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Reading: Handout (All yrs) Reading: Handout (All yrs) Document Transcript

  • Fibrosis and fibrosing dermatitis Philip E. LeBoit, M.D. Depts. of Pathology and Dermatology University of California, San Francisco Fibrosing dermatitis refers to inflammatory conditions affecting the skin that result in excess deposition of collagen. Along with these entities, we will consider the subject of cutaneous fibrosis in general. While the deposition of collagen in fibrosing dermatitis is driven by inflammatory cells, cytokines are also at work. These can evidently influence fibroblasts to lay down collagen even without the proximity of inflammatory cells. The various fibrosing dermatitides differ by virtue of the number of fibrocytes that are present, the types of inflammatory cells and their distribution, and the quality of collagen bundles that are laid down. Ackerman distinguishes between conditions that are characterized by sclerosis and those that are not. He defines sclerosis as a diminished number of fibroblasts, along with collagen fibers whose outlines are indistinct. An example of this is lichen sclerosus et atrophicus. A diminished number of fibroblasts, but maintenance of the outlines of collagen bundles occurs in morphea, scleroderma and some related conditions. While this distinction is interesting, the word sclerosis is used mostly by clinicians to denote any hardening of the skin, and the clinical definition and histopathologic definition are easily confused. Ackerman AB, Chongchitnant N, Sanchez J et al. Histologic Diagnosis of Inflammatory Skin Disease. Williams & Wilkins, Baltimore, 1997 p. 95 Ulcers, granulation tissue, and dense inflammatory infiltrates of many kinds (esp. neutrophils) can preceded fibrosis, in addition to the specific conditions we will review below. Scars are an under-explored area in dermatopathology. The recognition of scarring can be critical in medicolegal matters, as the presence of a scar can be a clue to a previous biopsy. Yet few pathology texts (or dermatopathology texts) give explicit criteria for scars: Scars- histopathologic findings ü Diminished or absent adnexal structures ü Horizontal orientation of fibrocytes and collagen bundles ü Vertical or diagonal orientation of thin, straight vessels ü Loss of the normal pattern of rete ridges and dermal papillae ü Fibroblasts increased in number early, decreased late Special kinds of scars include hypertrophic scars and keloids. Clinicians define a hypertrophic scar as one that protrudes above the skin surface, and keloids as scars that grow beyond their original bounds. Keloidal collagen bundles are thick, waxy, and often fuse with one another. Not all keloid scars have keloidal collagen bundles, and some hypertrophic scars do.
  • Hypertrophic scars- histopathologic findings ü Features noted above, for ordinary scars ü A nodular zone with markedly increased fibroblasts ü Fibroblasts often have nuclei in lacunar spaces ü Usually a zone of conventional scar is present between the nodular area and the epidermis Keloid scars- histopathologic findings ü Markedly protuberant, usually ü Areas resembling hypertrophic scars, sometimes ü Thick, waxy, and often fused collagen bundles ü Large fibrocytes with vesicular nuclei Keloidal collagen bundles can occur in the stroma of several neoplasms, including basal cell and squamous cell carcinoma. Fibrosis of the papillary dermis is a common finding due to inflammation or trauma (sometimes iatrogenic, as in the case of liquid nitrogen treatment). The papillary dermis is markedly expansible- it can be thickened upto 20 fold in some conditions. Common examples of papillary dermal fibrosis that are not true inflammatory diseases in the sense of being initiated by inflammatory cells include lymphedema, vascular stasis, the lamellar and concentric fibroplasia of “dysplastic nevi”, regression of many neoplasms (melanoma, mycosis fungoides, solar lentigo/lichenoid keratosis, superficial basal cell caricnoma, to name the most common). Fanti PA, Ragaz A, Ackerman AB. Expansibility of the papillary dermis. The position of the superficial vascular plexus relative to the epidermis. Am J Dermatopathol. 