Skin nontumor

Dermal collagen and elastic tissue alterations, and cutaneous deposits

Scleroderma

Authors: Juanita Duran, M.D., Jose A. Plaza, M.D.

Resident / Fellow Advisory Board: Caroline I.M. Underwood, M.D.

Minor changes: 23 September 2021

Copyright: 2002-2021, PathologyOutlines.com, Inc.

PubMed Search: Scleroderma pathology [TI]

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Table of Contents

Cite this page: Duran J, Plaza JA. Scleroderma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/skinnontumorscleroderma.html. Accessed December 3rd, 2021.

Definition / general

Rare autoimmune fibrosing entity subtyped based on clinical presentation (Clin Dermatol 2013;31:432, Annu Rev Pathol 2011;6:509)

Essential features

Dysregulation of collagen synthesis and degradation (Annu Rev Pathol 2011;6:509)
Vascular and immune dysfunction causes organ damaging fibrosis
Divided into subsets (J Eur Acad Dermatol Venereol 2017;31:1401, Clin Dermatol 2013;31:432, Lancet 2017;390:1685)
- Localized scleroderma (morphea: limited / circumscribed, generalized, linear, deep and mixed types)
- Systemic sclerosis:
  - Limited cutaneous systemic sclerosis
  - Diffuse cutaneous systemic sclerosis
  - Systemic sclerosis sine scleroderma

Terminology

Systemic sclerosis
Localized scleroderma / morphea

ICD coding

ICD-10:
- L94.0 - localized scleroderma (morphea)
- M34 - systemic sclerosis (scleroderma)
- M34.0 - progressive systemic sclerosis
- M34.1 - CREST syndrome
- M34.2 - systemic sclerosis induced by drug and chemical
- M34.8 - other forms of systemic sclerosis
- M34.81 - systemic sclerosis with lung involvement
- M34.82 - systemic sclerosis with myopathy
- M34.83 - systemic sclerosis with polyneuropathy
- M34.89 - other systemic sclerosis
- M34.9 - systemic sclerosis, unspecified

Epidemiology

Localized scleroderma
- Incidence 0.4 - 2.7 cases per 100,000 persons (J Rheumatol 1997;24:73, Rheum Dis Clin North Am 2002;28:603)
- F:M = 2.6 - 6:1, except in linear morphea (no sex predominance) (Br J Rheumatol 1988;27:286)
Systemic sclerosis
- Incidence: 0.3 - 2.8 per 100,000 per year (J Eur Acad Dermatol Venereol 2017;31:1401)
- African Americans > Caucasians (G Ital Dermatol Venereol 2018;153:208)
- F:M = 3:1 (J Eur Acad Dermatol Venereol 2017;31:1401)
- Positive family history increases the relative risk twelvefold (J Eur Acad Dermatol Venereol 2017;31:1401)
- Higher severity has been suggested in African American women (G Ital Dermatol Venereol 2018;153:208)
Scleroderma affects children and adolescents (Pediatr Clin North Am 2018;65:757)
- ~33% of cases of localized scleroderma begin in childhood, in contrast with < 10% of systemic sclerosis cases (Pediatr Clin North Am 2018;65:757, J Rheumatol 1997;24:73, J Rheumatol 2006;33:1004, Clin Rheumatol 2007;26:1259)

Sites

Localized scleroderma
- Skin, subcutaneous tissue, underlying muscle and bone
- When present on the face, head and underlying central nervous system may rarely be involved (J Am Acad Dermatol 2011;64:217)
Systemic sclerosis
- Skin and internal organs (heterogeneous presentation) (J Eur Acad Dermatol Venereol 2017;31:1401)
  - Limited cutaneous systemic sclerosis
    - Face and distal to elbows and knees
    - Internal organ involvement in later stages
  - Diffuse cutaneous systemic sclerosis
    - Face, trunk, proximal and distal extremities

Pathophysiology

Not completely understood (Clin Dermatol 2013;31:432)
Hypothesis: genetic predisposition followed by exogenous stimulus triggering an inflammatory cascade and fibrosis (Clin Dermatol 2013;31:432)
Pathogenesis involves abnormalities in vascular and immune systems, leading to organ fibrosis (Annu Rev Pathol 2011;6:509)

