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



CASE #7: OTHER CELL POOR INTERFACE DERMATOSES

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






MORBILIFORM VIRAL EXANTHUM AND MORBILIFORM DRUG ERUPTION

Clinical
These two forms of cell-poor interface dermatitis will be considered in concert as they have striking similarities at the light microscopic level. The rashes in morbiliform drug eruptions and viral exanthemata manifest as fine pinpoint diffuse erythema lacking islands of skin sparing. Among the viruses implicated in the morbiliform viral exanthem are Coxsackie, echovirus, rotavirus, respiratory syncytical virus, and influenza virus. However in most instances, the culprit virus is not identified. With respect to drugs, they fall primarily into the category of antibiotics and non-steroidal anti-inflammatory agents.

Histopathology
The epidermal thickness and the stratum corneum are normal. The epidermis shows subtle basilar vacuolopathy with a few lymphocytes tagging along the dermal-epidermal junction. Scattered randomly disposed necrotic keratinocytes are observed in the epidermis.


Interface Dermatitis Of Collagen Vascular Disease - Dermatomyositis

The phenomenon of lymphocyte satellitosis around necrotic keratinocytes is not typically encountered. If there is a dermal-based infiltrate, it is sparse and confined to the superficial vascular plexus. There is usually no tissue eosinophilia except in those cases of drug based etiology.

References

  1. Crowson AN. Superficial and deep perivascular dermatitis. In : Barnhill R, Crowson AN, Busam K, Granter S ed's. Textbook of Dermatopathology. New York : McGraw-Hill Co, 1998:69-81
  2. Crowson AN, Magro CM. Drug eruptions. In : Barnhill R, Crowson AN, Busam K, Granter S ed's. Textbook of Dermatopathology. New York : McGraw-Hill Co,1998:257-270
  3. Crowson AN, Magro CM. Recent advances in the pathology of cutaneous drug eruptions. Dermatol Clin 1999;17:537-60


ACUTE GRAFT-VERSUS-HOST DISEASE

Clinical/Pathogenesis
Graft versus host disease is a serious multiorgan inflammatory and fibrosing disorder that develops under 3 specific conditions:
  1. Following transplantation of donor recipient immunocompetent cells into a host
  2. Incompatibility between the host and donor
  3. Immunosupression of the host.
The most common case scenario in which graft versus host disease develops is following allogeneic bone marrow transplantation. However this condition has also been described in neonates relfecting maternal fetal transfusion and following heart transplantation in apparently healthy adults. There are risks for the development of graft versus host disease including an older age at receipt of the transplant, a female donor to male reciepient transfer and incompatibility of major and minor histocompatibility antigens.

There are two main forms of graft versus host disease: an acute form and a chronic form. The acute form develops within 7 days to 3 months following bone marrow transplantation. It is a multiorgan state of tissue injury mediated by donor lymphocytes whereby epithelial structures are the prime targets. There are 3 primary sites which are involved : the skin, the gastrointestinal tract and liver. A grading system has been applied to the clinical severity of acute graft versus host disease. Similarly there are 4 histologic grades which closely parallel the clinical grade: basalar vacuolopathy without keratinocyte necrosis(grade 1 lesions); basilar vacuolopathy with occasional necrotic keratinocytes ( grade II lesions); many necrotic keratinocytes with resultant subepidermal cleft formation (grade III lesions);confluent transepidermal necrosis resembling toxic epidermal necrolysis (grade IV lesions).

Clinically, the typical cutaneous eruption of acute GVHD occurs within the first month after bone marrow transplant and comprises erythematous macules. The skin is the most commonly involved organ in GVHD and offers a window for diagnosis. Although erythematous patches may remain localized to acral sites, they can generalize to cause erythroderma and, with increasing severity, blister formation and complete epidermal necrosis hence mimicking toxic epidermal necrolysis. These manifestations tend to be more pronounced in allogeneic, as opposed to autologous bone marrow transplants. Up to one-half of allogeneic bone marrow transplants are associated with GVHD even in HLA-matched recipients. In immuno-suppressed patients, transfusion of non-irradiated blood can provoke GVHD. Moderate doses of cyclosporine, possibly by promoting autoreactive T-cell clones in the peripheral circulation, can increase the incidence and severity of skin eruptions, a phenomenon further aggravated by the use of interferon.

