LC07-1_Alvaro C. Laga

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Connective tissue diseases with emphasis in uncommon histopathologic
manifestations
Alvaro C. Laga MD, MMsc
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 75
Francis St. Boston, MA USA
E-mail: [email protected]
Definition
Connective tissue diseases, also known as collagen vascular diseases or disorders, are a
heterogeneous group of syndromes with a common basic pathogenic mechanism:
autoimmunity. Examples of connective tissue disorders include systemic lupus
erythematosus, dermatomyositis, systemic sclerosis and localized scleroderma, lichen
sclerosus, rheumatoid arthritis and Sjogren’s syndrome. Systemic lupus erythematosus
(SLE) is the prototypic autoimmune disease, and one of the most common autoimmune
disorders with a diverse array of clinical, serologic and histopathologic manifestations
[1]. Given the relative frequency of biopsies for SLE and the varied histologic
presentations, SLE will be used to exemplify the cardinal manifestations of connective
tissue disease and uncommon histologic presentations that should –but rarely do- alert the
pathologist to the possibility of connective tissue disease will be presented.
Epidemiology
The reported prevalence of connective tissue diseases is difficult to estimate and
considered to vary considerably depending on the study, country, and criteria used to
define specific entities. Sjogren’s syndrome has the highest prevalence ranging between
0.5 and 3% of a given population. The prevalence of systemic lupus erythematosus is
estimated between 15 and 50 per 100,000 individuals, with a male to female ratio of 1:610. The prevalence of systemic sclerosis is lower and shows the greatest variation
between studies and countries. Overlap syndromes, particularly mixed connective tissue
disease, has an unknown prevalence. Dermatomyositis and polymyositis are regarded as
very rare rheumatic disorders [2].
Clinical features
Three major subtypes of lupus erythematosus (LE) are included in the nosologic concept
of the disease: systemic or acute cutaneous LE, subacute cutaneous LE (SCLE) and
chronic cutaneous LE, also known as discoid lupus erythematosus (DLE).
Systemic lupus erythematosus is a chronic relapsing, remitting disease that occurs in
women of child-bearing age in more than 90% of cases. The classic presentation is a triad
of fever, joint pain, and rash. In childhood, signs and symptoms such as malar rash,
ulcers, nephritis, seizures, thrombocytopenia, hemolytic anemia, fever and
lymphadenopathy are more common than in adults. Conversely, Raynaud’s phenomenon,
pleuritis and sicca are twice as common in adults compared to children and adolescents
[3]. Patients may present with any of the following:
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Constitutional (fatigue, fever, weight loss)
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Musculoskeletal (joint pain, arthropathy, muscle pain, avascular necrosis)
Dermatologic (malar rash, photosensitivity, discoid lesions)
Renal (acute or chronic renal failure, nephritic syndrome)
Neuropsychiatric (seizures, psychosis)
Pulmonary (pleurisy, pleural effusion, pneumonitis, pulmonary hypertension,
interstitial lung disease)
Gastrointestinal (nausea, abdominal pain, dyspepsia)
Cardiac (pericarditis, myocarditis)
Hematologic (leukopenia, anemia, thrombocytopenia) [3]
Discoid lupus (DLE). Perhaps the most common form of LE, is most frequently confined
to the skin except for 1% (localized form) to 5% (generalized form) in which it may be
associated with systemic disease. The typical lesion is an erythematous, scaly plaque,
which eventually develops scarring and sometimes ulceration. In patients with SLE,
discoid lesions are estimated to develop in approximately 20% of individuals. Discoid
lesions frequently occur in sun-exposed areas and a history of photosensitivity may be
elicited. The head and neck (scalp, ears, bridge of nose) are most commonly affected
(termed localized form), but the arms, hands and trunk may be involved (called
generalized form). Oral involvement is observed in up to a quarter of patients with DLE.
Subacute cutaneus lupus erythematosus. This subtype accounts for approximately 5-10%
of patients with LE and predominates in Caucasians over Blacks and Asians.
Approximately half of the patients with SCLE meet criteria for SLE as defined by the
American College of Rheumatologists ( ACR). The prototypical eruption consists of
symmetrical, non indurated, non scarring erythematosquamous lesions. The absence of
induration has been deemed a useful clinical feature to distinguish it from DLE.
