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Graft-versus-host disease (GVH) is a disease of modern medicine. It most commonly occurs in bone marrow transplant patients receiving an allogeneic transplant of immunocompetent lymphocytes. The donor cytotoxic T lymphocytes attack the recipient's organs including skin, gut, liver, and mucous membranes. It may occur in 50% of recipients of allogeneic bone marrow transplants.

GVH may also occur after maternofetal blood transfusions, intrauterine exchange transfusions, and administration of non-irradiated blood products to patients with metastatic malignancies or with immunodeficiencies.


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Graft-vs-Host Disease After Solid Organ Transplant

H. Evin Gulbahce, MD, Charlotte A. Brown, PhD, FACMG, Myra Wick, PhD, Miriam Segall, PhD, and Jose Jessurun, MD


Am J Clin Pathol 2003;119:568-573 Abstract quote

We identified 10 solid organ transplant recipients with a histologic diagnosis of graft-vs-host disease (GVHD). Histologic slides were reviewed, and information on the transplant, HLA match, and blood product transfusion history was obtained. Molecular testing to evaluate the presence of donor lymphocytes (chimerism) was done in 1 case.

All patients underwent at least 1 gastrointestinal biopsy; 1 patient also underwent a skin biopsy and 1 patient a liver biopsy; all specimens showed grade I to IV acute GVHD. Six patients had a diagnosis of GVHD within 3 months of blood product transfusion and/or solid organ transplantation, which is the time frame in which GVHD reportedly occurs after solid organ transplantation; 4 patients had a distant history of blood product transfusion or solid organ transplantation. In 1 patient, a molecular technique using the polymorphic marker DIS80 documented donor lymphocytes in the colonic tissue and blood (chimerism).

Although histologic findings of GVHD are quite specific, they are not pathognomonic. A GVHD-like histologic pattern can be seen in other conditions such as drug reactions and viral infections. Demonstration of donor lymphocytes in the involved organ helps support the diagnosis of GVHD in questionable cases.



Overexpression of Tissue Inhibitor of Metalloproteinases-3 in Intestinal and Cutaneous Lesions of Graft-versus-Host Disease.

Salmela MT, Karjalainen-Lindsberg ML, Jeskanen L, Saarialho-Kere U.

Departments of Dermatology (MTS, LJ, US-K) and Pathology (MLK-L), Helsinki University Central Hospital, Helsinki, Finland.

Mod Pathol 2003 Feb;16(2):108-14 Abstract quote

Matrix metalloproteinases (MMPs) have been implicated in the pathobiology of various T-cell-mediated inflammatory disorders of the intestine and skin. Their synthetic inhibitor has been shown to prevent lethal acute graft-versus-host disease in animal models. We intended to determine the expression of MMPs 1, 3, 7, 9, 10, 12, and 19 and tissue inhibitors of metalloproteinases (TIMPs) 1 and 3 in intestinal and cutaneous lesions of patients suffering from graft-versus-host disease after bone marrow transplantation. In situ hybridizations for MMPs 1, 3, 7, 10, and 12 as well as TIMPs 1 and 3 were performed using (35)S-labeled cRNA probes on intestinal (n = 13) and cutaneous specimens (n = 9) from patients with graft-versus-host disease.

Immunohistochemical stainings were carried out to localize MMP-9, MMP-19, TIMP-3, and TGF-beta1 proteins, and TUNEL staining, to detect apoptotic cells. TIMP-3 mRNA and protein were detected in cutaneous lesions in areas with vacuolar degeneration of the basal epidermal layer in all skin samples, and they colocalized with apoptotic keratinocytes and partly with staining for TGF-beta. None of the MMPs examined were overexpressed in skin lesions. Signals for MMP-1 and MMP-3 mRNA was found in 10/13 and 5/13 intestinal biopsies, respectively. In the gut, MMP-19-positive epithelial cells, particularly in the crypts, were found in 10/13 samples. Expression of MMPs 7, 9, 10, and 12 was absent or very low. TIMPs 1 and 3 were expressed by stromal cells in 12/13 and 10/13 gut samples, respectively. Whereas TIMP-1 was expressed particularly by subepithelial cells where epithelium had shed away, TIMP-3 was detected in deeper areas.

