- Email: [email protected]
The inflamed pancreas transplant: histological differential diagnosis
Seminars in Diagnostic Pathology (2004) 21, 255-259
The inflamed pancreas transplant: histological differential diagnosis Cinthia B. Drachenberg, MD, John C. Papadimitriou, MD, PhD From the Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland. KEYWORDS: Acute rejection; Chronic rejection; Peripancreatitis; CMV; Lymphoproliferative disorder; Percutaneous biopsy
Excellent results are obtained with pancreas transplantation for the treatment of diabetes mellitus. The clinical parameters indicating graft dysfunction are nonspecific, and evaluation of a graft biopsy is often necessary to determine the etiology of graft dysfunction and assess the status of the graft. Inflammation of the pancreas allograft is the most common histological feature seen in core biopsies. In most cases, the inflammation is secondary to acute rejection, chronic rejection, and infectious complications. Although in many ways the morphological features of these processes overlap, there are also important differences that can help the pathologist to reach the correct diagnosis. © 2005 Elsevier Inc. All rights reserved.
Pancreas transplantation is currently considered a good treatment option for patients with difficult to control Type I diabetes.1 Because in many patients diabetes mellitus is associated with renal failure, most pancreas transplants are done simultaneously with a kidney transplant (SPK). Patients who have previously undergone a successful kidney transplant may receive a pancreas after kidney (PAK) transplantation. In patients in whom pancreas transplantation is indicated (eg, brittle diabetes) but that have not yet developed advanced kidney disease, the transplantation of a pancreas alone (PA) is considered the treatment of choice. Best results are obtained with SPK with graft survival at 1 year of ⬎80%. After pancreas transplantation, normalization of the glucose metabolism has significant impact on the patient’s quality of life, and the systemic and vascular complications of chronic hyperglycemia can be prevented.1 As of October 2001, more than 17,000 pancreas transplants have been reported to the International Pancreas Transplantation Registry.2 The yearly number of pancreas transplants has continuously increased in the last decade, Address reprint requests and correspondence: Cinthia B. Drachenberg, MD, Department of Pathology, University of Maryland Hospital, 22 South Greene St., NBW43, Baltimore, MD 21201 E-mail address: [email protected].
0740-2570/$ -see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1053/j.semdp.2005.08.001
and this treatment is now offered in most major transplant centers. The most widely used surgical technique at the present time is whole-organ pancreas transplantation. The exocrine secretions are drained into a loop of the small intestine or into the urinary bladder. Pancreatectomy specimens from failed grafts always include a small fragment of either of these organs, depending on the drainage method. Intestinal drainage is becoming the preferred technique in recent years.3 Graft dysfunction is suspected when there is an increase in pancreatic enzymes in serum (amylase and lipase). In the case of a bladder drained pancreas, allograft dysfunction is often accompanied by a decrease in urinary amylase. It is known, however, that these laboratory parameters lack specificity. As with other solid organ transplants, histological evaluation of a tissue sample is necessary for the accurate diagnosis of the cause of graft dysfunction.4 Needle core biopsies are obtained through the percutaneous technique with sonographic guidance.5 Complications are rare (⬍3%), and adequate tissue is obtained in more than 88% of cases.5,6 A core biopsy containing at least two lobules of acinar tissue with two or three associated septal areas is considered
256
Seminars in Diagnostic Pathology, Vol 21, No 4, November 2004
adequate for evaluation.6 The overall quality and adequacy of the specimen are first assessed at low magnification. While scanning the specimen, it is important to determine whether the interlobular septa are normal or expanded. If the septa are expanded, usually due to fibrosis and/or inflammation, it is important to determine whether these processes also involve the associated acinar tissue. The histological differential diagnosis can be significantly narrowed if the pathologist is aware of the clinical presentation and the clinical indication for the biopsy (Table 1).
