—  SHORT COURSE  —

INFLAMMATORY DISORDERS OF THE SKIN AND SUBCUTIS:
A PRACTICAL AND ANALYTICAL APPROACH



CASE #10: MORPHEA

Cynthia M. Magro, M.D., A.Neil Crowson, M.D., and Martin C. Mihm Jr., M.D.




Introduction/Pathogenesis
Morphea is the most common form of scleroderma. It usually presents as one or several indurated plaques on the trunk or extremities, often with an ivory center and a lilac-colored border. Clinical subtypes include guttate, segmental, generalized, subcutaneous, keloidal and bullous forms; in some patients more than one type is present at the same time. The guttate form, which manifests as small, pale, indurated papules on the upper trunk resembling lichen sclerosis, is often associated with large plaque-like lesions. The more rare generalized form, seen mainly in children, is often associated with symmetrical large plaques on trunk and extremities, sometimes associated with atrophy and fibrosis of the soft tissues and underlying bony ankylosis which can lead to limb growth retardation. Subcutaneous morphea (morphea profunda) comprises one or more ill-defined deep sclerotic plaques with slow but relentless progression. Linear lesions of morphea, which are seen on both the extremities and face (the so-called "coup de sabre") comprise generally unilateral segmental lesions associated with dermal atrophy, and in some patients, with facial hemi-atrophy (so-called Perry-Romberg syndrome). Clinically, morphea may be mimicked clinically by the injection sites of pentazocine and vitamin K, the sites of radiation ports, such as for breast carcinoma, and, as regards to the guttate variant of morphea, lesions of lichen sclerosus. Finally, the atrophoderma of Pasini and Pierini closely mimics morphea and may be a form of morphea. Papular mucinosos/lichen myxedematosus has been recently reported as a cardinal manifestation of patients with systemic scleroderma.

Histopathology
The skin biopsy findings in morphea depend upon the age of the lesion biopsied. In its earliest phase, lesions of morphea may be highly inflammatory with a perivascular, interstitial, eccrinotrophic and perineural array of lymphocytes and plasma cells associated with abundant mesenchymal mucin deposition between collagen bundles.


Morphea
Morphea

This process most frequently begins in the reticular dermis, where the fibrosing reaction may be first appreciated close to the dermal subcutaneous interface. That initial fibrosing reaction comprises fine wavy collagen fibers beside and parallel to the native collagen bundles of the reticular dermis. Ultimately, the collagen bundles become thickened and the interfascicular spaces become narrowed. At this point, lesions are generally pauci-inflammatory; the fibrosing reaction obstructs both the excretion of eccrine products to the surface of the skin and the lymphatic and venous return. Thus, blood vessels become ectatic in the superficial dermis and the eccrine coil becomes dilated; ultimately this progresses to complete effacement of adnexal structures. Immunophenotypically, the dominant lymphoid infiltrate is of T-cell derivation. Eosinophils may be seen in some lesions, particularly those associated with drug injection or ingestion. Plasma cells in apposition to perineurium may be a significant clue. With respect to lichen sclerosis/morphea overlap, the aforementioned features are seen depending upon lesional age, but are accompanied by epidermal atrophy and a lymphocytic interface dermatitis with basilar vacuolar degeneration of keratinocytes, and ultimately, reduction in superficial vascular plexity density mimicking certain systemic collagen vascular diseases as described above. In lichen sclerosis/morphea overlap, like in lichen sclerosis, the superficial papillary dermis becomes homogenized and edematous. The late lesion of morphea is a non-inflammatory fibrotic process with collagen bundles oriented parallel to the epidermis and complete absence of adnexal structures. Similar changes are described in systemic sclerosis (scleroderma) except that dermal inflammation is less intense, and that a conspicuous endarteritis obliterans phenomenon is seen in the deep dermal arterioles and arteries. With respect to the latter, clinical associations include the ingestion of L-tryptophan (eosinophilia-myalgia syndrome) and systemic therapy with bleomycin, with ingestion of rape seed oil, and with polyvinyl chloride exposure. Other diseases with an identical morphology include the sclerodermoid tissue reaction of graft-versus-host disease, porphyria cutanea tarda, and mixed connective tissue disease; the histomorphology most mimics scleroderma in late-stage lesions of the aforementioned disorders. With respect to the early, inflammatory lesions, these may be mimicked by diffuse interstitial granuloma annulare, granulomatous mycosis fungoides, systemic connective tissue diseases with interstitial lymphocytic and histiocytic infiltrates, including both MCTD and systemic lupus erythematosus, and palisading granulomatous drug reactions. We have seen one patient with a longstanding history of inflammatory morphea who ultimately developed granulomatous mycosis fungoides in her morphea lesions. This is obviously a rare occurrence, but it should be emphasized that lymphomas can arise in the setting of lymphoid hyperplasias in patients with underlying collagen vascular disease. With respect to the diffuse interstitial granulomatous drug reaction, lesions are characteristically localized to the intertriginous zones: the inner aspects of the arms, joints and axillae. The drug history is positive, most typically, for the ingestion of angiotensin converting enzyme inhibitors, beta-blockers and calcium channel blockers. Other agents are implicated, although with lesser frequency. Such cases do not show dermal sclerosis and a plasma cell neuritis is not observed. In cases of inflammatory morphea showing conspicuous plasmacellular infiltrates, we recommend obtaining Borrelia serology.