Systemic lupus erythematosus (SLE). In addition to the variable cutaneous manifestations,
virtually any organ or system may be involved. The criteria developed by the ACR may
be helpful in establishing the diagnosis (four or more of eleven criteria must be met), but
-importantly- these criteria were developed to distinguish SLE from other autoimmune
conditions for clinical trials rather than to arrive at a diagnosis in individual patients.
Consequently, some patients with SLE will not meet criteria as defined by the ACR,
particularly early in the disease and in so-called overlap syndromes. Cutaneous
involvement occurs in the majority of patients with SLE (up to 90%). Lesions are
polymorphic and may mimic other dermatoses [1,3,4].
Uncommon clinical manifestations of lupus.
Few dermatopathology textbooks contemplate cutaneous involvement by SLE in the
differential diagnosis of non-bullous neutrophilic dermatoses. Neutrophilic infiltrates of
skin are well documented in bullous dermatosis and leukocytoclastic vasculitis associated
with SLE. More recently, there is a growing body of literature documenting neutrophilic
infiltrates of skin in SLE, and it may be the presenting symptom in up to a third (32%) of
cases according to a recent review.
The typical presentation consists of multiple erythematous or violaceous papules or
plaques on the extremities. Lesions may be described as annular or photo-distributed, and
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in most patients the clinical differential diagnosis includes SLE with vasculitis as the
main differential. The trunk and head and neck may also be affected, in descending order
of frequency. Patients with hydralazine induced lupus and neonatal lupus may also
develop or present with neutrophilic dermatoses [5-8].
Histopathology
Histopathology per se is not an optimal method to sub-classify patients with LE into the
subtypes mentioned above. In fact, there is poor correlation between histopathology and
clinical phenotype for the described categories (SLE, SCLE, and DLE).
With the exception of lupus erythematosus profundus and bullous dermatosis of LE, the
histopathologic changes of the various subsets of LE show considerable overlap such that
distinction by microscopic techniques is often difficult. Accurate diagnosis requires
careful correlation of clinical phenotype, serologic, and histopathologic and
immunofluorescence findings when available [1,4].
Chronic cutaneous (discoid) lupus erythematosus. An active lesion is characterized by
hyperkeratosis, follicular dilatation and keratin plugging with focal parakeratosis. The
epidermis frequently appears atrophic and shows vacuolar interface alteration. Basement
membrane thickening is usually evident and may be highlighted by the PAS reaction.
These changes may also be seen involving follicular epithelium. Abundant colloid bodies
and pigment incontinence are common. The presence of conspicuous perivascular and
periadnexal inflammatory infiltrates of lymphocytes and histiocytes is characteristic.
Deposition of so-called dermal mucin (glycosaminoglycans or acid
mucopolysaccharides) in the dermis is common in acute lesions. Healing lesions of DLE
may show hyperkeratosis and slightly acanthotic epidermis. The basement membrane
shows marked thickening and the dermis is fibrotic or sclerotic. Mucous membrane
lesions may be difficult to discern from lichen planus [1].
Subacute cutaneous lupus erythematosus. A prototypical biopsy of SCLE shows mild
hyperkeratosis and marked epidermal atrophy with effacement of the rete ridges. There
may be parakeratosis and there is only minimal -if any- basement membrane thickening.
Hair follicles are often unaffected or show only mild keratin plugging. There may be
prominent lymphocyte exocytosis with conspicuous apoptotic keratinocytes. Colloid
body formation and pigment incontinence are frequently inconspicuous. Indistinguishable
histologic changes may be seen in patients with Sjogren's syndrome and rheumatoid
arthritis [1].
Systemic or acute cutaneous lupus erythematosus. Changes in early lesions may be very
subtle. A biopsy of the characteristic malar rash often shows slight vacuolar interface
alteration, papillary dermal edema, and mild lymphocytic inflammation. Mucin
deposition between dermal collagen bundles is subtle in most cases. The histopathologic
changes of SLE are often indistinguishable from DLE and on occasion may be similar to
those of SCLE (see below) [1].
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Uncommon histopathologic manifestations
Neutrophilic dermatosis associated with lupus. Neutrophilic infiltrates of skin in patients
with SLE may be pauci-cellular or cell rich and indistinguishable from Sweet syndrome.