aside from the ischemic necrosis, has no other parenchymal or vascular abnormality.9 In contrast, acute rejection leading to early graft thrombosis shows arterial and venous endotheliitis, that usually affects small and large vessels. In contrast to idiopathic thrombosis that occurs early posttransplantation, thrombosis secondary to acute rejection can also occur at later time points. Rare cases of graft thrombosis occurring immediately after transplantation show typical features of hyperacute allograft rejection. This consists of fibrinoid necrosis of arteries and veins with thrombosis, and deposition of immunoglobulin and complement in the vascular walls.9
Inflammation in the early posttransplantation period
Peripancreatic abscess/fluid collection
The most common causes of graft dysfunction in the early posttransplantation period often represent complications of the transplantation surgical procedure itself. These complications, generally considered “technical failures,” are an important cause of graft loss.7
Acute ischemic pancreatitis Due to conditions inherent to the pancreas microcirculation and secondary to peritransplantation manipulation, it is common to find acute ischemic pancreatitis in the early days after transplantation.8 Acute graft pancreatitis shares identical morphological features with acute pancreatitis occurring in the native pancreas. In the milder forms, core biopsies show mild, septal, and acinar neutrophilic infiltrates. The interlobular septa are expanded and appear pale due to edema. The septa contain scattered lipid laden macrophages, and focal micro-hemorrhages can be seen occasionally. Aside from the neutrophilic inflammation, the lobules may be nearly normal, although some cases show small foci of coagulation necrosis. Although mild acute pancreatitis is often reversible, the presence of foci of necrosis in a core biopsy may be the first sign of a catastrophic ischemic event, usually secondary to thrombosis of the large pancreatic vessels.
Infections of the peripancreatic soft tissue and/or accumulation of peripancreatic fluid in the abdominal cavity represent an important complication in the early postoperative period.10 Some patients respond to conservative medical treatment, but in the most difficult cases, repeated laparotomies are required for drainage of fluid collections and performance of peritoneal washes. Tissue samples obtained from these patients show bands of very active fibroblastic proliferation. The fibrotic areas also show mixed inflammation composed mostly of lymphocytes and eosinophils. The bands separate nodules of lobular tissue. In this context, correlating the histological findings with the clinical information is very important. There are two possible pitfalls in the evaluation of these samples. The presence of extensive mixed inflammation in the septa may lead to a diagnosis of acute rejection. However, in contrast to acute rejection that shows preservation of the organ architecture, in biopsies from patients with peripancreatic abscesses, the fibrotic bands usually obliterate the septal structures. The fibrosis leads to the other possibility of misdiagnosis, which is the confusion with chronic rejection. Although chronic rejection can occur already in the first months posttransplantation, the pathologist should be careful not to confuse with chronic rejection the fibrosis seen in the organizing phases of peripancreatitis.
Early graft thrombosis
Acute and chronic allograft rejection
Usually early graft thrombosis is an irreversible event that requires graft pancreatectomy. Therefore, in most instances, the pathologist has the opportunity to evaluate the whole explanted pancreas with the attached fragment of donor duodenal cuff. The main purpose of the pathological examination in these cases is to determine whether the vascular thrombosis is “idiopathic” or if there are vascular changes that led to thrombosis. “Idiopathic” thrombosis causes rapid graft failure and usually occurs within the first week post transplantation. Idiopathic thrombosis is characterized by recent thrombotic occlusion of large arteries and/or veins in an organ that,
Acute allograft rejection Significant improvement has been seen in the outcome of pancreas transplantation due to a marked decrease in the rates of acute rejection.2 At least two systems for grading acute rejection have been proposed.6,11 The six-point grading system has the advantage of emphasizing the histological features while including the mildest forms of acute rejection. Protocol biopsies from well functioning allografts do not show significant inflammation or fibrosis (Grade 0). Sometimes there is sparse mononuclear septal inflammation that has no clear correlation with abnormal enzymes or
Inflammation in pancreas transplants: histological differential diagnosis Diagnosis
Acute rejection
Peripancreatitis/peripancreatic fluid collection
Acute rejection in a background of chronic rejection Chronic rejection
Cytomegalovirus pancreatitis
Posttransplant lymphoproliferative disorder
Bacterial or fungal infection
*
Clinical presentation
Cell type: Lymphocytes and eosinophils. Neutrophils if there is marked acinar injury. Plasma cells occasionally. Location: Septa, veins (venous endotheliitis), ducts, acini, arteries (depending on grade of acute rejection). No fibrosis. Cell type: Neutrophils, foamy macrophages. Location: Mostly septal. Other features: Fat necrosis, edema and interstitial hemorrhage. Patchy coagulation necrosis of clusters of acinar cells may be present. No fibrosis, the septa are expanded due to edema/fat necrosis. Cell type: Mixed (lymphocytes, plasma cells, eosinophils, neutrophils). Location: Septa and periphery of lobules. Other features: Dissecting bundles of active fibroblastic proliferation with obliteration of septal structures, relative preservation of lobules (“cirrhotic appearance”). Cell type: Same features as acute rejection. Neutrophils may accumulate in atrophying acini. Other features: Septal fibrosis, acinar loss/atrophy, transplant arteriopathy, fibrosis and loss of ducts. Cell type: Lymphocytes, plasma cells, rarely eosinophils. Neutrophils accumulate in atrophying acini. Location: Septa and acini. Other features: Septal fibrosis, acinar loss/atrophy, transplant arteriopathy, fibrosis and loss of ducts. Cell type: Mostly lymphocytes. Location: Septal and acinar, patchy. Other features: Cytomegalovirus cytopathic changes in acinar, endothelial and stromal cells. Fibrosis may be present if there is underlying chronic rejection. Cell type: Variable, polymorphic with lymphoblasts, plasma cells, eosinophils in low grade disease, to monomorphic, predominantly lymphoid in high grade disease (lymphoma). Other features: Lymphoid proliferation is nodular, expansive. Necrosis may be present. Cell type: Varies. Purulent inflammation, abscesses, granulomas. Location: Random. Other features: Same as bacterial and fungal infections in other organs.