1984 Jun;6(3):273-9 Dermatofibromas are considered as a form of fibrosing inflammation by some, and as fibrosing neoplasms by others. There is certainly a resemblance between some examples of dermatofibroma and granulation tissue, and other dermatofibromas and scars. Other studies have shown clonality in dermatofibromas. Anetoderma is a condition that presents with atrophy of the skin. There is often maintenance of normal color and of the appearance of the surface, but palpation results in a finger easily indenting the surface. Anetoderma was conceived of at one time as being either “inflammatory” or “non-inflammatory”, but most studies support the concept that inflammation is its antecedent in the vast majority of cases, the others being due to neoplasms. Anetoderma- histopathologic features ü Nearly normal appearance at scanning magnification ü Inflammatory cells scant- some giant cells may be present ü Slightly increased numbers of fibrocytes, sometimes
  • ü Diminished elastic tissue fibers in the mid-dermis on special stains ü Preserved elastic tissue around vessels, adnexa Venencie PY, Winkelmann RK. Histopathologic findings in anetoderma. Arch Dermatol. 1984 Aug;120(8):1040-4. Venencie PY, Winkelmann RK, Moore BA. Anetoderma. Clinical findings, associations, and long-term follow-up evaluations. Arch Dermatol. 1984 Aug;120(8):1032-9. Inflammatory diseases with fibrosis, principally of the papillary dermis Inflammatory diseases resulting in fibrosis of the papillary dermis include lichen sclerosus et atrophicus, radiation sclerosis and acrodermatitis chronica atrophicans. Lichen sclerosus et atrophicus is a condition that usually affects anogenital skin, but also occurs at other sites. Its lesions are usually hypopigmented (cream colored rather than ivory). Genital lesions are often intensely pruritic, while extragenital ones are not. Genital lichen sclerosus et atrophicus is associated with squamous cell carcinoma, while extragenital diseaese is not. The reasons for this are unknown. Lichen sclerosus et atrophicus, early changes ü Bandlike infiltrates of lymphocytes ü Psoriasiform epidermal hyperplasia ü Many lymphocytes in the basal layer of the epidermis (resembling mycosis fungoides) ü Distinctive changes in the papillary dermis (see below)may only be evident in levels Fung MA, LeBoit PE. Light microscopic criteria for the diagnosis of early vulvar lichen sclerosus: a comparison with lichen planus. Am J Surg Pathol. 1998 Apr;22(4):473-8. Lichen sclerosus et atrophicus, fully developed changes ü Thickening of the papillary dermis ü Diminished fibroblasts in the papillary dermis ü Pallor and homogenization of the papillary dermis ü Variable degrees of lichen simplex chronicus Acrodermatitis chronica atropihicans is a late complication of Lyme disease in which striking atrophy occurs on acral skin. It is a more frequent complication in Europe, with very few cases in North America. There are bandlike infiltrates with plasma cells early, an atrophic epidermis, and fibrosis of the papillary dermis. Inflammatory diseases with fibrosis principally of the reticular dermis View slide
  • By far the most important spectrum of disease in which the reticular dermis is the seat of fibrosing inflammation is that of morphea and scleroderma. The dividing line between these conditions is not razor sharp, but they are distinct. The changes of morphea are confined to the skin, and usually to discrete areas of the skin, while scleroderma is a systemic disease (progressive systemic sclerosis) with many internal manifestations. Both conditions begin with inflammatory cells, although they may be scant in scleroderma. Some patients with morphea have superficial changes that are indistinguishable from those of lichen sclerosus et atrophicus. This has led to the hypothesis that they are two expressions of the same disease. An