Histopathology
The histomorphology of cutaneous GVHD ranges from basilar vacuolization to a toxic epidermal necrolysis-like pattern with complete epidermal necrosis. A grading system has been implemented by which skin biopsy specimens from GVHD may be classified, namely: grade 0 - no pathological change; grade 1- basilar vacuolization; grade 2 - basilar vacuolization with necrotic keratinocytes and dermal inflammation; grade 3 - confluence of basilar vacuolopathy; grade 4 - separation of epidermis from dermis. A characteristic hallmark of grades 2 through 4 is lymphocyte satellitosis to apoptic keratinocytes, reflecting the pathophysiologic effect of perforin elaborated by CD8 positive T-cells. This particular cytotoxic effect is accentuated in follicular epithelia and frequently in eccrine structures, sometimes including the eccrine coil. Grades 1 and 2 GVHD are indistinguishable from chemotherapy effects. Thus, such changes within the first thirty days of a bone marrow transplant are indeterminate for GVHD versus chemotherapy effect. Loss of polarity of keratinocytes resulting in disordered maturation of the epidermis may reflect drug-induced alterations of the keratinocyte cell cycle and is often accompanied by individual cell keratinocyte necrosis. Similarly, patients recovering from cyto-reductive therapy, such as for acute leukemia, show a similar morphology, as do those receiving cyclosporine, coincident with the return of lymphocyte counts in the peripheral stream. Apart from the entities described above, the interface dermatitis of AIDS, namely the cell-poor vaculopathic form, mimics acute GVHD. The lesions of chronic GVHD more closely mimic lichenoid eruptions and morpheiform eruptions and will not be discussed in this section.

Differential Diagnosis
Graft verus host disease in its early phase (i.e less than 20 days following bone marrow transplantation) can not be reliably distinguished from other disorders which could conceivably develop in this setting, specifically virally mediated infections and drug hypersensitivity and or toxic reactions. At a light microsocpic level the identification of intraepidermal bile pigment may be a useful distinguishing criterion to separate it from the aforesaid other diagnostic possibilities; unfortunately this finding is only identified in less than 6% of biopsies. Among distinctive drug reactions which can impose diagnostic dilemas with respect to distinction from graft versus host disease are acral erythema of chemotherapy and Grover's like disease following high-dose chemotherapy and either allogeneic/autologous bone marrow transplantation or autologous stem cell infusion. In chemotherapy associated acral erythema the phenomenon is a purely toxic one and hence the observation of features of cellular cytoxic immunity (ie lymphocyte satellitosis around necrotic keratinocytes) in the epidermis would be exceptional in contrast with its ubiqutious identification in lesions of graft versus host disease. The Grover's like eruption manifests a Darier's pattern of acantholysis along with scattered chemotherapy associated toxic epidermal changes such as the etoposide star burst keratinocyte.

Pathogenesis
The pathophysiological events appear to involve a combination of CD4-positive T-helper cells dominantly localized to acrosyngringia and follicular structures early in the infiltrate, followed by a CD8 positive T-cell response later in the evolution of the disease. Thus, initial lesions are folliculotrophic and eccrinotropic while later lesions involve the interfollicular epidermis. HLA-DR expression in eccrine structures and hair follicles are associated with T-helper-restricted interactions explaining the distribution of infiltrates early in the GVH reaction. Perforin, a natural killer (CD8 positive) T-cell product, by producing plasma membrane pores, appears to be an effector of keratinocyte injury.

One recent study demonstrated that donor lymphocytes appeared in the skin of female patients undergoing allogeneic bone marrow transplant starting day 13. The concept that acute graft versu host disease is an exclusively cytotoxic CD8 mediated disease does not appear to be correct; the effector cells can be either a CD4 or CD8 positive lymphocyte, either in the context of a predominance of either cell type or a biphenotypic mixture. For example, in grade 2 lesions there appears to be a predominance of CD4 positive lymphocytes in the dermis while a CD8 phenotypic dominant infiltrate is present within the epidermal component. One of the characteristic features of graft versus host disease is an interface dermatitis involving the follicular epithelium with variable necrosis. The brunt of injury is apparently directed at the bulge epithelium of hair follicles, possibly reflecting the high concentration of stem cells in this area of the follicule; hence the stem cell may be a preferential target. Apoptosis appears to be the mechanism of keratinocyte injury as confirmed by endonuclease-mediated DNA fragmentation. The apoptosis has 2 waves: an initial one is due to the effects of keratinocyte derived tumor necrosis factor alpha while the second wave is mediated by cytotoxic T lymphocytes. Both tumor necrosis factor alpha (TNFalpha) and Fas ligand (FasL) have been implicated in the pathogenesis of graft-versus-host disease (GVHD). In one study, neutralizing anti-FasL and/or anti-TNFalpha monoclonal antibody (MoAb) was given to mice with lethal acute GVHD. Treatment with either anti-FasL or anti-TNFalpha MoAb alone significantly delayed the mortality and improved the body weight whereby a complete protection was achieved by the administration of both MoAbs.