Increase in amylase and lipase in serum. Decrease in urinary amylase.* May be subclinical. Hyperglycemia in severe acute rejection (necrosis). Increase in amylase and lipase in serum. Decrease in urinary amylase.* Hyperglycemia if there is extensive necrosis.
Local or systemic infectious symptoms, abdominal pain, peritonitis. Peripancreatic fluid accumulation. Increase in amylase and lipase in serum. See “Acute Rejection.” See “Chronic Rejection.”
Often asymptomatic until significant proportion of functioning parenchyma is lost. Slow deterioration in glucose metabolism with increasing need for insulin. Sometimes persistent increase in serum lipase and amylase. Increase in serum amylase and lipase. Duodenal cuff perforation. Systemic symptoms if generalized disease.
The Inflamed Pancreas Transplant
Posttransplant ischemic pancreatitis
Main histological findings
Drachenberg and Papadimitriou
Table 1
Asymptomatic, or increase in serum amylase and lipase. Lymphadenopathy. Tumor mass. May coexist with acute rejection. Systemic and/or localized infectious symptoms. Peritonitis, duodenal cuff perforation. Increase in serum amylase and lipase.
In bladder drained grafts.
257
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Seminars in Diagnostic Pathology, Vol 21, No 4, November 2004
Acute on chronic allograft rejection Active acute rejection with all the features described above may coexist with chronic rejection. In fact, repeated episodes of acute rejection lead to chronic rejection.12 The grades of both acute and chronic rejection in these cases have independent prognostic significance.
Other causes of inflammation in pancreas allografts
Figure 1 Acute rejection. Acinar tissue with mixed inflammation including lymphocytes and eosinophils.
response to antirejection treatment. In the six-point grade system, these changes are considered of undetermined significance (Grade I) and may by totally inconsequential or may represent early or treated acute rejection. Minimal acute rejection (Grade II) consists of septal accumulation of activated lymphocytes often associated with eosinophils. The inflammation relates closely to the small septal veins and causes venous endotheliitis. Ductal inflammation and minimal acinar inflammation can be present. In mild rejection (Grade III), in addition to changes seen in grade II or sometimes in isolation, there is frank lobular inflammation with patchy acinar cell damage (cell necrosis or apoptosis) (Figures 1 and 2). Moderate acute rejection (Grade IV) is characterized by arterial inflammation consisting of endotheliitis and/or arteritis. Severe rejection (Grade V) is defined by parenchymal necrosis that results from the extensive inflammation and the vascular damage. Islets are not targeted specifically in acute or chronic rejection, but they may appear inflamed if the adjacent acinar tissue is involved by the rejection process.
