superficial and deep perivascular lymphocytic infiltrates
► -Interstitial histiocytes
► -Rings of histiocytes surrounding degenerating (and regenerating collagen) and
► -A few neutrophils and some dust around necrotic venules in the centers of
► -Elastic tissue absent from centers of granulomatous foci
► Differential diagnosis: Necrobiosis lipoidica, rheumatoid
nodule, palisaded neutrophilic and granulomatous
3-• Deep GA
► -Large oval mass of histiocytes surrounding less cellular area
► -Degenerating collagen and mucin in the center, but more brightly
eosinophlic than in conventional palisaded granuloma annulare
► Differential diagnosis: Rheumatoid nodule, phaeohyphomycotic
4-• Actinic GA
► -Palisaded histiocytes around fibrosis
► -Giant cells commonly present
► -Elastotic material in cytoplasm of giant cells
(A) Pink papules
B) and (C) Palisaded
granulomas with mucin in
D) colloidal iron stain
ANNULAR ELASTOLYTIC GIANT
CELL GRANULOMA (AEGCG)
A 'GA in sun-exposed areas
AEGCG is caused by severe degeneration of skin elastic tissues in response to
While the clinical features of AEGCG and GA are similar and these conditions are
often treated with the same approach, they are histologically distinct.
AEGCG is characterized by a central zone of dermal atrophy that lacks elastic
Additionally, AEGCG lesions do not show necrobiosis and palisading granuloma.
An association of AEGCG with malignancy, (eg T-cell leukemia).
PATCHY GRANULOMATOUS INFILTRATE IN
Gimesa statin showing consumption of
elatic tissue in reticular dermis
Hematoxylin-eosin stain (original magnification
×550) showing mild hyperkeratosis with deposition of pale
eosinophilic degenerated elastin in the dermis. Note made of
the multinucleated giant cells.
Elastin van Gieson stain
showing thinned out
epidermis and extensive
phagocytosis of elastic
fibers is also seen.
► Necrobiotic xanthogranuloma with paraproteinemia (NXG) is a rare
condition, but one that is important to recognize as it can maim patients, and
some patients have died of its complications.
► Its name refers to its infiltrates of foamy histiocytes, zones of necrobiosis
(degenerating and regenerating collagen) and frequent paraproteinemia.
Despite the paraprotein, and the rare eventuation of myeloma in patients with
NXG, it seems to be an inflammatory and not a neoplastic condition.
► Age: Middle-aged or elderly patients.
► Clinical presentation: Lesion presents as reddish, partly xanthomatous nodules or
plaques. These are usually located around the periorbital area. Other sites include
extremities & trunk.
► Frequently associated with paraproteinemia and lymphoproliferative diseases.
► • Yellow plaques on limbs, with perioccular/periorbital lesions in most patients
► • Progression of lesions in some patients
► • Hyperlipidemia/hypercholesterolemia
► • Many patients diabetic
► • Serum paraprotein (usually IgG κ)
► • Loss of limbs or eye possible .
► Paraprotein levels play an important role in the pathogenesis of NXG because
they might be autoantibodies that stimulate fibroblast proliferation and dermal
► The paraproteins cause a giant-cell inflammatory response after being
complexed with lipids and deposited in skin.
► Activated monocytes accumulate lipids and are deposited in the skin, thereby
eliciting a giant-cell foreignbody response
►Extensive areas of hyaline necrobiosis surrounded by a
palisade of histiocytes & multinucleated giant cells ;
Large numbers of necrotic inflammatory cells in the
reticular dermis ;
Superficial and deep perivascular lymphoplasmacytic
Presence of foam cells, multinucleated giant cells
(Touton & foreign body types), cholesterol clefts &
extracellular lipid ; Lymphoid follicles may be present ;
Extensive areas of fat necrosis in the subcutaneous tissue.
► • Infiltrate mid- and deep dermis, and both subcutaneous lobules and septa
► • Superficial and deep perivascular infiltrates of lymphocytes and plasma cells,
sometimes very dense
► • Lymphoid follicles
► • Palisaded foamy histiocytes surrounding homogeneous eosinophilic material
► • Foamy histiocytes and Touton giant cells in subcutis (“Touton cell panniculitis”)
► • Giant cells with scalloped margins
► • Cholesterol clefts surrounded by rings of foamy histiocytes (cholesterol
giant cells including
► Successful IVIg treatment of
paraproteinemiaassociated dermatoses, such
as scleromyxedema, has been .
► , IVIg showed a striking therapeutic effect on
NXG. Given the association of NXG with IgG-
monoclonal gammopathy (more often IgG-
than IgG-) and with multiple myeloma
VS NECROBIOSIS LIPODICA
► NXG is often mistaken for NLD, as both can present as yellow
plaques on the limbs of diabetic patients.
► Cholesterol clefts surrounded by foamy histiocytes are practically
pathognomomonic of the condition(NXG) .
► Cholesterol clefts were present in specimens of NLD in one study,
but not surrounded by foamy macrophages and Touton giant cells.