intersting sidelight is the occurrence of morphea on the trunk and limbs, and lichen sclerosus et atrophicus on the genitalia of some European patients infected with B. burgdorferi. Morphea- histopathologic findings in early cases ü Superficial and deep, perivascular and interstitial infiltrates of lymphocytes and plasma cells (eosinophils or neutrophils, sometimes) ü Some lymphocytes in the basal layer (may resemble mycosis fungdoides) ü Thickening of collagen bundles may be subtle Morphea- histopathologic findings in fully developed lesions ü Inflammatory infiltrates less dense than in above ü Thickened collagen bundles in the reticular dermis ü Diminished spaces between them ü Hyperpigmentation of the basal layer ü Homogenization (but not usually pallor) of the papillary dermis Morphea- histopathologic findings in late lesions ü As in above ü Inflammation sparse ü Adnexa often absent or show degenerative changes ü Fibrocytes scant The histopathologic findings in scleroderma are usually identical to those in late morphea. Variants with different histopathologic findings - ü Bullous morphea ü Keloidal scleroderma ü Morphea profunda ü Eosinophilic fasciitis View slide
  • The late stages of necrobiosis lipoidica can simulate morphea. Necrobiosis lipoidica is a grnaulomatous dermatitis that results in fibrosis. Early lesions show palisaded granulomatous infiltrates affecting the entire width of most biopsy specimens, with fibrosis and degeneration of collagen bundles in the centers of the granulomatous foci. There are infiltrates of lymphocytes and plasma cells. In late lesions, the granulomatous changes can be subtle, and fibrosis marked. Both conditions can have plasma cells. A clue to the diagnosis of necrobiosis lipoidica is that an elastic tissue stain will show near absence of elastic fibers, while those are mostly preserved in morphea. Several epidemics due to toxic substances resulted in hardening of skin simulating scleroderma or morphea, and recently, scleromyxedema. ü Spanish olive oil-epidemic syndrome ü L-tryptophan (eosinophilia/myalgia syndrome) ü Nephrogenic fibrosing dermopathy The first two conditions resemble scleroderma/morphea under the microscope: ü Thickened collagen bundles throughout reticular dermis ü Diminished spaces between thick collagen bundles ü Superficial and deep perivascular and interstitial lymphocytic infiltrates, plasma cells around deep plexus ü Variable eosinophils ü Perineural infiltrates ü Mucin deposits sometimes greater than in conventional morphea ü In Spanish toxic olive oil epidermic syndrome, some cases have increased fibroblasts or myofibroblasts Nephrogenic fibosing dermopathy/nephrogenic systemic fibrosis occurs in patients with renal disease who have been exposed to Gadolinium via radiologic procedures, MRI and MRA. The Gadolium particles accumulate in lesional skin. Histopathologically, it can resemble scleromyxedema but clinically it is quite distinct. ü Increased fibroblasts (esp. myofibroblasts) throughout dermis and subcutaneous septa ü Small osteoclast like giant cells in cellular lesions ü Increased interstitial mucin ü Dystrophic calcification, sometimes It differs from idiopathic scleromyxedema in that: ü There is no paraprotein in serum ü Face is usually spared ü Waxy papules do not occur ü No internal/psychiatric disease ü No infiltrates of plasma cells ü Mucin does not accumulate in “lakes”
  • Cowper SE, Su LD, Bhawan J, Robin HS, LeBoit PE. Nephrogenic fibrosing dermopathy. Am J Dermatopathol. 2001 Oct;23(5):383-93. Cowper SE, Robin HS, Steinberg SM, Su LD, Gupta S. LeBoit PE. Scleromyedema-like cutaneous diseases in renal-dialysis patients. The Lancet. 