Necrotizing infections of the pancreas allograft, due to bacterial or fungal infections cause formation of parenchymal abscesses and purulent inflammation with the well-known histological features. Infections may lead to leaks and dehiscences of graft anastomoses. The latter can also result from technical surgical problems.13 Cytomegalovirus pancreatitis is characterized by patchy septal and acinar inflammation not significantly different from minimal and mild acute rejection. The inflammation is predominantly mononuclear and there is patchy acinar damage. Cytomegalovirus cytopathic changes are seen in acinar, endothelial, and stromal cells. Immunohistochemical stain for CMV is useful to confirm the diagnosis.14,15 EBV-related posttransplant lymphoproliferative disorders should be considered in the differential diagnosis of acute allograft rejection. The distinction of these two entities may be difficult in needle biopsies, particularly in cases of polymorphous low grade PTLD.16 In most cases, however, the lymphoproliferative process can be recognized due to the presence of large, nodular, and expansile aggregates of lymphoid cells. A wide spectrum of changes can be seen, from the mixed population of lymphoid cells, plasma cells, eosinophils characteristic of the polymorphous disease to frank malignant lymphoma. The vast majority of the EBVrelated posttransplant lymphoproliferative disorders have a B-cell phenotype. Lymphocyte markers and special studies
Chronic allograft rejection/graft sclerosis Chronic rejection is characterized by progressive degrees of fibrosis and associated acinar loss.12 Sparse lobular and septal inflammation is characteristic of chronic rejection. The inflammation is predominantly lymphocytic. Plasma cells may also be seen. In patches of atrophying acini, neutrophils are not uncommon. Pancreatectomy specimens from pancreas allografts that have failed due to chronic rejection show chronic inflammation, fibrosis with proportional parenchymal atrophy, and transplant arteriopathy. Recent and organized thrombosis are commonly seen in medium and small vessels. These changes may be seen rarely in pancreas transplant core biopsies.
Figure 2
Acute rejection. Septal and ductal inflammation.
Drachenberg and Papadimitriou
The Inflamed Pancreas Transplant
to confirm an EBV infection are necessary to confirm the diagnosis.17 Recurrent autoimmune diabetes mellitus is very rare in whole pancreas allografts. In the early stages of the process, selective lymphocytic inflammation of the islets with destruction of beta cells can be seen. After the beta cells have disappeared, the inflammation subsides and the pancreas may appear within normal limits except for the lack of beta cells. The latter has to be demonstrated with special stains for insulin. Patients with recurrence of autoimmune diabetes present with hyperglycemia and antibodies against beta cells can be demonstrated in serum.18,19
References 1. Odorico JS, Sollinger HW: Technical and immunosuppressive advances in transplantation for insulin-dependent diabetes mellitus. World J Surg 26:194-211, 2002 2. Gruessner AC, Sutherland DE: Pancreas transplant outcomes for United States (US) cases reported to the United Network for Organ Sharing (UNOS) and non-US cases reported to the International Pancreas Transplant Registry (IPTR) as of October 2000. Clin Transpl 45-72, 2000 3. Lo A, Stratta RJ, Hathaway DK, et al: Long-term outcomes in simultaneous kidney-pancreas transplant recipients with portal-enteric versus systemic-bladder drainage. Am J Kidney Dis 38:132-143, 2001 4. Papadimitriou JC, Drachenberg CB, Wiland A, et al: Histologic grading of acute allograft rejection in pancreas needle biopsy. Correlation to serum enzymes, glycemia and response to immunosuppressive treatment. Transplantation 66:1741-1745, 1998 5. Klassen DK, Weir MR, Cangro CB, et al: Pancreas allograft biopsy: safety of percutaneous biopsy-results of a large experience. Transplantation 73:553-555, 2002 6. Drachenberg CB, Papadimitriou JC, Klassen DK, et al: Evaluation of pancreas transplant needle biopsy: reproducibility and revision of histologic grading scheme. Transplantation 63:1579-1586, 1997
259
7. Troppmann C, Gruessner AC, Dunn DL, et al: Surgical complications requiring early relaparotomy after pancreas transplantation: a multivariate risk factor and economic impact analysis of the cyclosporine era. Ann Surg 227:255-268, 1998 8. Grewal HP, Garland L, Novak K, et al: Risk factors for post-implantation pancreatitis and pancreatic thrombosis in pancreas transplant recipients. Transplantation 56:609-612, 1993 9. Drachenberg CB, Papadimitriou JC, Farney A, et al: Pancreas transplantation: the histologic morphology of graft loss and clinical correlations. Transplantation 71:1784-1791, 2001 10. Patel BK, Garvin PJ, Aridge DL, et al: Fluid collections developing after pancreatic transplantation: radiologic evaluation and intervention. Radiology 181:215-220, 1991 11. Nakhleh RE, Sutherland DER: Pancreas rejection. Significance of histopathologic findings with implications for classification of rejection. Am J Surg Pathol 16:1098-1107, 1992 12. Papadimitriou JC, Drachenberg CB, Klassen DK, et al: Histological grading of chronic pancreas allograft rejection/graft sclerosis. Am J Transplant 3:599-605, 2003 13. Hesse UJ, Sutherland DE, Simmons RL, et al: Intra-abdominal infections in pancreas transplant recipients. Ann Surg 203:153-162, 1986 14. Klassen DK, Drachenberg