► Necrobiosis lipoidica (NL), originally known as necrobiosis lipoidica diabeticorum, is a disorder of
collagen degeneration with a granulomatous response and thickening of blood vessels.
Diabetes mellitus is present in more than half the patients with necrobiosis lipoidica.
► Age & sex: Average age of onset is 30 years (may occur at any age) and females are commonly
► Site: Most cases are located on the leg specially above the tibiae, but may also occur on the face,
scalp, forearm and trunk.
► Clinical presentation: Lesions may be single but multiple lesions are more common. NL may present as
red papules which may enlarge to form patches or plaques with an atrophic yellowish-brown and
slightly depressed center.
The lesions may resolve spontaneously or become persistent chronic lesions which may ulcerate.
► • Most lesions bilaterally on shins
► • Early lesions are red papules with sharp borders
► • Later, yellow, hard atrophic plaques
► • 60% have frank diabetes, another 20% abnormal glucose tolerance o
► Necrobiotic granuloma and inflammatory infiltrate:
► Full thickness of the dermis is involved with extension into the subcutis.
► The inflammatory cells are composed of histiocytes, lymphocytes, plasma cells and occasional eosinophils are arranged in two or three tiers. These are aligned parallel to the skin
► There are several layers of necrobiosis within the reticular dermis. Necrobiotic areas are rimmed by histiocytes and multinucleate Langhans or foreign body giant cells.
► The necrobiosis is irregular and less complete than in granuloma annulare.
► ( Note: Palisaded granuloma in necrobiosis lipoidica- Early lesions show prominent collagen degeneration. Late lesions show crowded and thickened collagen bundles. )
► The intervening areas of the dermis are also abnormal.
Lymphoid cell aggregates with germinal centers may be present.
► Abnormalities present in the reticular dermis are also present in the septa of the subcutaneous tissue (septal panniculitis with granulomatous inflammation).
► Vascular changes:
► Vascular changes are more prominent in diabetic patients.
► Superficial and deep perivascular inflammatory infiltrate.
► Plasma cells are conspicuous.
► Superficiall vessels are telangiectatic & increased in number.
► Deeper vessels may show endothelial swelling.
► Lymphocytic vasculitis may be present.
► Epithelioid granulomas within or adjacent to the vessel wall.
► Other features:
Intradermal nerves are reduced in number.
► Old and atrophic lesions show dermal fibrosis and thickened septa of the subcutaneous fat .
► Lipid in the upper part of the dermis can be demonstrated by Sudan black and oil red O stain.
► Stains for mucin (colloidal iron or alcian blue) are usually negative.
PALISADED NEUTROPHILIC AND
GRANULOMATOUS DERMATITIS (PNGD
► A disease spectrum described in patients with systemic diseases of various kinds.
► Terms such as rheumatoid papules, Churg-Strauss granuloma, extravascular necrotizing granuloma and
Winkelmann granuloma also refer to this condition.
► The main clinical presentation is of small, umbilicated papules on the dorsal aspects of joints, esp. those of
the fingers, elbows and knees.
► The range of systemic diseases in patients with PNGD includes patients with:
► Systemic lupus erythematosus
► Rheumatoid arthritis (incl. seronegative cases)
► Wegener‟s granulomatosis
► Inflammatory bowel disease
PALISADED NEUTROPHILIC AND
► The salient histopathologic features differ for each stage of PNGD:
► Fibrin around vessel walls
► Neutrophils and abundant nuclear debris around vessels around fibrin
► Fully developed:
► Palisaded histiocytes around neutrophils and their debris
► Thick, but discolored collagen bundles
► Evidence of vasculitis, sometimes
► Palisaded histiocytes around zones of fibrosis with few neutrophils
► No vasculitis
► Early lesions have increased dermal spindle cells
► Increased mucin with thin elastic fibres
► Later lesions have more epithelioid or stellate cells that may extend into
septa in subcutaneous fat
► Thick collagen bundles
► The spindle cells are fibrocytes that are positive immunohistochemically with
both CD34 and mprocollagen
EARLY PALISADED NEUTROPHILIC AND GRANULOMATOUS
DERMATITIS. THERE IS A PALISADE OF HISTIOCYTES AROUND
CENTRAL FOCUS OF NECROTIC COLLAGEN.
Late palisaded neutrophilic and granulomatous
dermatitis/interstitial granulomatous dermatitis wit arthritis. The
central necrosis has disappeared to leave a diffuse granulomatous
dermatitis. In contrast to granuloma annulare, there are neutrophils,
no collections of mucin and the process is diffuse.
► large interstitial histiocytes, and a more subtle palisaded pattern. It
presents with dusky erythema in flexural areas. There are small foci
in which degenerated neutrophils and/or eosinophils are present
► Palisaded foci surrounding degenerated neutrophils and eosinophils
are not yet reported, but histiocytes form rosettes that surround and
adhere to thick collagen bundles, demarcated from the rest of the
dermis by clefts.