Pathogenesis
Tissue growth factor is a potent stimulator of collagen synthesis. It is increased in lesions of morphea. Tissue ischemia/anoxia is a potent stimulator of TGFb production. Thus, endothelial injury, in this case likely of immune-based etiology, may be critical to the pathogenesis of the fibrosing reaction in morphea. Platelet-derived growth factor (PDGF) is a potent growth factor for mesenchynmal cells, especially firboblasts. It can promote fibroblast proliferation, hence enhancing extracellular matrix synthesis. It is also a chemoattractant for fibroblasts. Northern blot analysis shows that cultured fibroblasts from scleroderma biopsies have higher expression of PDGF b-chain and PDGF b-receptor mRNA than those from normal control. A 2.8 kb PDGF b-chain mRNA transcripts which has a more efficient translation ability is the more predominantly expressed one.

A recent study evaluated the degree and nature of collagen production in lesions associated with increased collagen production, namely scleroderma, sceredema, and sarcoidosis. It was established that the amount of pro-alpha 1 (I) collagen and beta-actin mRNA levels was increased from lesional skin compared to healthy skin by approximately 3 fold.

In the scleroedematous stage (grade 1) showing edema in both papillary and reticular dermis with variable homogenization of collagen bundles in the reticular dermis mast cell (MC) skin density, as a whole, was significantly increased as compared with normal skin. In the sclerotic stage characterized byhomogenization of collagen bundles in the entire dermis, MC skin density was significantly decreased as compared with normal skin.

Some cases, particularly in Europe, appear to be associated with seropositivity for Borrelia burgdorferi; the organism can also be demonstrated in tissue by polymerase chain reaction methodologies. While in our experience the primary tick inoculation site of Lyme disease may indeed show a sclerodermoid tissue reaction closely mimicking morphea, actual cases of morphea or scleroderma in which organisms are demonstrable are uncommon in North America. There is no statistical evidence to support a spirochetal etiology in lesions of morphea in the United States.

More important in our view is the recent association of Parvovirus B19 infection with scleroderma; the viral DNA is demonstrable by molecular methods in the bone marrow and skin of scleroderma patients, at least those cases studied by us that represented a select group of Italian patients. It appears that Parvovirus B19 can infect or parasitize endothelial cells in patients who lack a virus-clearing serum IgM response, most often atopic women and girls. Endothelial parasitism then provokes a humoral-based microanbgiopathy to reduce oxygen tension and thus lead to the fibrosing process essentuial to the pathophysiology of morphea and scleroderma.

References

  1. Akimoto S, Ishikawa O, Igarashi Y, Kurosawa M, Miyachi Y. Dermal mast cells in scleroderma: their skin density, tryptase/chymase phenotypes and degranulation. Br J Dermatol 1998;138:399-406
  2. Colome-Grimmer MI, Payne DA, Tyring SK, Sanchez RL. Borrelia burgdorferi DNA and Borrelia hermsii DNA are not associated with morphea or lichen sclerosus et atrophicus in the southwestern United States. Arch Dermatol 1997;133:1174
  3. Crowson AN, Magro CM, Dawood MR. A causal role for parvovirus B19 infection in adult dermatomyositis and other autoimmune syndromes. J Cutan Pathol 2000;27:505-15
  4. Ferri C, Zakrzewska K, Longombardo G et al. Parvovirus B19 infection of bone marrow in systemic sclerosis patients. Clin Exp Rheumatol 1999;718-720
  5. Magro CM, Crowson AN, Nuovo G, Ferri C. Parvovirus B19 infection of endothelial cells and stromal fibroblasts: a possible pathogenetic role in scleroderma. Lab Invest 2002;82:101A-102A
  6. Magro CM, Crowson AN, Dawood M, Nuovo GJ. Parvoviral infection of endothelial cells in cutaneous lesions - possible role in vasculitis and autoimmune diseases. J Rheumatol 2002 (in press)
  7. Reed RJ, Clark WH, Mihm MC Jr. The cutaneous collagenoses. Hum Pathol 1973;4:165-86
  8. Sawada Y, Seishima M, Funabashi M, Noda T, Maeda M, Kitajima Y. Papular mucinosis associated with scleroderma. Eur J Dermatol 1998;8:497-500
  9. Tasanen K, Palatsi R, Oikarinen A. Demonstration of increased levels of type I collagen mRNA using quantitative polymerase chain reaction in fibrotic and granulomatous skin diseases. Br J Dermatol 1998 Jul;139:23-6
  10. Zheng XY, Zhang JZ, Tu P, Ma SQ. Expression of platelet-derived growth factor b-chain and platelet-derived growth factor b-receptor in fibroblasts of scleroderma. J Dermatol Sci 1998 Nov;18:90-7