CB, Papadimitriou JC, et al: CMV allograft pancreatitis: diagnosis, treatment, and histological features. Transplantation 69:1968-1971, 2000 15. Lo A, Stratta RJ, Egidi MF, et al: Patterns of cytomegalo virus infection in simultaneous kidney-pancreas transplant recipients receiving tacrolimus, mycophenolate mofetil, and prednisone with ganciclovir prophylaxis. Transpl Infect Dis 3:8-15, 2001 16. Drachenberg CB, Abruzzo LV, Klassen DK, et al: EBV-related posttransplantation lymphoproliferative disorder involving pancreas allografts: Histological differential diagnosis from acute allograft rejection. Hum Pathol 29:569-577, 1998 17. Nelson BP, Nalesnik MS, Bahler DW, et al: Epstein-Barr virusnegative post-transplant lymphoproliferative disorders: a distinct entity? Am J Surg Pathol 24:375-385, 2000 18. Tyden G, Reinholt FP, Sundkvist G, et al: Recurrence of autoimmune diabetes mellitus in recipients of cadaveric pancreatic grafts. N Engl J Med 335:888-890, 1996 19. Sutherland DE, Goetz FC, Sibley RK: Recurrence of disease in pancreas transplants. Diabetes 38:85-87, 1989
The inflamed pancreas transplant: histological differential diagnosis Cinthia B. Drachenberg, MD, John C. Papadimitriou, MD, PhD From the Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland. KEYWORDS: Acute rejection; Chronic rejection; Peripancreatitis; CMV; Lymphoproliferative disorder; Percutaneous biopsy
Excellent results are obtained with pancreas transplantation for the treatment of diabetes mellitus. The clinical parameters indicating graft dysfunction are nonspecific, and evaluation of a graft biopsy is often necessary to determine the etiology of graft dysfunction and assess the status of the graft. Inflammation of the pancreas allograft is the most common histological feature seen in core biopsies. In most cases, the inflammation is secondary to acute rejection, chronic rejection, and infectious complications. Although in many ways the morphological features of these processes overlap, there are also important differences that can help the pathologist to reach the correct diagnosis. © 2005 Elsevier Inc. All rights reserved.
Pancreas transplantation is currently considered a good treatment option for patients with difficult to control Type I diabetes.1 Because in many patients diabetes mellitus is associated with renal failure, most pancreas transplants are done simultaneously with a kidney transplant (SPK). Patients who have previously undergone a successful kidney transplant may receive a pancreas after kidney (PAK) transplantation. In patients in whom pancreas transplantation is indicated (eg, brittle diabetes) but that have not yet developed advanced kidney disease, the transplantation of a pancreas alone (PA) is considered the treatment of choice. Best results are obtained with SPK with graft survival at 1 year of ⬎80%. After pancreas transplantation, normalization of the glucose metabolism has significant impact on the patient’s quality of life, and the systemic and vascular complications of chronic hyperglycemia can be prevented.1 As of October 2001, more than 17,000 pancreas transplants have been reported to the International Pancreas Transplantation Registry.2 The yearly number of pancreas transplants has continuously increased in the last decade, Address reprint requests and correspondence: Cinthia B. Drachenberg, MD, Department of Pathology, University of Maryland Hospital, 22 South Greene St., NBW43, Baltimore, MD 21201 E-mail address: [email protected].
0740-2570/$ -see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1053/j.semdp.2005.08.001
and this treatment is now offered in most major transplant centers. The most widely used surgical technique at the present time is whole-organ pancreas transplantation. The exocrine secretions are drained into a loop of the small intestine or into the urinary bladder. Pancreatectomy specimens from failed grafts always include a small fragment of either of these organs, depending on the drainage method. Intestinal drainage is becoming the preferred technique in recent years.3 Graft dysfunction is suspected when there is an increase in pancreatic enzymes in serum (amylase and lipase). In the case of a bladder drained pancreas, allograft dysfunction is often accompanied by a decrease in urinary amylase. It is known, however, that these laboratory parameters lack specificity. As with other solid organ transplants, histological evaluation of a tissue sample is necessary for the accurate diagnosis of the cause of graft dysfunction.4 Needle core biopsies are obtained through the percutaneous technique with sonographic guidance.5 Complications are rare (⬍3%), and adequate tissue is obtained in more than 88% of cases.5,6 A core biopsy containing at least two lobules of acinar tissue with two or three associated septal areas is considered
256
Seminars in Diagnostic Pathology, Vol 21, No 4, November 2004
adequate for evaluation.6 The overall quality and adequacy of the specimen are first assessed at low magnification. While scanning the specimen, it is important to determine whether the interlobular septa are normal or expanded. If the septa are expanded, usually due to fibrosis and/or inflammation, it is important to determine whether these processes also involve the associated acinar tissue. The histological differential diagnosis can be significantly narrowed if the pathologist is aware of the clinical presentation and the clinical indication for the biopsy (Table 1).