References

  1. Aractingi S, Chosidow OCutaneous graft-versus-host disease. Arch Dermatol 1998;134:602-12
  2. Demircay Z, Gurbuz O, Alpdogan TB, Yucelten D, Alpdogan O, Kurtkaya O, Bayik M Chemotherapy-induced acral erythema in leukemic patients: a report of 15 cases. Int J Dermatol 1997;36:593-8
  3. Greinix HT, Volc-Platzer B, Rabitsch W, Gmeinhart B, Guevara-Pineda C, Kalhs P, Krutmann J, Honigsmann H, Ciovica M, Knobler RM. Successful use of extracorporeal photochemotherapy in the treatment of severe acute and chronic graft-versus-host disease. Blood 1998;92:3098-104
  4. Harvell JD, Hashem C, Williford PL, White WLGrover's-like disease in the setting of bone marrow transplantation andautologous peripheral blood stem cell infusion. Am J Dermatopathol 1998;20:179-84
  5. Hattori K, Hirano T, Miyajima H, Yamakawa N, Tateno M, Oshimi K, Kayagaki N, Yagita H, Okumura K Differential effects of anti-Fas ligand and anti-tumor necrosis factor alpha antibodies on acute graft-versus-host disease pathologies.Blood 1998;91:4051-5
  6. Hitchins L, Fucich LF, Freeman SM, Millikan LE, Marrogi AJ Immunophenotyping as a diagnostic tool to differentiate lichen planus fromchronic graft-versus-host disease: diagnostic observations on two patients. J Investig Med 1997;45:463-8
  7. Horn TD, Haskell J. The lymphocytic infiltrate in acute cutaneous allogeneic graft-versus-host reactions lacks evidence for phenotypic restriction in donor-derived cells. J Cutan Pathol 1998;25:210-4
  8. Horn TD. Interface dermatitis. In : Barnhill R, Crowson AN, Busam K, Granter S ed's. Textbook of Dermatopathology. New York : McGraw-Hill Co, 1998. 33-54.
  9. Johnson ML, Farmer ER. Graft-versus-host reactions in dermatology. J Am Acad Dermatol 1998;38:369-392.
  10. Kohler S, Hendrickson MR, Chao NJ, Smoller BR. Value of skin biopsies in assessing prognosis and progression of acute graft-versus-host disease. Am J Surg Pathol 1997;21:988-96
  11. Levi-Schaffer F, Goldenhersh MA, Segal V, Nagler ANedocromil sodium ameliorates skin manifestations in a murine model of chronicgraft-versus-host disease.Bone Marrow Transplant 1997;19:823-8
  12. Parkes IR, Zaki I, Stevens A, Davies JM, Allen BR. Graft-versus-host disease-like eruption in a patient with non-Hodgkin's lymphoma. Br J Dermatol 1997;137:137-9
  13. Weedon D. The lichenoid reaction pattern. Skin Pathology. Edinburgh : Churchill Livingstone. 1997:29-63.
  14. Yoo YH, Gilliam AC, Whitaker-Menezes D, Korngold R, Murphy GFExperimental induction and ultrastructural characterization of apoptosis inmurine acute cutaneous graft-versus-host disease.Arch Dermatol Res 1997;289:389-98


LICHENOID TISSUE REACTIONS

General Considerations:
The morphologic reaction pattern of "lichenoid interface dermatitis" is characterized by a band-like lymphocytic infiltrate in intimate apposition to the epidermis with variable epithelial injury. Lichenoid interface dermatitis is seen in numerous conditions including lichen planus, lichenoid hypersensitivity reactions of drug or contact-based etiology, lichenoid reactions in the setting of hepatobiliary disease, secondary syphilis, and collagen vascular disease. Each will be considered separately, specifically emphasizing discriminating light microscopic features. When a lichenoid interface dermatitis is present, the onus is on the clinician to investigate the patient for various disorders. The concept of "lichenoid dermatitis" will be illustrated by case 7. A brief discussion of other forms of lichenoid dermatitis will be given.