We conclude that MMPs are differentially regulated in the skin and gut lesions of graft-versus-host disease. In agreement with previous data on cancer cells, TIMP-3, induced by TGF-beta1, may contribute to the apoptosis of keratinocytes in cutaneous graft-versus-host disease lesions, leading to typical histopathological changes. We also conclude that MMPs play a less important role as effector molecules in intestinal graft-versus-host disease than in celiac or inflammatory bowel disease.


Acute graft-versus-host disease after liver transplantation diagnosed by fluorescent in situ hybridization testing of skin biopsy specimens.

Department of Dermatology, Mayo Clinic, Rochester, Minnesota 55905, USA.

J Am Acad Dermatol. 2006 Oct;55(4):642-6 Abstract quote

Acute graft-versus-host disease after orthotopic liver transplantation is an underrecognized entity with a guarded prognosis.

We describe a patient who underwent orthotopic liver transplantation with an HLA-matched donor liver. She had an uneventful recovery from operation up until day 36 posttransplantation, when she developed a generalized, erythematous, mostly macular eruption, accompanied by ascites, diarrhea, and fever.

The diagnosis of graft-versus-host disease was considered but a drug rash could not be excluded. A polymerase chain reaction-based chimerism assay failed to identify donor DNA in peripheral blood. A confirmatory fluorescent in situ hybridization analysis revealed significant numbers of donor lymphocytes in biopsied skin, with lesser amounts in biopsy specimens from the stomach and colon. Despite immunosuppressive treatment, the patient died of overwhelming sepsis 18 weeks after transplantation.

We conclude that early testing of skin biopsy specimens using fluorescent in situ hybridization in sex-mismatched patients with orthotopic liver transplantation can serve as an early diagnostic tool for graft-versus-host disease.


Classically, acute and chronic disease has been based on time combined with clinical and histological parameters

The criterion of 100 days after transplantation for separating acute versus chronic disease has been used

However, this is an arbitrary division as the lichenoid rash of the chronic phase has been observed as early as 31 days and acute GVH may occur after day 100 in rare cases

Early acute phase
Erythematous macular rash with diarrhea, vomiting, and liver dysfunction
Chronic phase
Lichenoid phase resembling lichen planus
Poikilodermatous phase
Poikilodermatous lesions
Sclerodermoid phase
Localized or generalized lesions

Sclerodermatous graft-vs-host disease: clinical and pathological study of 17 patients.

Penas PF, Jones-Caballero M, Aragues M, Fernandez-Herrera J, Fraga J, Garcia-Diez A.

Department of Dermatology, Hospital Universitario de la Princesa, Diego de Leon 62, 28006 Madrid, Spain.

Arch Dermatol 2002 Jul;138(7):924-34 Abstract quote

OBJECTIVE: To collect and review all cases of sclerodermatous chronic graft-vs-host disease from January 1, 1982, through December 31, 2000.

SETTING: University hospital in Madrid, Spain.

PATIENTS: During the study period, 493 allogenic bone marrow transplantations were performed. Sclerotic lesions developed in 17 patients.

RESULTS: Sclerotic lesions appeared after a mean of 529 days. Previously, 10 (59%) of 17 patients showed a leopard-skin eruption. Sclerosis was generalized in 12 patients and localized in 5. Nine patients presented with rippling of the skin and 8 with lichen sclerosus lesions. We found no anti-Scl-70 or anti-centromere antibodies. Results of histological analysis showed pandermal or deep-dermal sclerosis, slight vacuolar degeneration of the basal cell layer, and follicular damage with follicular plugs. In 6 (50%) of the 12 patients with evaluable biopsy specimens, septal panniculitis was found. Squamous syringometaplasia and mucin deposits were also detected. Treatment with high doses of prednisone and azathioprine helped in 8 of 9 patients. In 12 patients, sclerosis disappeared after 487 days.