Etiology

Postulated etiologic stimuli (J Am Acad Dermatol 2011;64:217):
- Lyme disease
- Trauma
- Radiation (most frequently described)
- Medications (bleomycin, pentazocine and cocaine)
- Viral infections (cytomegalovirus and parvovirus B19)
- Occupational and industrial exposures (vinyl chloride, silica dust and organic solvents)
- Gadolinium based contrast agents

Diagrams / tables

Images hosted on other servers:

Localized scleroderma

Clinical features

Localized scleroderma: see Diagrams / tables (J Eur Acad Dermatol Venereol 2017;31:1401)
Systemic sclerosis
- Skin (J Eur Acad Dermatol Venereol 2017;31:1401)
  - Raynaud phenomenon: > 90% of patients
    - Typically affects hands, less commonly feet; it may also involve ears, nose and tongue
  - Onset: edema of fingers and hands
  - Sclerotic changes cause dermatogenic contractures, sclerodactili, perioral plications, microstomia and mask-like facial stiffness
  - With or without hair loss, decreased sweating, hyperpigmentation / hypopigmentation / depigmentation and pruritus
  - Digital ulcers
  - Calcinosis cutis
  - Late stage: diminished skin fibrosis of trunk and proximal extremities
- Musculoskeletal (J Eur Acad Dermatol Venereol 2017;31:1401)
  - Arthralgia
  - Musculoskeletal pain
  - Muscle weakness
  - Overlap syndromes (myositis and rheumatoid arthritis)
- Pulmonary (J Eur Acad Dermatol Venereol 2017;31:1401)
  - Interstitial lung disease (65%)
  - Pulmonary arterial hypertension (15%)
- Gastrointestinal manifestations
  - Involvement of esophagus (80%), stomach (40 - 70%) and small and large intestine
  - Upper gastrointestinal involvement in nearly all patients in longstanding disease
- Cardiovascular (J Eur Acad Dermatol Venereol 2017;31:1401)
  - Myocardial fibrosis, manifestations depend on severity and extension
- Renal (J Eur Acad Dermatol Venereol 2017;31:1401)
  - Slowly progressive obliterative vasculopathy
  - Scleroderma renal crisis (malignant hypertension and oligo / anuric acute renal failure) - rare but severe

Diagnosis

Localized scleroderma
- Routine systemic workup is not recommended
- Clinical presentation
  - Physical examination
  - Localized scleroderma cutaneous assessment tool (LoSCAT) (Rheumatology (Oxford) 2010;49:373)
- Histopathology - not possible to differentiate between localized scleroderma or localized scleroderma subtypes
  - Biopsy sufficiently deep
  - Only if the clinical presentation is inconclusive
- Laboratory
  - Blood differential and chemistry
  - Creatine kinase (suspected myositis)
  - Autoantibodies may be present but their routine screening is not recommended
- Imaging
  - Brain MRI and head CT (i.e. en coup de sabre or progressive facial hemiatrophy):
    - Detect muscle, joint or bone involvement
    - Detect potential subcortical calcifications or brain atrophy
    - Surgical planning
Systemic sclerosis
- Clinical presentation
  - Physical examination
  - Capillaroscopy
  - Modified Rodnan skin score (mRSS)
- Histopathology - not possible to differentiate between localized scleroderma and systemic sclerosis or localized scleroderma subtypes
  - Biopsy sufficiently deep
- Laboratory
  - Blood differential and chemistry
    - Creatine kinase (suspected myositis)
- Autoantibodies
  - Antinuclear antibody (ANA) (95%)
  - Systemic sclerosis specific antibodies
    - Centromere
    - Topoisomerase 1
    - RNA polymerase III
    - Exosomal ribonucleoprotein (PM / Sd)
  - Systemic sclerosis associated antibodies
    - Extractable nuclear antigens (Ro / La)
    - Cyclic citrullinated peptide (CCP)
    - Rheumatoid factor (Fc portion of IgG)
    - Mitochondrial Ag M2
  - Organ oriented diagnostic workup
    - Laboratory
    - Imaging

Radiology images

Images hosted on other servers:

13 year old boy with juvenile systemic scleroderma

Calcifications

Calcinosis cutis in a 15 year old boy

Whole body MRI in a juvenile with scleromyositis

Prognostic factors

Localized scleroderma
- 25% of patients experience reactivation of disease after resolution (Br J Dermatol 2015;172:722)
  - Factors associated with reactivation:
    - Early age of onset of disease (Br J Dermatol 2015;172:722)
    - Subtype of localized scleroderma
  - Skin and soft tissue atrophy, contractures (may affect functionality)
Systemic sclerosis
- Chronic and unpredictable course
- Quality of life and psychosocial well being are often affected
- Multidisciplinary care is required due to involvement of several organs