LICHENOID CONNECTIVE TISSUE DISEASE SYNDROMES

Introduction
The prototypic lichenoid connective tissue disease syndromes include:
  1. subacute cutaneous lupus erythematosus (SCLE)
  2. anti-Ro associated systemic lupus erythematosus (SLE)
  3. mixed connective tissue disease (MCTD)

Clinical
The lichenoid connective tissue disease syndromes have in common a polycyclic annular and/or papulosquamous photo-distributed eruption involving the head, neck, arms, and the "v" of the chest and upper back. In subacute cutaneous lupus erythematosus (SCLE) there are no significant extra cutaneous stigmata of collagen vascular disease. Serologic testing reveals anti-Ro antibodies in the majority of cases. Some cases of SCLE are of drug-based etiology where the main implicated drugs include calcium channel blockers, Griseofulvin, and thiazides. In anti-Ro associated systemic lupus erythematosus (SLE), while the cutaneous eruption may be morphologically indistinguishable from SCLE, there are other extracutaneous stigmata indicative of a systemic connective tissue disease syndrome, including renal dysfunction, musculo-skeletal complaints, pulmonary disease and central nervous system manifestations. As well, the patients may have cutaneous and extra-cutaneous stigmata indicative of vascular compromise as manifested by ulceration, digital infarcts, palpable purpura, mononeuritis multiplex, gastrointestinal ulcerations, and myocardial infarction. In mixed connective tissue disease (MCTD), the patients have a constellation of characteristic extracutaneous manifestations (see Table 5) which include Raynaud's phenomenon, sclerodactyly, and pulmonary hypertension. In MCTD, while patients may have a skin rash that resembles SCLE, other characteristic features allow the distinctions, namely anti-RNP antibodies, sclerodactyly, variable myositis, Raynaud's phenomenon and pulmonary hypertension.

Histopathology
The prototypic histomorphology of the lichenoid connective tissue disease syndrome is one of variable epidermal hyperplasia and atrophy accompanied by an interface dermatitis that ranges in quality from being lichenoid in nature to a cell-poor vacuolar dermatitis. There is variable mid and deep dermal perivascular extension of the infiltrate. Dermal mucinosis is ubiquitous. Also characteristic is the presence of superbasilar dyskeratosis, with lymphocyte satellitosis around degenerating keratinocytes. Other concomitant inflammatory cell elements such as epithelioid histiocytes, plasma cells, and eosinophils are uncommon, although emphasized that in a small minority of cases of drug-associated SCLE, eosinophils and granulomata may be observed. It has been our experience that a significant vasculopathy is not present in SCLE. In contrast, in both anti-Ro associated systemic lupus erythematosus and MCTD, a microangiopathy similar to that encountered in dermatomyositis is a frequent finding. In particular, one may observe zones of vascular density reduction, endothelial cell necrosis and variable luminal fibrin deposition.

References

  1. Bhan AK, Harrist TJ, Murphy GF, Mihm MC Jr. T cell subsets and Langerhans cells in lichen planus: In situ characaterization using monoclonal antibodies. Br J Dermatol 1981;105: 617-622
  2. Crowson AN, Magro CM. The role of microvascular injury in the pathogenesis of cutaneous lesions of dermatomyositis. Hum Pathol 1996;27:15-19
  3. Crowson AN, Magro CM. Idiopathic perniosis and its mimics : A clinical and histological study of 38 cases. Hum Pathol 1997;28:474-484
  4. Crowson AN, Magro CM. Subacute cutaneous lupus erythematosus in the setting of calcium channel blocker therapy. Hum Pathol 1997;28:67-73
  5. Crowson AN, Magro CM. The cutaneous pathology of lupus erythematosus. J Cutan Pathol 2001;28:1-23
  6. Magro CM, Crowson AN. The immunofluorescence findings in cutaneous lesions of dermatomyositis : a comparative study versus lupus erythematosus. J Cutan Pathol 1997;24:543-552
  7. Magro CM, Crowson AN, Harrist TJ. The use of antibody to C5b-9 in the subclassification of lupus erythematosus Br J Dermatol 1996;134:855-862
  8. Magro CM, Crowson AN, Regauer S. The dermatopathology of mixed connective tissue disease. Am J Dermatopathol 1997;19:205-212
  9. Magro CM, Crowson AN. The clinical and histological features of 23 non-SCLE patients with anti-Ro antibodies. Am J Dermatopathol 1999;21:129-37
TABLE 2
Revised criteria of the American Rheumatology Association for the classification of systemic lupus erythematosus
  1. Malar rash
  2. Discoid rash
  3. Photosensitivity
  4. Oral ulcers
  5. Arthritis
  6. Serositis:
    1. pleuritis, or
    2. pericarditis
  7. Renal disorder:
    1. proteinuria >0.5g/24h or 3+, persistently, or
    2. cellular casts
  8. Neurological disorder:
    1. seizures or
    2. psychosis (having excluded other causes, e.g. drugs)
  9. Hematologic disorder:
    1. hemolytic anaemia or
    2. leukopenia <4.0 x 109/l on two or more occasions
    3. lymphopenia <1.5 x 109/l on two or more occasions
    4. thrombocytopenia <100 + 109/l
  10. Immunologic disorders:
    1. positive LE cell or
    2. raised anti-native DNA antibody binding or
    3. anti-Smith antibody or
    4. false positive serologic test for syphilis, present for at least 6 months
  11. Antinuclear antibody in raised titre