REACTIONS TO FOREIGN MATERIAL
►Histiocytes can be radially arranged around
a variety of foreign substances, including
suture material, beryllium, and injectable
►The mechanism by which the dermis is
altered in some of these reactions is
► Clinical features
► • Symmetrical papules and nodules
► • Usually subcutaneous, sometimes fixed to tendons
► • Skin color unchanged, sometimes yellow (simulating xanthomas)
► • Extensive disease with joint destruction (rheumatoid nodulosis)
► Histopathologic features
► • Large oval mass in deep dermis/subcutis
► • Palisaded histiocytes surrounding degenerated collagen, large amounts of fibrin, neutrophils
and nuclear dust
► • Mucin scant or absent
► • Vasculitis in adjacent vessels rarely .
► The vast majority of diagnoses of RN in well children are misdiagnoses of deep
Granulomatous ulceration of the mucous membranes that includes chronic sinusitis, nasal crusting, and
► Gingivitis called „strawberry gums‟,
► Accompanied by a slow loss of nasal cartilage leading to the „saddle nose‟ deformity.
► A fulminant process with acute respiratory symptoms, often with alveolar hemorrhage
► Cardiac involvement with necrotizing coronary vasculitis and pancarditis
► Constitutional symptoms including fever, weight loss, anorexia, and arthralgia, as well as cough .
► The most common cutaneousWGlesions are clinically
1. papulonecrotic lesions or palpable purpura,
2. usually on the extremities.
3. Less common lesions include vesicles, petechiae, subcutaneous nodules, and frank ulcerations with
thrombosis and necrosis.
► An acneiform presentation has been reported in children.chest and pain.
HISTOPATHOLOGIC PATTERNS OF
►The most common histologic pattern seen within WG
lesions of the skin is that of a necrotizing vasculitis
►Palisading necrotizing granuloma :Focal necrobiosis
with peripheral palisading,
►Granulomatous vasculitis, No mucin/fibrin
►Lymphomatoid granulomatosis-like pattern:vasculitis
infiltrated with atypical lymphocytes, but not true
granuloma due to
► It has three distinct phases. The first clinical phase of CSS is the prodromal or allergic
► phase,:asthma, which may or not be preceded by allergic rhinitis. Nasal obstruction,
recurrent sinusitis, and nasal polyposis frequently develop.
► The second clinical phase of CSS features marked peripheral eosinophilia and
eosinophilic infiltrates of the respiratory and intestinal tracts (eosinophilic
gastroenteritis.):Abdominal pain is common and may reflect bowel perforation,
peritonitis, intestinal obstruction, mesenteric vasculitis, or cholecystitis
► The third phase of CSS development can include a neuropathy
► skin lesion(Churg–Strauss granuloma)::a papule or subcutaneous nodule:erythematous
orviolacious, and are often symmetrically distributed.
► They are persistent and tender, often become crusted or ulcerated, and resolve with
scarring within 2–3months. These lesions usually occur on the extremitiesand scalp, and
less commonly on the trunk, with the most common sites located over pressure points,
especially the elbows, fingers, and thumbs.
► The palisading Churg–Strauss granuloma consists of leukocytoclastic vasculitis
and degeneration of the surrounding collagen, with an extravascular
palisading granulomatous reaction, consisting of mononuclear cells,
macrophages, and eosinophils around the necrobiotic collagen
► The degenerated collagen becomes admixed with polymorphonuclear
leukocytes and leukocytoclastic debris
► The palisading granulomatous infiltrate probably develops due to an influx of
eosinophils which degranulate and develop pyknotic, fragmented nuclei.
► fibrinoid swelling and increased degeneration of the collagen fibers, with the
eventual destruction of the fibers.
► Macrophages infiltrate the area, palisading around the central necrotic core,
and Langhans or foreign body-type giant cells appear
EOSINOPHILIC CELLULITIS (WELL‟S
► Patients can become febrile and develop peripheral eosinophilia
► typically erupts suddenly as single or multiple edematous, erythematous, well-defined
annular plaques on a limb that often initially appear urticarial
► lesions include papules, vesicles, poorly demarcated erythematous plaques, or nodules.
► The subsequent edema may become so severe as to generate bullae. Although the affected
area clinically resembles a bacterial cellulitis, the skin is cool to the touch
► As the acute edema and erythema subsides, the affected area becomes indurated and
acquires a bluish or greenish gray color, clinically resembling morphea
► The cause: a hypersensitivity reaction to some triggering event including insect bites, fungal
infections, herpes simplex virus flares,,underlying hematologic disorders, ,oxocara canis
infections, or drug hypersensitivities
► The biopsy of a newly developing EC lesion shows a papillary
dermis that is markedly edematous with overlying spongiosis and
intraepidermal spongiotic vesicles.
► The dermis is heavily infiltrated with eosinophils
► As the lesion develops, eosinophils degranulate and then
degenerate. Fragments of the degenerated eosinophils and their
expelled granules are deposited onto the surrounding collagen
fibers, producing „flame figures‟
► Older lesions show a granulomatous infiltrate comprised of large
histiocytes and giant cells that surround the flame figures
EARLY PHASES OF
LATE PHASE OF