aside from the ischemic necrosis, has no other parenchymal or vascular abnormality.9 In contrast, acute rejection leading to early graft thrombosis shows arterial and venous endotheliitis, that usually affects small and large vessels. In contrast to idiopathic thrombosis that occurs early posttransplantation, thrombosis secondary to acute rejection can also occur at later time points. Rare cases of graft thrombosis occurring immediately after transplantation show typical features of hyperacute allograft rejection. This consists of fibrinoid necrosis of arteries and veins with thrombosis, and deposition of immunoglobulin and complement in the vascular walls.9
Inflammation in the early posttransplantation period
Peripancreatic abscess/fluid collection
The most common causes of graft dysfunction in the early posttransplantation period often represent complications of the transplantation surgical procedure itself. These complications, generally considered “technical failures,” are an important cause of graft loss.7
Acute ischemic pancreatitis Due to conditions inherent to the pancreas microcirculation and secondary to peritransplantation manipulation, it is common to find acute ischemic pancreatitis in the early days after transplantation.8 Acute graft pancreatitis shares identical morphological features with acute pancreatitis occurring in the native pancreas. In the milder forms, core biopsies show mild, septal, and acinar neutrophilic infiltrates. The interlobular septa are expanded and appear pale due to edema. The septa contain scattered lipid laden macrophages, and focal micro-hemorrhages can be seen occasionally. Aside from the neutrophilic inflammation, the lobules may be nearly normal, although some cases show small foci of coagulation necrosis. Although mild acute pancreatitis is often reversible, the presence of foci of necrosis in a core biopsy may be the first sign of a catastrophic ischemic event, usually secondary to thrombosis of the large pancreatic vessels.
Infections of the peripancreatic soft tissue and/or accumulation of peripancreatic fluid in the abdominal cavity represent an important complication in the early postoperative period.10 Some patients respond to conservative medical treatment, but in the most difficult cases, repeated laparotomies are required for drainage of fluid collections and performance of peritoneal washes. Tissue samples obtained from these patients show bands of very active fibroblastic proliferation. The fibrotic areas also show mixed inflammation composed mostly of lymphocytes and eosinophils. The bands separate nodules of lobular tissue. In this context, correlating the histological findings with the clinical information is very important. There are two possible pitfalls in the evaluation of these samples. The presence of extensive mixed inflammation in the septa may lead to a diagnosis of acute rejection. However, in contrast to acute rejection that shows preservation of the organ architecture, in biopsies from patients with peripancreatic abscesses, the fibrotic bands usually obliterate the septal structures. The fibrosis leads to the other possibility of misdiagnosis, which is the confusion with chronic rejection. Although chronic rejection can occur already in the first months posttransplantation, the pathologist should be careful not to confuse with chronic rejection the fibrosis seen in the organizing phases of peripancreatitis.