TABLE 3
Criteria for myopathic dermatomyositis (after Bohan and Peter)
  1. proximal symmetric muscle weakness
  2. elevated serum levels of muscle derived enzymes
  3. abnormal electromyogram
  4. abnormal muscle biopsy
  5. cutaneous disease compatible with dermatomyositis

TABLE 4 : Histopathologic criteria for subtypes of lupus erythematosus (after Magro et al. Br J Dermatol 1996)
  1. Systemic lupus erythematosus
    • pauci-inflammatory interface dermatitis
    • slight to absent epidermal atrophy
    • basement membrane zone of normal thickness
    • no follicular plugging
    • prominent papillary dermal edema and reticular dermal mucin accumulation
  2. Subacute cutaneous lupus erythematosus
    • prominent suprabasilar exocytosis of lymphocytes +dyskeratosis extending into upper spinous layers
    • prominent epidermal atrophy
    • follicular plugging or basement membrane zone thickening minimal or absent
    • mild to moderate mononuclear cell infiltrate confined to the superficial dermis
  3. Discoid lupus erythematosus
    • lymphocyte rich interface dermatitis
    • less epidermal atrophy than SCLE; sometimes acanthosis
    • prominent basement membrane zone thickening
    • prominent follicular hyperkeratosis
    • dense superficial and deep perivascular and periadnexal infiltrates with follicular degeneration
    • dermal fibrosis

TABLE 5 : Criteria for MCTD

A diagnosis of MCTD is based upon the presence of 1 criterion from category I, plus the criterion from category II,
plus >/=1 criteria from category III

  1. Common symptoms:
    1. Raynaud's phenomenon
    2. Swollen fingers or hands
  2. Anti-nRNP antibody
  3. Mixed findings:
    1. SLE-like findings:
      1. Polyarthritis
      2. Lymphadenopathy
      3. Facial erythema
      4. Pericarditis or pleuritis
      5. Leukocytopenia or thrombocytopenia
    2. PSS-like findings:
      1. Sclerodactyly
      2. Pulmonary fibrosis, restrictive changes of the lung or reduced diffusion capacity
      3. Hypomotility or dilatation of the esophagus
    3. DM-like findings:
      1. Muscle weakness
      2. Increased serum level of myogenic enzymes (CPK)
      3. Myogenic pattern at electromyography

Abbreviations:

DM - dermatomyositis
CPK - creatine phosphokinase
PSS - progressive systemic sclerosis
RNP - ribonucleoprotein
SLE - systemic lupus erythematosus

Immunofluorescent findings
Immunofluorescent testing is very useful. In SCLE, one typically observes nuclear and/or cytoplasmic decorating keratinocytes for IgG and C5b-9. There is no C5b-9 staining of the cutaneous vasculature. The lupus band test is negative. In anti-Ro associated systemic lupus erythematosus, the aforementioned epidermal decoration for IgG and C5b-9 is observed in concert with a positive lupus band test and C5b-9 deposition within the cutaneous vasculature. In MCTD, a similar pattern of epidermal decoration for IgG and C5b-9 is seen. The lupus band test is variably positive. As well, decoration of the cutaneous vasculature for C5b-9 is seen.

Pathogenesis
The pathogenetic basis of the lichenoid connective tissue disease syndrome is one of antibody dependent cellular immunity. In particular, with ultraviolet exposure, specific RNA antigens such as La and Ro are displaced from the nucleus and/or cytoplasm to the surface of the keratinocytes where the antigen becomes accessible to circulating antibody. The C5b-9 membranolytic attack complex is the effector mechanism of the epidermal injury.