CONCLUSIONS: Leopard-skin eruption, follicular involvement, ripply skin, and lichen sclerosus lesions have been described poorly or not at all in sclerodermatous graft-vs-host disease. The presence of lichen sclerosus, morphea, septal fibrosis, and fasciitis suggests that the sclerosis can start at and affect any level of the skin. Treatment with prednisone and azathioprine seems to halt the process. Most patients have a good prognosis with treatment. Although most lesions disappear, small areas of fibrosis may remain that do not produce any physical or functional impairment.

Late appearance of acute GVH after suspending or tapering immunosuppressive drugs

Arch Dermatol 2001;137:61-65

Rash occurred between days 153 to 192 days after transplantation with allogeneic bone marrow transplantation or peripheral blood stem cell transplantation

Late flare corresponded to tapering or supsending cyclosporine or corticosteroids

Eczematoid Graft-vs-Host Disease: A Novel Form of Chronic Cutaneous Graft-vs-Host Disease and Its Response to Psoralen UV-A Therapy.

Department of Dermatology, King's College Hospital, Denmark Hill, London SE5 9RS, England.


Arch Dermatol. 2007 Sep;143(9):1157-62. Abstract quote

BACKGROUND: Chronic cutaneous graft-vs-host disease (GVHD) is generally classified by whether lesions have a lichenoid or sclerodermatous morphology. Other unusual clinical forms have been reported that exhibit the features of dermatomyositis and lupus erythematosus. Within a large population of individuals who underwent allogeneic stem cell transplantation because of hematologic malignancy, a group of patients was identified in whom severe and persistent eczema developed.

OBSERVATIONS: We prospectively evaluated 10 adult patients with unexplained eczematous dermatosis after allogeneic hematopoietic stem cell transplantation. The dermatosis developed between 2 and 18 months (mean, 7.5 months) after receipt of the transplant, exhibited the typical clinical features of dermatitis, and became erythrodermic in each case. The patient group had strong risk factors for chronic cutaneous GVHD: 8 had received a transplant from an unrelated donor, 7 had evidence of extracutaneous GVHD, and 7 had a history of acute cutaneous GVHD. Sampling of lesional skin revealed the histologic features of GVHD coexisting with the changes of dermatitis. The patients were treated with topical corticosteroid and systemic immunosuppressive agents. Six patients also received psoralen-UV-A. Four patients achieved prolonged remission. Six patients died, 5 of infective complications and 1 of relapsed leukemia.

CONCLUSIONS: The eczematous dermatosis observed represents a novel form of chronic cutaneous GVHD that we named eczematoid GVHD. Eczematoid GVHD is an aggressive, chronic dermatosis that requires substantial immunosuppression therapy to achieve control. It is associated with a poor prognosis. Although atopy can be transmitted to an individual from a hematopoietic stem cell transplant, none of the donors in this series gave a history of an atopic disorder. Therefore, other factors must be implicated in provoking the expression of an eczematous phenotype in individuals with underlying chronic graft-vs-host activity.
Lichen sclerosus and eosinophilic fasciitis as manifestations of chronic graft-versus-host disease: expanding the sclerodermoid spectrum.

Schaffer JV, McNiff JM, Seropian S, Cooper DL, Bolognia JL.

Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut, USA.
J Am Acad Dermatol. 2005 Oct;53(4):591-601. Abstract quote  

Chronic cutaneous graft-versus-host disease (GVHD) is classically divided into two major clinical categories--lichenoid and sclerodermoid. Although diffuse areas of sclerosis as in scleroderma characterize the more advanced stages of the sclerodermoid form, the initial circumscribed plaques would be more correctly described as morpheaform.

Eosinophilic fasciitis (EF) (a fibrosing disorder related to deep morphea) and lichen sclerosus (LS) have also been reported as manifestations of sclerodermoid GVHD. However, these two presentations of GVHD have not been emphasized in the dermatologic literature.