356:1000-01, 2000. Porphyria cutanea tarda can also result in fibrosing dermatitis. The lesions are usually in sun exposed skin. A distinctive finding is the presence of thick walled blood vessels whose walls can be stained with PAS-D. Radiation sclerosis is a late complication of radiation exposure. The changes in the reticular dermis resemble those of morphea, but fibroblasts can be large, or even have bizarre nuclei (so-called radiation fibroblasts). Radiation fibroblasts fail to stain with factor XIIIa or CD34, making them unlikely precursors of atypical fibroxanthoma or of dermatofibrosarcoma protuberans. The findings in the papillary dermis can resemble those of lichen sclerosus et atrophicus. Blood vessels can have fibrin deposits in their walls or lumens, or can be necrotic. Changes that resemble morphea rather than radiation sclerosis can occur following radiation for breast carcinoma. Meehan SA, LeBoit PE. An immunohistochemical analysis of radiation fibroblasts. J Cutan Pathol. 1997 May;24(5):309-13. Chronic fibrosing vasculitis There are two forms of leukocytoclastic vasculitis that result in fibrosis, erythema elevatum diutinum and granuloma faciale. In erythema elevatum diutinum (EED), there are hemorrhagic papules that evolve into plaques and nodules on the dorsal surfaces of joints. The distribution is bilateral, and strikingly symmetrical in many cases. EED is associated with streptococcal infection, HIV disease and hematologic disorders of several kinds. In granuloma faciale (GF) there is usually a solitary plaque on the face. Sometimes extrafacial lesions occur as well- but these are usually solitary, and if multiple, are not distributed in the distinctive manner seen in erythema elevatum diutinum. Erythema elevatum diutinum-early lesions ü leukocytoclastic vasculitis involving small vessels in the dermis ü An increase in small vessels, sometimes Erythema elevatum diutinum-fully developed lesions ü Dense, diffuse infiltrates of neutrophils and neutrophilic debris ü Residual foci of vasculitis, sometimes
  • ü Increased fibroblasts ü Thin collagen fibers increased Erythema elevatum diutinum-late lesions ü Protuberant contour ü Parallel, thin collagen bundles ü Neutrophils and dust between bundles ü Vasculitic foci rare In granuloma faciale, early lesions are almost never biopsied, as they are solitary lesions on the face. Granuloma faciale-fully developed lesions ü Neutrophils and dust around small vessels ü Fibrin in vessel walls ü Eosinophils and plasma cells ü Sparing of perifollicular adventitial dermis, often Granuloma faciale-late lesions ü Features noted above ü Concentric fibrosis around vessels Changes similar to those in either condition can sometimes occur as random, single lesions. Carlson JA, LeBoit PE. Related Articles, Links Localized chronic fibrosing vasculitis of the skin: an inflammatory reaction that occurs in settings other than erythema elevatum diutinum and granuloma faciale. Am J Surg Pathol. 1997 Jun;21(6):698-705. LeBoit PE, Cockerell CJ. Nodular lesions of erythema elevatum diutinum in patients infected with the human immunodeficiency virus. J Am Acad Dermatol. 1993 Jun;28(6):919-22. LeBoit PE, Yen TS, Wintroub B. The evolution of lesions in erythema elevatum diutinum. Am J Dermatopathol. 1986 Oct;8(5):392-402. Fibrosing conditions of the subcutis The subcutaneous septa can be thickened in several panniculitdes. In erythema nodosum, fibrous septa are inflamed and thickened, but revert to normal thickness with healing. In morphea profunda and in eosinophilic fasciitis (see above), there are usually changes in
  • the reticular dermis as well; sometimes those in the subcutis dominate the picture. In necrobiosis lipoidica, a biopsy that extends into the subcutis will demonstrate marked thickening of the septa. Sclerosing panniculitis (lipodermatosclerosis) is a condition in which the subcutis is altered by ischemia secondary to venous stasis. It results in woody, indurated plaques, usually unilateral. Sclerosing panniculitis- histopathologic findings ü Changes of venous stasis in the papillary dermis ü Thickening and fibrosis of septa ü Ischemic necrosis of the centers of lobules ü Lipomembranous change in lobules (corrugated membranous structures) Jorizzo JL, White WL, Zanolli MD, Greer KE, Solomon AR, Jetton RL. Sclerosing panniculitis. A clinicopathologic assessment. Arch Dermatol. 1991 Apr;127(4):554-8.