OTHER LICHENOID DERMATOSES:

LICHEN PLANUS

Introduction/Clinical Features
Lichen planus is a common eruption of unknown etiology, characterized by violaceus, flat-topped papules which are usually pruritic. The surface of the papules may manifest a reticulated, white scale referred to as Wickham's striae. There is a predilection for the flexor surfaces of the wrists, trunk, thighs and genitalia; oral lesions are common. Spontaneous resolution of lichen planus is usual within twelve months, although post-inflammatory pigmentation may persist. Lichen planus-like eruptions may be observed in various systemic disorders which will be considered separately. These fall primarily in the category of hepatobiliary disease.

Pathogenesis
Cell-mediated immunity appear to be operative. Initially the response is one of CD4 positive lymphocytes in the dermis, suggesting a delayed-type hypersensitivity reaction. After several weeks, however, a CD8 lymphocyte-dominant infiltrate is present. The presence of degenerative epithelial changes in association with lymphocyte satellitosis around degenerating keratinocytes also suggests a role for cellular cytotoxicity. A lichen planus-specific antigen has been detected in the epidermis and a circulating antibody to it has been found in the serum of some individuals with lichen planus, however, this may be an epiphenomenon rather than being of any pathogenetic significance. A subclass of T-lymphocytes, the gamma delta T-lymphocyte, has been identified in established lesions.

Histopathology
The epidermis can either be irregularly thickened or may demonstrate retiform effacement with epithelial atrophy depending upon the age of lesion biopsied. The granular cell layer is increased, often in a wedge-shaped fashion, and the epidermis is surmounted by an orthohyperkeratotic scale. A dense band-like lymphocytic infiltrate in the superficial dermis obscures the dermal-epidermal junction. The destruction of the basal layer results in the exposure of the spinous layer to the dermis, defining the phenomenon of squamotization of the basal layer. Prominent suprabasilar dyskeratosis is unusual, most of the degenerative epithelial alterations being confined to the basilar and parabasilar portions of the epidermis. Mid and deep dermal perivascular extension is not a feature of idiopathic lichen planus. Eosinophils or plasma cells are either absent or at most infrequently observed. In any given biopsy, alternating zones of epidermal hyperplasia with atrophy is unusual, as would be alternating zones of lichenoid interface inflammation with areas of a cell-poor interface dermatitis. As the lesions resolve, the intensity of the dermal-based inflammatory cell infiltrate lessens and one can observe laminated superficial dermal fibroplasia with vascular ectasia in a fashion reminiscent of poikiloderma. Necrotic keratinocytesis may be seen as PAS-positive colloid bodies within the papillary dermis. When the basilar destruction is acute and confluent, separation of the epidermis from the dermis may be observed, producing clefts referred to as Max-Joseph spaces. Direct immunofluorescence shows changes compatible with interface change, namely, an intense band of fibrinogen along the dermal-epidermal junction and within the papillary dermis with decoration of colloid bodies for all classes of immunoglobulins. There is typically conspicuous acrosyringeal and follicular involvement, the latter asociated with follicular hyperkeratosis.

References

  1. Bhan AK, Harrist TJ, Murphy GF, Mihm MC Jr. T cell subsets and Langerhans cells in lichen planus: In situ characaterization using monoclonal antibodies. Br J Dermatol. 1981; 105: 617-622
  2. Hood AF, Kwan TH, Mihm MC Jr, Horn TD. Primer of Dermatopathology. 2nd Ed'n. Boston: Little, Brown & Co, 1993
  3. Horn TD. Interface dermatitis. In : Barnhill R, Crowson AN, Busam K, Granter S ed's. Textbook of Dermatopathology. New York : McGraw-Hill Co, 1998. 33-54
  4. Toussaint S, Kamino H. Noninfectious erythematous, papular, and squamous diseases. In: Elder D, Elenitsas R, Jaworsky C, Johnson B, Ed's. Lever's Histopathology of the skin, 8th Ed'n, Philadelphia: Lippincott-Raven, 1998
  5. Requena L, Kutzner H, Escalonilla P, Ortiz S, Schalleri J, Rohwedder A. Cutaneous reactions at sites of herpers zoster scars : an expanded spectrum. Br J Dermatol 1998;138:161-8
  6. Weedon D. The lichenoid reaction pattern. Skin Pathology. Edinburgh : Churchill Livingstone. 1997:29-63


LICHEN PLANUS-LIKE ERUPTIONS SEEN IN THE SETTING OF HEPATOBILIARY DISEASE

Lichen planus-like eruptions may be observed in setting of certain underlying hepatic disorders, particularly those associated with a cholestatic picture such as hepatitis C and primary biliary cirrhosis. Clinically the lesions are no different from those observed in idiopathic lichen planus. The histopathology is very similar to idiopathic lichen planus, but there are a few subtle additional light microscopic clues that might point toward the diagnosis. In particular, there may be a significant admixture of epithelioid histiocytes producing a morphology for which we use the appellation lichenoid and granulomatous dermatitis. Because of possible cross reactivity of eccrine duct epithelium with bile duct epithelium, the antigenic target in the setting of hepatitis C and primary biliary cirrhosis, a concomitant lymphocytic eccrine hidradenitis may be an additional clue.