Moderately cellular variants that fall in-between the above described categories have also
been described. The paucicellular variant of SLE-associated neutrophilic dermatosis is
characterized by a mildly cellular neutrophilic infiltrate with abundant karyorrhexis in the
papillary dermis and superficial reticular dermis. Although red-cell extravasation may be
seen in paucicellular lesions, they may be distinguished from SLE-associated
leukocytoclastic vasculitis by the absence of fibrinoid necrosis; most cases of SLEassociated neutrophilic dermatosis reported in the literature had vasculitis as exclusion
criteria. Papillary microabscesses indistinguishable from those of bullous LE or
dermatitis herpetiformis may be observed. Vacuolar interface alteration has been
documented in approximately half of the patients described in the literature and dermal
mucin may be present rarely. Cellular lesions show a conspicuous neutrophilic infiltrate
centered in the dermis with abundant karyorrhectic debris.
A subtle neutrophilic infiltrate with karyorrhexis (as observed in paucicelluar SLEassociated neutrophilic dermatosis) has been described in Still's disease. Still's disease is
a rare autoimmune condition characterized by arthritis or arthralgias, fever, leukocytosis,
neutrophilia and a characteristic rash. Of interest, the histologic descriptions of the
characteristic (salmon-colored, evanescent) eruption of Still's disease are difficult to find
in standard dermatopathology texts and contradictory. A recent case series (14 biopsies
from 10 patients) documented a spectrum of histopathologic changes with predominantly
lymphocytic perivascular infiltrates in 6 patients, mixed lymphoid and neutrophilic
infiltrates in 4 patients, and predominantly neutrophilic in the remaining 4 patients. While
these study suggests that the findings in biopsies of the evanescent rash of Still's disease
are nonspecific, a distinctive variant also exists and is characterized by prominent
epidermal apoptosis, especially involving the upper layers [5-8].
Special studies
Direct immunofluorescence on fresh tissue may be performed to search for
immunoglobulin and complement deposition at the dermal-epidermal junction. IgM is
most commonly identified, and IgG, IgA and C3 are also frequently present in a so-called
"full-house" pattern (meaning all immunoreactants present). IgG deposits appear to be
most specific for lupus erythematosus. Deposits are usually homogeneous, granular and
thready patterns have also been described. Homogenous bands are associated with
chronic lesions while granular deposits may be observed in normal skin. The thready
pattern has been described in early, active lesions. This is called the lupus band test and is
positive in involved skin in 50-90% of patients with SLE and 60-80% of those with DLE.
The test can also be performed on uninvolved skin, with sun-exposed skin showing
positivity i 60-70% of cases. Normal individuals will have a positive lupus band test 20%
of the time, making non sun-exposed skin the ideal substrate if non lesional skin is to be
tested [1].
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Etiology
Autoimmunity refers to the production of antibodies to self antigens and tissues
(autoantibodies) and is thought to be mediated by disregulation of self tolerance. The two
main factors thought to play a central role in the development of autoimmunity are the
inheritance of susceptibility genes (eg, HLA) and environmental triggers such as
infection [1,2].
References
1. Luzar B, Calonje E. Idiopathic Connective Tissue Diseases. In: McKee's
Pathology of the Skin. Calonje, Brenn, Lazar, McKee eds. 2013 Elsevier.
2. Gaubitz M. Epidemiology of connective tissue disorders. Rheumatology
2006;45:3-4.
3. Uva L, Miguel D, Pinheiro C. et al. Cutaneous Manifestations of Systemic Lupus
Erythematosus. Autoimmune Diseases 2012; Article ID 834291.
4. Bertsias GK, Pamfil C, Fanouriakis A, Boumpas DT. Diagnostic criteria for
systemic lupus erythematosus: has the time come? Nat. Rev. Rheumatol 9, 687694.
5. Saeb-Lima M, Charli-Joseph Y, Rodriguez-Acosta ED, Dominguez-Cherit J.
Autoimmunity-Related Neutrophilic Dermatosis: A Newly Described Entity That
is Not Exclusive of Systemic Lupus Erythematosus. Am J Dermatopathol
2013;35:655-660.
6. Larson AR, Granter SR. Systemic Lupus Erythematosus-associated Neutrophilic
Dermatosis: A Review and Update. Adv Anat Pathol 2014; 21:248-253.
7. Larson AR, Granter SR. Systemic lupus erythematosus-associated neutrophilic
dermatosis-an underrecognized neutrophilic dermatosis in patients with systemic
lupus erythematosus. Human Pathology (2014) 45, 598-605.
8. Larson AR, Granter SR. The Spectrum of Histopathologic Findings in Cutaneous
Lesions in Patient's with Still's Disease. [under review].

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