We describe 6 patients, all of whom developed LS and two of whom also developed EF in the context of chronic GVHD. Each patient presented clinically with hypopigmented plaques that exhibited wrinkling, scaling, and follicular plugging. These lesions demonstrated the classic histologic features of LS including epidermal atrophy; a subepidermal zone of pale-staining, homogenized collagen; and a bandlike lymphocytic infiltrate. Although all patients eventually developed morpheaform and/or sclerodermoid GVHD, LS was a prominent part of the initial presentation of chronic cutaneous GVHD in every case. The LS lesions tended to occur on the neck and upper to mid aspect of the trunk, whereas morpheaform lesions favored the lower aspect of the trunk. EF involved the extremities (sparing the hands and feet), and was characterized clinically by an acute onset of pain and edema followed by induration with a rippled appearance.

This case series serves to expand the spectrum of sclerodermoid GVHD, with LS as the most superficial and EF as its deepest manifestation.



Am J Surg Pathol 1997;21:988-996
J Am Acad Dermatol 1998;38:548-554
Arch Dermatol 2000;136:717-721

For many years, the skin biopsy was used to establish or confirm the diagnosis

Recently, several publications have concluded that the pathologic findings are not helpful in the management of a potential GVH rash since the histologic features are indistinguishable from a drug hypersensitivity reaction, the usual clinical and histological differential diagnostic dilemma

Histological Evaluation of Acute Mucocutaneous Graft-Versus-Host Disease in Nonmyeloablative Hematologic Stem Cell Transplants with an Observation Predicting an Increased Risk of Progression to Chronic Graft-Versus-Host Disease.

From the *Departments of Dermatology; daggerHematology, and Oncology, Indiana University School of Medicine; double daggerIndiana University School of Dentistry, Indianapolis; and section signDepartment of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN.

Am J Dermatopathol. 2007 Feb;29(1):1-6. Abstract quote

The incorporation of nonmyeloablative conditioning prior to the transplantation of allogeneic hematopoietic cells has emerged as an alternative to myeloablative chemo- and/or radiotherapy for the treatment of hematologic malignancies. Graft-versus-host disease (GVHD) remains a significant complication of both types of hematopoietic cell transplantation (HCT). The clinical phenomenon of late-onset (>100 days after HCT) acute GVHD recently has been described following nonmyeloablative allogeneic transplantation (NMAT); however, there has been no detailed histologic description of acute GVHD in this setting.

We sought to characterize the histopathologic features of acute GVHD following NMAT. The clinical and pathologic features of 20 patients with acute GVHD following NMAT over a three-year period were reviewed. Late-onset acute GVHD was diagnosed in 10 of 20 patients with a mean onset of 109.8 days (range 8-410 days); eight (40%) of these subjects with acute GVHD also had concomitant histologic features of chronic lichenoid chronic GVHD. Cases with "composite" histologic features were more likely to progress to fully developed chronic GVHD compared to those without this finding (87.5% vs 25%, P < 0.01).

These findings support the existence of late-occurring mucocutaneous GVHD after NMAT and define a strong clinical/laboratory predictor for the subsequent development of chronic GVHD. Patients with composite skin GVHD may benefit from an earlier, more aggressive immunosuppressive interventional strategy.

Tissue eosinophils and the perils of using skin biopsy specimens to distinguish between drug hypersensitivity and cutaneous graft-
versus-host disease.

Marra DE, McKee PH, Nghiem P.

Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
J Am Acad Dermatol. 2004 Oct;51(4):543-6. Abstract quote  

Graft-versus-host disease (GvHD) is a frequent and serious complication of bone-marrow transplantation (BMT), and carries a high morbidity and mortality if not promptly recognized and treated. The rash of acute GvHD is often difficult to distinguish clinically from a drug eruption, and skin biopsies are often performed in an attempt to render a diagnosis.

Histologically, eosinophils are classically associated with hypersensitivity reactions, and their presence in inflamed tissue is considered suggestive of a drug-induced dermatitis. We present 3 cases of acute exanthema in BMT recipients in whom the presence of eosinophils on skin biopsy specimen led to an initial diagnosis of drug eruption over GvHD. As a result, these patients experienced delays in the institution of definitive immunosuppressive therapy for GvHD.