References

  1. Magro CM, Crowson AN. Interface and granulomatous dermatitis as a manifestation of antecedent microbial infection : the superantigen id reaction. J Cutan Pathol 1998;28:538-44.
  2. Magro CM, Crowson AN. Lichenoid and granulomatous dermatitis : a novel cutaneous reaction pattern. Int J Dermatol 2000;39:126-33.


LICHEN PLANUS-LIKE ERUPTIONS OF SECONDARY SYPHILIS

Occasionally patients with secondary syphilis may develop a papulosquamous eruption resembling lichen planus, both clinically and histologically. The main differentiating points at a light microscopic level are the presence of granulomata, typically confined to the superficial dermis and a conspicuous plasmacellular infiltrate. Lichenoid drug reactions (Tables 6 + 7)

Clinical
Lichenoid drug eruptions resemble lichen planus (LP) clinically with eruptions developing over weeks to months, with individual lesions being violaceous papules, sometimes with a superadded psoriasiform appearance. However, the eruptions are more extensive than LP, and oral involvement is unusual Slow resolution follows drug cessation, and post-inflammatory pigmentation is often pronounced. Implicated drugs are listed in the Table.

Histopathology
Like LP, the lichenoid drug reaction shows a band-like lymphocytic infiltrate along the dermo-epidermal junction, with vacuolopathic basal layer keratinocyte degeneration and colloid body formation, but with more frequent suprabasilar lymphocytosis around degenerating keratinocytes with globular collections of colloid bodies in the papillary dermis. Unlike LP, parakeratosis, eosinophils and plasma cells are frequently present, and deeper perivascular extension is the rule.

Differential diagnosis
Acanthosis is less striking in the lichenoid drug eruption than in LP, and the wedge-shaped hypergranulosis of LP is uncommon. Lichenoid patterns of inflammation may be seen in certain connective tissue diseases (discussed elsewhere). However, such cases often manifest at least focal epidermal atrophy, and virtually never exhibit tissue eosinophilia, unless they are of drug induced etiology.


TABLE 6
Lichenoid drug reactions


CLINICAL FEATURES
Extensive violaceous papular eruption, sometimes with psoriasiform appearance
Individual lesions resemble lichen planus
Post-inflammatory hyperpigmentation more pronounced than lichen planus
Clear following drug withdrawal


HISTOPATHOLOGY
Band-like lymphocytic intfiltrate hugs dermoepidermal junction
Basilar vacuolopathy of keratinocytes and colloid body formation
Patchy parakeratosis often seen
Mixed lymphohistiocytic, eosinophilic and/or plasmacellular dermal infiltrate
Mid-dermal perivascular extension


DIFFERENTIAL DIAGNOSIS
Lichen planus
Connective tissue diseases with lichenoid infiltrates:
      Subacute cutaneous lupus erythematosus
      Discoid lupus erythematosus
      Systemic lupus erythematosus in the setting of anti-Ro antibodies
      Mixed connective tissue diseasePost-herpetic eruptions

Other lichenoid hypersensitivity reactions, including:
      Some insect bite reactions (especially spider bites)
      Lichenoid contact reactions (ie color photodeveloper fluids)

Erythema multiforme

TABLE 7
Causes of lichenoid drug eruptions
Beta-blockers
Captopril
Methyldopa
Thiazides
Lasix
Gold
Antimalarials
Quinidine
Oral hypoglycemic agents
Phenytoin and carbamazepine
Antituberculous agents
Phenylbutazone
Antipsychotics (including phenothiazines)
Bismuth
P-aminosalicylic acid
Lithium

References

  1. Crowson AN, Magro CM. Drug eruptions. In : Barnhill R, Crowson AN, Busam K, Granter S ed's. Textbook of Dermatopathology. New York : McGraw-Hill Co, 1998:257-270.
  2. Magro CM, Crowson AN. Lichenoid and granulomatous dermatitis. Int J Dermatol 2000;39:126-33.