Case reports

22 year old woman, gravida 1 para 0, at 7 months gestation complaining of skin thickening on the breasts (Dermatol Online J 2017;23:13030)
28 year old woman with myasthenia gravis who developed linear scleroderma 7 years after diagnosis (J Dermatol 2000;27:31)
44 year old woman status postlumpectomy and chemoradiation with skin erythema, sclerosis and contracture of her right breast 15 months after completion of treatment (Histopathology 2018;72:342)

Treatment

Localized scleroderma
- Systemic therapy
  - Systemic corticosteroids
  - Methotrexate
  - Mycophenolate mofetil
  - Others systemic medications
- Phototherapy
- Physical therapy
- Surgical interventions
Systemic sclerosis
- Organ based approach (determine organ involvement and disease activity)
Reference: J Eur Acad Dermatol Venereol 2017;31:1401

Clinical images

Contributed by Cristian Rocha, M.D.

En coup de sabre

Generalized localized scleroderma / morphea

Microscopic (histologic) description

Localized scleroderma and systemic sclerosis have indistinct histologic features (J Eur Acad Dermatol Venereol 2017;31:1401)
Early disease (J Eur Acad Dermatol Venereol 2017;31:1401)
- Thickened collagen bundles within papillary and reticular dermis
- Dense perivascular and periadnexal inflammatory infiltrate, as well as between collagen bundles and limit of dermis and subcutis
- Inflammatory infiltrate: predominantly lymphocytes; plasma cells, histocytes and eosinophils are also seen
- Overlying epidermis may be unaffected or atrophic
Late / fibrotic stage (J Eur Acad Dermatol Venereol 2017;31:1401)
- Relatively avascular skin
- Adnexal structures are atrophic or absent
- Minimal inflammation
- Highly packed, eosinophilic collagen bundles

Microscopic (histologic) images

Contributed by Jose A. Plaza, M.D., Mark R. Wick, M.D. and Joel Pinczewski, M.D., Ph.D.

Early scleroderma lesion

Breast skin, morphea

Late stage morphea lesion

Sample pathology report

Skin, trunk, biopsy:
- Scleroderma (see comment)
- Comment: Sections show a punch biopsy with squared silhouette and thickened dermal collagen. Adnexal structures are atrophic and entrapped within the collagenous stroma. There is dense perivascular and periadnexal lymphoplasmacytic infiltrate, as well as between collagen bundles and at the dermal subcutis junction. Altogether, these findings are consistent with scleroderma. Clinical correlation is advised for subclassification.

Differential diagnosis

Scleredema:
- Hypertrophied collagen bundles with intervening mucin
- No inflammatory infiltrate
Radiation dermatitis:
- Skin changes in clinical examination
- Radiation induced changes (atypia, elastosis and superficial capillary ectasia)
Lichen sclerosus el atrophicus:
- Sclerosis limited to papillary dermis
- Vacuolar change in basal cells
- Edema of superficial dermis
Keloid:
- Raised lesion
- Dense and thickened dermal collagen bundles
- Markedly eosinophilic, hyalinized (bubble gum) collagen bundles
- Decreased dermal vascularity, with occasional ectatic vessels
Hypertrophic scar:
- Raised lesion
- Dense and thickened dermal collagen bundles
- Lacks hyalinized collagen bundles
- Perpendicularly oriented vessels

Board review style question #1

What histopathologic characteristic helps to differentiate between localized and systemic sclerosis?

Edema of superficial dermis
Fibrosis limited to papillary dermis
Histological features are indistinct
Perivascular inflammation

Board review style answer #1

C. Histological features are indistinct. Localized scleroderma and systemic sclerosis have indistinct histologic findings and require clinical correlation for their classification and subclassification.

Comment Here

Reference: Scleroderma

Board review style question #2

Systemic sclerosis may involve, in addition to skin and soft tissue, which of the following organs?

Heart
Heart and lung
Heart, lung and kidney
Heart, lung, kidney and gastrointestinal system

Board review style answer #2

D. Heart, lung, kidney and gastrointestinal system. Systemic sclerosis may involve a variety of organ systems including the integumentary, cardiopulmonary, renal and gastrointestinal.

Comment Here

Reference: Scleroderma