We review the growing literature suggesting that no single or combined histologic feature, including tissue eosinophils, is useful in differentiating GvHD from drug eruptions in BMT recipients. Indeed, in most cases, the cause of a new-onset blanchable erythematous rash in a BMT recipient is most accurately determined by close examination and follow-up of the clinical features without a skin biopsy.

Lack of specificity in skin biopsy specimens to assess for acute graft-versus-host disease in initial 3 weeks after bone-marrow transplantation.

Kuykendall TD, Smoller BR.

Department of Pathology and Dermatology, University of Arkansas for Medical Sciences, 4301 W. Markham Street, Little Rock, AR 72205, USA.
J Am Acad Dermatol. 2003 Dec;49(6):1081-5. Abstract quote  

Acute graft-versus-host disease is a serious and common complication after allogeneic bone-marrow transplantation, occurring in more than 20% of HLA antigen-identical sibling transplants and unrelated donor transplants.

Bone-marrow transplantation is considered standard therapy for several hematologic malignancies and several nonhematologic disorders. In this retrospective study, we searched our institutional dermatopathology database between January 1998 and November 2002 for patients in whom skin biopsy specimens were examined less than 3 weeks after bone-marrow transplantation. A total of 40 slides from 38 patients were examined for the presence of the histologic features characteristic of acute graft-versus-host disease. Specimens of skin biopsies examined in the study varied from 3 to 21 days, with a mean of 12 days, status post-bone-marrow transplantation.

The histologic findings of the 40 slides we examined were nonspecific and could be accounted for by a number of diagnoses. In summary, we propose that skin biopsies need not be preformed before 3 weeks status post-bone-marrow transplantation if the sole purpose is to rule out acute graft-versus-host disease.
SKIN-ACUTE A histologic grading scheme divides the disease into acute and a chronic phase. The table below classifies acute changes.
Normal skin
Basal vacuolar damage
Dyskeratotic cells in the epidermis and/or follicles with dermal lymphocytic infiltrate
Fusion of basilar vacuoles to form clefts and microvesicles
Separation of epidermis from dermis

As the lesions mature, a lichenoid infiltrate may intervene resembling lichen planus

Still later, lesions may undergo a sclerodermoid phase with epidermal atrophy and basal vacuolation, resembling scleroderma

Lichenoid graft vs. host disease following liver transplantation.

Walling HW, Voigt MD, Stone MS.

Department of Dermatology, Division of
Gastroenterology-Hepatology, Department of Internal Medicine, and Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, USA.
J Cutan Pathol. 2004 Feb;31(2):179-84 Abstract quote.  

BACKGROUND: Graft vs. host disease (GVHD) is a common complication of bone marrow transplantation (BMT) but is rarely seen after solid organ transplantation.

METHODS: We report a case of lichenoid GVDH arising in a 60-year-old man 10 weeks after orthotopic liver transplantation.

RESULTS: Skin biopsies revealed changes suggestive of lichenoid GVHD, but histological features differed from those described in post bone marrow (stem cell) transplant GVHD, in that a dense lymphoid infiltrate was present. The brisk infiltrate contained eosinophils that initially led to concern for a lichenoid drug eruption. The patient developed multiorgan GVHD after reduction in immunosuppression. The diagnosis of chronic GVHD was confirmed by the demonstration of chimerism in the patient's peripheral blood. The generalized cutaneous eruption and systemic manifestations responded to salvage therapy including intravenous immunoglobulin infusion, increased immunosuppression with high-dose steroids, mycophenolate mofetil, and systemic and topical tacrolimus.

CONCLUSIONS: In interpreting skin biopsies, it is important to recognize that brisk inflammation may be seen in GVHD in the setting of solid organ transplantation, in contrast to the more sparse inflammation typical of GVHD following BMT. The clinical and histologic differential diagnosis included the eruption of lymphocyte recovery, drug reaction, and viral exanthem. We provide a conceptual framework for evaluating generalized cutaneous changes that may occur post transplantation.
Columnar epidermal necrosis

One unusual histologic variant of transfusion associated cutaneous GVH

It is characterized by loss of the entire epidermis in a columnar fashion replaced with mononuclear inflammatory cells
The stratum corneum contains eosinophilic dyskeratotic cells.