LICHENOID ("CHRONIC") GRAFT-VERSUS-HOST DISEASE

Introduction/Pathogenesis/Clinical
Clinically, chronic GVHD is characterized by a cutaneous eruption comprising lichen planus-like discrete erythematous papules generally occurring more than 100 days after bone marrow transplant. One recent study suggested that lichenoid GVHD could be seen in a wide time range (33-832 days) post transplantation and was associated with an increase in the death rate from GVHD.

Histopathology
Although there are areas of cell poor interface change focally the density of the superficial infiltrate is of sufficient magnitude to assume a band-like disposition. A narrow band of subepidermal fibroplasia with pigment incontinence is typical. The intensity of the lichenoid process is not as striking as lichen planus. The lichenoid process may manifest follicular accentuation. In cases which occur earlier in the post transplantation course (ie day 30), the distinction from acute grade II/III graft versus host disease may be difficult. However a diagnosis which favors chronic graft versus host disease is the absence of gastrointestinal or hepatobiliary symptoms of acute grade II/III graft versus host disease .

Differential Diagnosis
The differential diagnosisis that of the lichenoid eruptions, namely, lichen planus, connective tissue diseases with lichenoid infiltrates (ie subacute cutaneous lupus erythematosus, discoid lupus erythematosus, systemic lupus erythematosus in the setting of anti-Ro antibodies and mixed connective tissue disease), post-herpetic zosteriform eruptions, and lichenoid hypersensitivity reactions.

Immunophenotyping can aid in the distinction of chronic graft versus host disease from acute graft versus host disease. Specifically while both types of lichenoid tissue reaction can show CD3 positivity, the infiltrate in chronic graft versus host disease is CD8 dominant while that in lichen planus comprises mainly CD4 positive cells. In addition the lymphokine natural killer cell activity (LAK) markers anti-CD16 and anti-CD28 are largely nonreactive in lesions of lichen planus and strongly positive in lesions of chronic graft versus host disease.

Pathogenesis
Acute graft versus host disease is a critical determinant in the development of chronic graft versus host disease. Regarding the latter there are two broad cateogries of skin involvement: the lichenoid lesion and the sclerodermoid tissue reaction. With respect to the latter, dermal fibrosis, loss of cutaneous appendages, and loss of subcutaneous fat are the dominant features of sclerodermoid chronic graft versus host disease.

The question obviously arises as to the mechanism of fibrosis in chronic graft versus host disease. Mast cells have always been postulated to play a role in the propogation of tissue fibrosis in sclerodermoid graft versus host disease. One recent study examined the benefits of a mast cell stabilized (sodium chromylate) and a mast cell activator on cutaneous graft versus host disease. Sodium chromylate ameliorated skin features of chronic graft versus host disease while the mast cells activator caused skin changes reminiscent of mild chronic graft versus host disease in control mice. In addition there are extracutaneous stigmata in chronic graft versus host disease which recapitulates collagen vascular disease inclduing Sjogren's syndrome, primary biliary cirrhosis, entrappment neuropathy, polymyositis, lymphopenia, Combs hemolytic anemia, autoimmune thrombocytopenia and a sundry of positive autoimmune serology (i.e.anti-nuclear antibody, anti-smooth muscle antibodies). The mechanism of extracutaneous chronic graft versus host disease is poorly understood but appears to be mediated by allogenic and autoreactive T cell clones. The mergence of the latter may be due to defective thymic self deletion of autoreactive T cell clones stemming from acute graft versus host reactions on thymic epithelium.

Reference

  1. Horn TD, Zahurak ML, Atkins D, Solomon AR, Vogelsang GB. Lichen planus-like histopathologic chracteristics in the cutaneous graft-versus-host reaction. Arch Dermatol 1997;133:961-5.


LICHENOID MYCOSIS FUNGOIDES

There are rare case of mycosis fungoides (MF) which present with a lichenoid dermal infitlrate associated with lichen planus-like acanthosis, hopergranulosis, basal layer vacuolation and squamotization. Eosinophils and plasma cells, the former reflecting a Th2-dmoinant cytokine profile, may also be seen. Cerebriform mononuclrear cells are present histologically. It has been suggested that this morphology may herald a more aggressive clinical course.

Reference

  1. Guitart J, Peduto M, Carow WA, Roenigk HH. Lichenoid change in mycosis fungoides. J Am Acad Dermatol 1997;36:417-422.