Early graft thrombosis
Acute and chronic allograft rejection
Usually early graft thrombosis is an irreversible event that requires graft pancreatectomy. Therefore, in most instances, the pathologist has the opportunity to evaluate the whole explanted pancreas with the attached fragment of donor duodenal cuff. The main purpose of the pathological examination in these cases is to determine whether the vascular thrombosis is “idiopathic” or if there are vascular changes that led to thrombosis. “Idiopathic” thrombosis causes rapid graft failure and usually occurs within the first week post transplantation. Idiopathic thrombosis is characterized by recent thrombotic occlusion of large arteries and/or veins in an organ that,
Acute allograft rejection Significant improvement has been seen in the outcome of pancreas transplantation due to a marked decrease in the rates of acute rejection.2 At least two systems for grading acute rejection have been proposed.6,11 The six-point grading system has the advantage of emphasizing the histological features while including the mildest forms of acute rejection. Protocol biopsies from well functioning allografts do not show significant inflammation or fibrosis (Grade 0). Sometimes there is sparse mononuclear septal inflammation that has no clear correlation with abnormal enzymes or
Inflammation in pancreas transplants: histological differential diagnosis Diagnosis
Acute rejection
Peripancreatitis/peripancreatic fluid collection
Acute rejection in a background of chronic rejection Chronic rejection
Cytomegalovirus pancreatitis
Posttransplant lymphoproliferative disorder
Bacterial or fungal infection
*
Clinical presentation
Cell type: Lymphocytes and eosinophils. Neutrophils if there is marked acinar injury. Plasma cells occasionally. Location: Septa, veins (venous endotheliitis), ducts, acini, arteries (depending on grade of acute rejection). No fibrosis. Cell type: Neutrophils, foamy macrophages. Location: Mostly septal. Other features: Fat necrosis, edema and interstitial hemorrhage. Patchy coagulation necrosis of clusters of acinar cells may be present. No fibrosis, the septa are expanded due to edema/fat necrosis. Cell type: Mixed (lymphocytes, plasma cells, eosinophils, neutrophils). Location: Septa and periphery of lobules. Other features: Dissecting bundles of active fibroblastic proliferation with obliteration of septal structures, relative preservation of lobules (“cirrhotic appearance”). Cell type: Same features as acute rejection. Neutrophils may accumulate in atrophying acini. Other features: Septal fibrosis, acinar loss/atrophy, transplant arteriopathy, fibrosis and loss of ducts. Cell type: Lymphocytes, plasma cells, rarely eosinophils. Neutrophils accumulate in atrophying acini. Location: Septa and acini. Other features: Septal fibrosis, acinar loss/atrophy, transplant arteriopathy, fibrosis and loss of ducts. Cell type: Mostly lymphocytes. Location: Septal and acinar, patchy. Other features: Cytomegalovirus cytopathic changes in acinar, endothelial and stromal cells. Fibrosis may be present if there is underlying chronic rejection. Cell type: Variable, polymorphic with lymphoblasts, plasma cells, eosinophils in low grade disease, to monomorphic, predominantly lymphoid in high grade disease (lymphoma). Other features: Lymphoid proliferation is nodular, expansive. Necrosis may be present. Cell type: Varies. Purulent inflammation, abscesses, granulomas. Location: Random. Other features: Same as bacterial and fungal infections in other organs.
Increase in amylase and lipase in serum. Decrease in urinary amylase.* May be subclinical. Hyperglycemia in severe acute rejection (necrosis). Increase in amylase and lipase in serum. Decrease in urinary amylase.* Hyperglycemia if there is extensive necrosis.
Local or systemic infectious symptoms, abdominal pain, peritonitis. Peripancreatic fluid accumulation. Increase in amylase and lipase in serum. See “Acute Rejection.” See “Chronic Rejection.”
Often asymptomatic until significant proportion of functioning parenchyma is lost. Slow deterioration in glucose metabolism with increasing need for insulin. Sometimes persistent increase in serum lipase and amylase. Increase in serum amylase and lipase. Duodenal cuff perforation. Systemic symptoms if generalized disease.
The Inflamed Pancreas Transplant
Posttransplant ischemic pancreatitis
Main histological findings
Drachenberg and Papadimitriou
Table 1
Asymptomatic, or increase in serum amylase and lipase. Lymphadenopathy. Tumor mass. May coexist with acute rejection. Systemic and/or localized infectious symptoms. Peritonitis, duodenal cuff perforation. Increase in serum amylase and lipase.
In bladder drained grafts.
257
258
Seminars in Diagnostic Pathology, Vol 21, No 4, November 2004
Acute on chronic allograft rejection Active acute rejection with all the features described above may coexist with chronic rejection. In fact, repeated episodes of acute rejection lead to chronic rejection.12 The grades of both acute and chronic rejection in these cases have independent prognostic significance.
Other causes of inflammation in pancreas allografts
Figure 1 Acute rejection. Acinar tissue with mixed inflammation including lymphocytes and eosinophils.
response to antirejection treatment. In the six-point grade system, these changes are considered of undetermined significance (Grade I) and may by totally inconsequential or may represent early or treated acute rejection. Minimal acute rejection (Grade II) consists of septal accumulation of activated lymphocytes often associated with eosinophils. The inflammation relates closely to the small septal veins and causes venous endotheliitis. Ductal inflammation and minimal acinar inflammation can be present. In mild rejection (Grade III), in addition to changes seen in grade II or sometimes in isolation, there is frank lobular inflammation with patchy acinar cell damage (cell necrosis or apoptosis) (Figures 1 and 2). Moderate acute rejection (Grade IV) is characterized by arterial inflammation consisting of endotheliitis and/or arteritis. Severe rejection (Grade V) is defined by parenchymal necrosis that results from the extensive inflammation and the vascular damage. Islets are not targeted specifically in acute or chronic rejection, but they may appear inflamed if the adjacent acinar tissue is involved by the rejection process.
