Grade 0

Grade 1 Grade 2

Grade 3

Grade 4

Normal skin

Perivascular Perivascular mononuclear mononuclear cell infiltrates cell infiltrates

Grade 2 changes plus epidermolysis and bulla formation (from fusion of basilar vacuoles)

Denudation of epidermis (separation of epidermis from dermis)

Vacuolar degradation of Vacuolar degradation epidermal-dermal junction

Dyskeratotic cells or eosinophilic bodies in the epidermis

Dyskeratotic cells or eosinophilic bodies in the epidermis specific for GVHD alone and can occur in a variety of other cutaneous diseases and reactions. Many skin eruptions occur posttransplant in response to the preparative regimen, hypersensitivity to drugs (e.g., antibiotics), infections, and even the recovery of leukocytes, and, therefore, there is no "gold standard" for accurate pathologic diagnosis of GVHD.7 Moreover, there is no correlation between the numbers of infiltrating mononuclear cells or of dyskeratotic cells in skin specimens and the clinical outcome.7 The diagnosis of cutaneous GVHD is based on exclusion of other confounding contributors such as drugs and viral exanthems, and depends upon clinicopathologic correlation, i.e., clinical history and manifestations supported by characteristic pathologic changes. Indeed, the timing of the clinical manifestations is an important component of the diagnosis, as some pathologists will consider GVHD in the differential only if characteristic histopathologic changes occur during or after engraftment.

Involvement of the gut and liver in GVHD is usually accompanied by skin changes, but, rarely, these tissues can be involved separately or together without skin manifestations. The primary clinical manifestation of gut GVHD is diarrhea and abdominal pain. The diarrhea is initially watery in nature but, commonly, becomes bloody requiring transfusion support with platelets and red cells. The volume of diarrhea defines the different stages of gut involvement. Rectal biopsy is helpful in the diagnosis of gut GVHD, particularly when diarrhea occurs in the absence of cutaneous eruptions. The early finding of lymphocytic infiltrates at the crypts—accompanied by necrosis and dropout of crypt cells—is characteristic of the diagnosis, but, again, is not pathognomonic for GVHD. Like the skin, different pathologic stages are recognized culminating in mucosal denudation (grade 4), and the differential includes drug reactions and infection (particularly cytomegalovirus infection). Hepatic GVHD is manifested by a rise in the conjugated bilirubin, and the level of total bilirubin elevation defines the clinical stages of liver disease. Lymphocytic infiltrates in the interlobular and marginal bile ducts are characteristic histopathologic findings, which lead to the clinically identifiable cholestatic picture.

As mentioned above, the timing of skin, gut, and liver changes is a critical component of the diagnosis of GVHD. Although a "hyperacute" form of GVHD can occur typically in HLA-mismatched donor—recipient pairs, manifested by fever and markedly accelerating skin changes with diarrhea and hyperbilirubinemia before engraftment, most acute GVHD will initially present about the time of engraftment or thereafter. Within the past several years, characteristic clinical findings of an "engraftment syndrome" have been described in recipients of both autologous and allo-geneic stem cell transplants.8-10 This syndrome typically consists of noninfectious fever, a maculopapular skin eruption resembling GVHD, capillary leak with resultant weight gain and pulmonary infiltrates/effusions, and, not uncommonly, hyperbilirubinemia and diarrhea. The fact that these changes occur in autolo-gous transplant recipients indicates that the patho-physiology of this entity does not depend on alloreac-tivity per se. Interestingly, the skin biopsy findings are consistent with GVHD.8 Treatment of this syndrome requires prompt administration of corticosteroids to prevent complications of capillary leak, including renal dysfunction and pulmonary failure.

The pathophysiology of the engraftment syndrome may overlap with that of acute GVHD. The common feature in these entities may be primary endothelial damage as a consequence of inflammatory mediators such as IL-2, TNF-a and IFN-7, released locally by infiltrating perivascular lymphocytes.811-13 In GVHD, however, there is also evidence of direct cell-mediated immunologic reactivity resulting in microvascular injury.14 One effect of combining cyclosporin A and rapamycin is to modify the migration capabilities of lymphocytes, by altering lymphocyte and/or endothe-lial adhesive structures mediating lymphocyte recruitment from the vasculature and into the tissue. In this regard, corticosteroids, the first-line pharmacologic agents in the treatment of acute GVHD, also profoundly affect lymphocyte migration to lymphoid and extra-lymphoid tissues,1516 and decreased lymphocyte infiltrates in affected tissues are a prognostic sign for steroid-responsiveness in GVHD therapy.17

In Billingham's classic description of the elements required for the development of GVHD,18 three requirements were emphasized: (1) The host must be incapable of rejecting the graft; (2) The graft must contain immunocompetent cells; and (3) There must be incompatibilities in transplantation antigens between donor and host. Despite the fact that this description needs to be modified somewhat in light of evidence of GVHD occurring in the setting of blood transfusions, solid organ transplants, and in the case of cyclosporin-induced autologous GVHD (due to induction of autoreactive T cells19), Billingham's tenets reflect important basic principles in the biology of GVHD. However, given the data reviewed above and the pathologic evidence of lymphocytic infiltrates consistently accompanying GVHD-induced tissue injury, a fourth requirement to Billingham's criteria must be proposed: effector lymphocytes must migrate to the target tissues in GVHD.

The pathologic hallmark of acute GVHD is mononuclear cell infiltrates in the involved tissues.2021 The pathogenesis of acute GVHD involves the migration of both alloreactive lymphocytes and of NK cells into target tissues.22-25 A central role for alloreactive T cells in the development of GVHD is indicated by the fact that T-cell depletion of donor marrow significantly abrogates the incidence of GVHD.26 Indeed, the lympho-cytic infiltrates of dermal GVHD are composed of donor-derived cells.27 Infiltrating NK cells may contribute to tissue damage in GVHD by their local release of inflammatory cytokines such as TNF-a and IFN-7.28'29 The NK cell infiltrates are also donor-derived,30 indicating that their localization in tissues is likewise due to recruitment from the circulation.

Think Clean and Green to Flawless Skin

Think Clean and Green to Flawless Skin

Lets accept the fact: many of us are skin conscious. As much as possible, we wanted to have a fresh, good looking skin. However, many of us failed to recognize that simple steps are the best ways to attain it.

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