Eruption of lymphocyte recovery

This occurs in the setting of acute myelogenous leukemia patients following cytotoxic chemotherapy but who have not received a bone marrow transplant

A similar change occurs after cyclosporin A administration with a maculopapular eruption occurs about 14-21 days after therapy and correlates with the return of lymphocytes into the circulation

Biopsies show features identical to acute mild GVH


Bile Duct Apoptosis and Cholestasis Resembling Acute Graft-Versus-Host Disease After Autologous Hematopoietic Cell Transplantation

Michael D. Saunders, M.D.; Howard M. Shulman, M.D.; Carol S. Murakami, M.D.; Thomas R. Chauncey, M.D., Ph.D.; William I. Bensinger, M.D.; George B. McDonald, M.D.

From the Gastroenterology/
Hepatology (M.D.S., C.S.M., G.B.M.), Pathology (H.M.S.), and Oncology Sections (T.R.C., W.I.B.), Fred Hutchinson Cancer Research Center, Puget Sound Veterans Affairs Medical Center, and the University of Washington School of Medicine, Seattle, Washington

Am J Surg Pathol 2000;24:1004-1008 Abstract quote

BACKGROUND: Acute graft-versus-host disease (GVHD) of the liver is a frequent complication of allogeneic hematopoietic cell transplantation. This report describes hepatic GVHD following autologous transplantation.

METHODS: We reviewed 116 consecutive autologous transplant recipients. A diagnosis of GVHD was based on histology (segmental to subtotal destruction of bile ductal epithelial cells with apoptosis and lymphocytic infiltrates), clinical criteria (elevated serum alkaline phosphatase), a response to immunosuppressive therapy, and finding no other cause for cholestatic liver disease.

RESULTS: Two patients developed cholestatic liver disease (alkaline phosphatase levels over five times the normal upper limit) and had liver biopsies showing apoptotic and dysmorphic ductular epithelial cells typical of GVHD. Three additional patients developed cholestasis and intestinal symptoms but had gastric biopsies only, showing apoptotic crypt epithelial cells and crypt cell drop-out typical of GVHD.

CONCLUSION: Two recipients of autologous hematopoietic cells developed histologic abnormalities of small bile ducts and cholestatic liver disease resembling GVHD of the liver after allogeneic transplant. The mechanisms of bile duct damage in this setting may involve immune dysregulation related to reconstitution of immunity with peripheral blood stem cells.

Pulmonary Cytolytic Thrombi A Previously Unrecognized Complication of Bone Marrow Transplantation

H. Evin Gulbahce, M.D.; J. Carlos Manivel, M.D.; Jose Jessurun, M.D.

From the Department of Laboratory Medicine and Pathology, University of Minnesota, Fairview-University Medical Center, Minneapolis, Minnesota

Am J Surg Pathol 2000;24:1147-1152 Abstract quote

Lung injury is a frequent and severe complication of bone marrow transplantation (BMT).

Over the past 5 years we have recognized a new noninfectious pulmonary complication of allogeneic BMT in 12 patients, presenting with fever, pulmonary nodules on chest computed tomography, and distinctive histopathologic appearance descriptively termed ``pulmonary cytolytic thrombi'' (PCT).

All but one patient were children transplanted for malignant (9) and nonmalignant (3) conditions. Ten of the patients had active graft-versus-host disease (GVHD) of skin, bowel, or both at the time of diagnosis of the PCT. In all cases occlusive vascular lesions were present, most of them associated with hemorrhagic infarcts. The endothelial cell layer was discontinuous in all cases stained with antibody to CD31. The thrombi had entrapped recognizable leukocytes and CD45-positive cell fragments embedded in a tenacious basophilic material. The symptoms and radiologic findings resolved in weeks to months.

PCT may represent a previously unrecognized form of pulmonary acute GVHD.

Gastric Graft-Versus-Host Disease Revisited: Does Proton Pump Inhibitor Therapy Affect Endoscopic Gastric Biopsy Interpretation?

Welch DC, Wirth PS, Goldenring JR, Ness E, Jagasia M, Washington K.