Necrotizing infections of the pancreas allograft, due to bacterial or fungal infections cause formation of parenchymal abscesses and purulent inflammation with the well-known histological features. Infections may lead to leaks and dehiscences of graft anastomoses. The latter can also result from technical surgical problems.13 Cytomegalovirus pancreatitis is characterized by patchy septal and acinar inflammation not significantly different from minimal and mild acute rejection. The inflammation is predominantly mononuclear and there is patchy acinar damage. Cytomegalovirus cytopathic changes are seen in acinar, endothelial, and stromal cells. Immunohistochemical stain for CMV is useful to confirm the diagnosis.14,15 EBV-related posttransplant lymphoproliferative disorders should be considered in the differential diagnosis of acute allograft rejection. The distinction of these two entities may be difficult in needle biopsies, particularly in cases of polymorphous low grade PTLD.16 In most cases, however, the lymphoproliferative process can be recognized due to the presence of large, nodular, and expansile aggregates of lymphoid cells. A wide spectrum of changes can be seen, from the mixed population of lymphoid cells, plasma cells, eosinophils characteristic of the polymorphous disease to frank malignant lymphoma. The vast majority of the EBVrelated posttransplant lymphoproliferative disorders have a B-cell phenotype. Lymphocyte markers and special studies
Chronic allograft rejection/graft sclerosis Chronic rejection is characterized by progressive degrees of fibrosis and associated acinar loss.12 Sparse lobular and septal inflammation is characteristic of chronic rejection. The inflammation is predominantly lymphocytic. Plasma cells may also be seen. In patches of atrophying acini, neutrophils are not uncommon. Pancreatectomy specimens from pancreas allografts that have failed due to chronic rejection show chronic inflammation, fibrosis with proportional parenchymal atrophy, and transplant arteriopathy. Recent and organized thrombosis are commonly seen in medium and small vessels. These changes may be seen rarely in pancreas transplant core biopsies.
Figure 2
Acute rejection. Septal and ductal inflammation.
Drachenberg and Papadimitriou
The Inflamed Pancreas Transplant
to confirm an EBV infection are necessary to confirm the diagnosis.17 Recurrent autoimmune diabetes mellitus is very rare in whole pancreas allografts. In the early stages of the process, selective lymphocytic inflammation of the islets with destruction of beta cells can be seen. After the beta cells have disappeared, the inflammation subsides and the pancreas may appear within normal limits except for the lack of beta cells. The latter has to be demonstrated with special stains for insulin. Patients with recurrence of autoimmune diabetes present with hyperglycemia and antibodies against beta cells can be demonstrated in serum.18,19
References 1. Odorico JS, Sollinger HW: Technical and immunosuppressive advances in transplantation for insulin-dependent diabetes mellitus. World J Surg 26:194-211, 2002 2. Gruessner AC, Sutherland DE: Pancreas transplant outcomes for United States (US) cases reported to the United Network for Organ Sharing (UNOS) and non-US cases reported to the International Pancreas Transplant Registry (IPTR) as of October 2000. Clin Transpl 45-72, 2000 3. Lo A, Stratta RJ, Hathaway DK, et al: Long-term outcomes in simultaneous kidney-pancreas transplant recipients with portal-enteric versus systemic-bladder drainage. Am J Kidney Dis 38:132-143, 2001 4. Papadimitriou JC, Drachenberg CB, Wiland A, et al: Histologic grading of acute allograft rejection in pancreas needle biopsy. Correlation to serum enzymes, glycemia and response to immunosuppressive treatment. Transplantation 66:1741-1745, 1998 5. Klassen DK, Weir MR, Cangro CB, et al: Pancreas allograft biopsy: safety of percutaneous biopsy-results of a large experience. Transplantation 73:553-555, 2002 6. Drachenberg CB, Papadimitriou JC, Klassen DK, et al: Evaluation of pancreas transplant needle biopsy: reproducibility and revision of histologic grading scheme. Transplantation 63:1579-1586, 1997
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