*Department of Pathology, Division of Gastroenterology, Vanderbilt Medical Center, Nashville, TN daggerSection of Surgical Sciences, Division of Gastroenterology, Vanderbilt Medical Center, Nashville, TN double daggerDepartment of Internal Medicine, Division of Gastroenterology, Vanderbilt Medical Center, Nashville, TN section signDepartment of Internal Medicine, Division of Hematology-Oncology, Vanderbilt Ingram Cancer Center, Department of Medicine, Vanderbilt Medical Center, Nashville, TN.

Am J Surg Pathol. 2006 Apr;30(4):444-449. Abstract quote  

Accurate diagnosis of gastrointestinal graft-versus-host disease (GvHD) is important, as it contributes significantly to postallogeneic stem cell transplant (SCT) morbidity and mortality.

To test the hypothesis that proton pump inhibitor (PPI) therapy may interfere with histologic evaluation of gastric GvHD by inducing apoptosis, we evaluated epithelial apoptotic body counts in antral and fundic biopsies from SCT recipients and control patients, both taking and not taking PPIs at the time of endoscopic biopsy.

Hematoxylin and eosin-stained slides of gastric biopsies from 130 patients (75 allogeneic SCT with GvHD on clinical and histologic grounds, and a comparison group of 55 age- and sex-matched nontransplant patients with histologically normal gastric biopsies) were reviewed. The groups were further stratified into patients taking (PPI+) and not taking PPIs (PPI-) at the time of biopsy. Apoptotic bodies (AB)/10 (400x) high power fields (HPF) were quantified for each case. Mean apoptotic body counts were then calculated for each case group. Seventy antral cases (31 control and 39 transplant) were also evaluated via gastrin immunohistochemistry, and the mean number of gastrin positive cells/400x HPF calculated. In the PPI- groups, apoptosis was increased in biopsies from transplant patients, compared with controls, both in antral and fundic mucosa. In PPI+ patients, there was significantly more apoptosis in the gastric body in transplant patients than in controls. However, comparing antral biopsies from control and transplant PPI+ patients, there was no significant difference in AB quantitation. More apoptosis was seen in antral biopsies from PPI+ control patients when compared with PPI- control patients (P=0.009). Mean numbers of gastrin positive cells/400x HPF were increased in both control and transplant patients taking PPIs (85 and 58, respectively) compared with samples from those patients not taking PPIs (48 and 51, respectively).

PPI therapy is associated with increased apoptosis in antral biopsies and may interfere with the evaluation of GvHD in biopsies from this site. A similar increase in apoptosis was not seen in fundic biopsies; biopsy of the gastric fundus rather than antrum may be preferable for the diagnosis of upper gastrointestinal GvHD.


ACUTE PHASE-SKIN Erythema multiforme
Drug reaction
Toxic epidermal necrolysis
Subacute radition dermatitis
Lichenoid drug eruptions

Host-vs.-altered-host eruptions in patients on liposomal doxorubicin.

Skelton H, Linstrum J, Smith K.

Laboratory Corporation of America, Herndon, Virginia, The Washington Clinic, Chevy Chase, Maryland, National Naval Medical Center, Bethesda, Maryland.

J Cutan Pathol 2002 Mar;29(3):148-53 Abstract quote

BACKGROUND: Anthracycline antitumor antibiotics are the most commonly used chemotherapeutic agents. One of these is doxorubicin. Liposomal doxorubicin was developed as a drug delivery system in order to deliver the active drug intracellularly while decreasing the systemic toxicity, particularly hematological and cardiac toxicity.

METHODS: The clinical and histologic findings of the cutaneous eruptions of associated with liposomal doxorubicin are reviewed.

RESULTS:: The eruptions occurred in three women with metastatic ovarian carcinoma who were treated with liposomal doxorubicin. These three patients developed erythematous macular/papular to plaque cutaneous lesions, and in one patient a vesicular component. The eruptions involved the trunk and extremities approximately 3-4 weeks after completions of therapy. None of the patients had any documented infections, and none of the patients had symptoms other than pruritus. The eruptions cleared over a period of weeks to months. Histologic features included an interface dermatitis with numerous apoptotic/dyskeratotic cells within the epidermis, with involvement the intra-epidermal sweat ducts and the infundibulum of hair follicles.

CONCLUSION: We believe that these eruptions represented a chemotherapy induced host-vs.-altered host reaction.


Keratinocyte dysplasia: an usual finding after transplantation or chemotherapy.

Castano E, Rodriguez-Peralto JL, Lopez-Rios F, Gomez C, Zimmermann M, Iglesias Diez L.

Department of Dermatology, Department of Pathology, and Department of Oncology, Hospital Universitario 12 de Octubre, and Staticon International Espana, SA, Madrid, Spain.

J Cutan Pathol 2002 Nov;29(10):579-84 Abstract quote

BACKGROUND: Keratinocyte dysplasia is a histologic abnormality that has rarely been described in the first weeks after chemotherapy or transplantation. The purpose of this study was to determine the prevalence of early keratinocyte dysplasia after chemotherapy or transplant and to analyze the relationship between dysplasia and chemotherapeutic agents, transplantation or development of acute graft vs. host disease (GvHD).

METHODS: A computer search for transplant patients was performed in the Departments of Hematology, Oncology and Surgery. Only patients with a skin biopsy taken within the first days of transplantation or chemotherapeutic treatment were included in the analysis.

RESULTS: Forty-four patients were included, of these 19 were women and 25 were men. Thirty-four (77.3%) of 44 biopsies showed keratinocyte dysplasia. This dysplasia was severe in 18 cases (40.9%). Cyclophosphamide was more likely to be associated with severe keratinocyte maturation disturbances (OR = 5.51) (p < 0.01) whereas cytarabine was associated with a lower risk (OR = 0.19) (p < 0.05).

CONCLUSIONS: Severe keratinocyte dysplasia is a usual histologic finding in patients who have received chemotherapy and/or transplantation (40.9%). Cyclophosphamide is the main chemotherapeutic agent significantly associated with a higher risk of severe dysplasia (OR = 5.51). Causes other than GvHD or preconditioning treatment may be involved in the keratinocyte dysplasia, as it can be also found in transplanted patients who have not received chemotherapy and/or have not developed GvHD.



Tacrolimus Ointment in the Treatment of Chronic Cutaneous Graft-vs-Host Disease A Case Series of 18 Patients

Caroline J. Choi, MD; Paul Nghiem, MD, PhD

Arch Dermatol. 2001;137:1202-1206 Abstract quote

Tacrolimus (formerly FK 506) is an immunosuppressive drug that works by inhibiting calcineurin, a calcium-dependent protein phosphatase required for immune function. Tacrolimus has been shown to be effective topically in atopic dermatitis and systemically in psoriasis and graft-vs-host disease (GVHD). However, its efficacy in treating cutaneous GVHD when applied topically has not been reported.

To assess the therapeutic efficacy of 0.1% tacrolimus ointment on chronic cutaneous GVHD in patients with symptoms refractory to systemic corticosteroid therapy.

Tacrolimus ointment effectively treated pruritus and/or erythema in 13 (72%) of 18 patients with chronic GVHD. Responding patients had a rapid effect within several hours to days. Effectiveness was measured by means of patient report, results of physical examination, side-by-side comparisons of tacrolimus vs a vehicle control, and temporal flares of the cutaneous symptoms of the disease in the context of stopping tacrolimus ointment therapy. Because of the progression of GVHD and in 2 cases, loss of drug efficacy, all patients eventually went on to receive more aggressive treatment, including increases in steroid dosage, psoralen–UV-A therapy, and extracorporeal photopheresis.

This case series suggests that tacrolimus ointment has efficacy in treating the erythema and pruritus of steroid-refractory, chronic cutaneous GVHD in most patients. The rapid response of tacrolimus ointment may provide a useful therapeutic bridge to systemic therapies that have slower onset, such as psoralen–UV-A therapy or extracorporeal photopheresis.

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Satellite cell necrosis-Clustering of lymphocytes around damaged epidermal keratinocytes (lymphocyte associated apoptosis).

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