Metastatic sites for common cancers

Winter 131Metastatic sites for common cancersCancer Site Stomach adenocarcinoma, pancreatic cancerVirchows left supraclavicular nodeBreast cancerLung , boneColorectal cancerLiverRenal adenocarcinomaLungLungAdrenal / liverMelanomaLiver/lungProstateBoneTesticular tumorParaaortic nodesA Jalan1Note: in a given organ , the most common malignant tumor is a metastasis rather than a primary tumor.Ex: Mets to liver more common than primary HCC

Frequency of leukemia by age bracketAgeLeukemia typeNew born to 14 yearsALL15-39 years

AML40-60 yearsAML (>60%)CML (~40%)>60 yearsCLL2Winter 13A JalanTransplantation immunology and pathologyWinter 133A JalanTypes of graftAutograft:Transfer of tissue from Self to selfAssociated with best survival rateSyngenetic graft (isograft)Transplants between identical twinsAllograft:Transplant between genetically different individuals of the same speciesXenograft:Transplant between two species ( heart valve from pig to human)Winter 134A JalanWhat kind of grafts (transplants) do you know? Autograft: graft of one's own tissues:e.g skin graft from thigh to the armIsograft: graft from identical twin (also known as syngeneic graft)Allograft: graft between genetically different individuals

AutologousTissue or organ transferred into a new position in the body of the same individual. Syn: autotransplant, autogeneic graft, autologous graft, autoplastic graft.SyngenicA tissue or organ transplanted between genetically identical individuals. Syn: isogeneic graft, isologous graft, isoplastic graft, syngeneic graft, isograft.AllogenicA graft transplanted between genetically nonidentical individuals of the same species. Syn: allogeneic graft, homologous graft, homoplastic graft, homograft.Xenogenic A graft transferred from an animal of one species to one of another species. Syn: heterologous graft, heteroplastic graft, xenogeneic graft, heterograft.

4To improve graft survivalFollowing improve graft survival:ABO group compatibility (most important)Absence of preformed cytotoxic antibodies against donor HLA antigensHLA compatibility, particularly with the D lociWinter 135A JalanTransplant or graft rejectionOccurs due to humoral or cell mediated host response to MHC antigens in the donor graftThree Types of transplant rejections:Hyperacute rejectionAcute rejectionChronic rejectionWinter 136A JalanHyperacute rejectionOccurs within minutes of attaching the allograft to the recipients blood supplyWinter 137A JalanDue to the presence of an ABO mismatch or preformed cytotoxic antibodies in the host against foreign HLA antigens in the donor tissue (example; a blood group A recipient would have anti-B IgM antibodies and would react against a group B donor heart)

7Hyperacute rejectionPathogenesis:Due to presence of preformed anti-HLA antibodies or anti ABO antibodies in the recipient.Antibodies (IgG or IgM) bind to endothelial cells of transplanted tissue complement activation fibrinoid necrosis thrombosis of vessels ischemic damage to transplanted organ.Pathologic finding: Vessel thrombosis, fibrinoid necrosis in vessel wallWinter 138A JalanWhat are the features of a hyperacute transplant rejection? Occurs within minutes of transplantation.Mediated by preformed anti-donor antibodies present in the recipient's circulation (e.g., ABO incompatibility).Antigens in the endothelium of the transplanted organ are recognized by the preformed antibodies (IgM and IgG) capable of complement activation resulting in thrombosis and fibrinoid necrosis, followed by ischemic necrosis of the transplanted organ.

Fibrionoid necrosis of arterioles necrosis of the arterioles in which the necrotic tissue has some staining reactions resembling fibrin and becomes deeply eosinophilic, homogenous, and refractile.

8Hyperacute rejectionExample:Blood group A person receives a blood group B kidney.Anti-B IgM antibody in recipient attack group B ag on endothelial cells of renal vessels in the donor kidney activate complement MAC formation fibrinoid necrosis and vessel thrombosis ischemic damage to kidney.Kidney becomes cyanotic, flaccid and excretes only a few drops of bloody fluid.Winter 13A Jalan9Occurs within minutes of attachment of the allograft to the recipients blood supply.This kind of rejection is recognized by the surgeon just after the vascular anastomosis is completed.Virtually all vessels show fibrinoid necrosis and thrombosis resulting in ischemic damage to kidney.This type of rejection does not commonly occur, since ABO and antiHLA cytotoxic antibody screening is performed prior to the transplant surgery.9Hyperacute rejectionHyperacute rejection is rare** because ABO and anti-HLA cytotoxic antibody screening is performed prior to the surgery for transplantation.Winter 1310A JalanAcute Rejection Is the most common** transplant rejection encountered.Usually occurs within the first 3 months** of the transplantationAcute rejection is caused by both: Cellular (T cell mediated) and Humoral immune responses (Antibody mediated damage).T Cell mediated damage plays most important** role in graft rejection.The most imp effector cell in graft destruction are CD8+ T cells.

Winter 13A Jalan11What are the characteristics of an acute transplant rejection? Occurs within days or months after the transplantation or at any time after the withdrawal of immunosuppressive therapy.Mediated by both humoral (antibody-mediated) and cellular (T cell-mediated) mechanisms.Vasculitis is a prominent feature. It is mediated by anti-donor antibodies that attack the vessel wall, with subsequent thrombosis and thickening of the arterioles. Vascular changes cause an ischemia of the transplanted organ.Interstitial accumulation of lymphocytes is a prominent feature. It is associated with parenchymal cell injury (e.g., tubular epithelium of kidneys or myocytes in the heart).

11Pathogenesis The cell-mediated component involves:Cytotoxic T cells produce extensive interstitial infiltrate** in the graft tissue with damage to the tissue (Type IV hypersensitivity*)

Winter 13A Jalan12Sequence of events in cell mediated damage:APCs in graft have foreign class I and class II antigensHost CD 8 cells react against class I agHost CD4 cells react against class II agForeign antigen bearing macrophages release IL-1 proliferation of host CD4 T cells.CD4 T cells release:Lymphokines B cell production of ab against graftIL-2 proliferation of B cells, CD4 T cells, and CD8 T cellsCD8 T cells destroy the graft by interacting with foreign class I ag.

12Pathogenesis Antibody mediated component: Due to newly synthesized (not preformed) anti-donor HLA antibodies.These antibodies attack blood vessel in graft tissue with activation of complement.This produces necrotizing vasculitis and vessel thrombosis.

Winter 13A Jalan13The type II antibody-mediated hypersensitivity produces a necrotizing vasculitis with subsequent vessel damage and intravascular thrombosis

Acute rejection is potentially reversible with the use of immunosuppressive drugs such as:Cyclosporin AInhibits CD4 T cell release of IL-2CorticosteroidsInhibits macrophage production and release of IL-1Toxic to immature thymocytes

13Chronic rejectionTakes place months or years after transplant.Characterized by progressive organ dysfunction( i.e. renal failure in renal transplant)Pathogenesis:Not well characterizedInvolves continued injury to vessels by cytokines leading to vessel fibrosis ischemia to tissue.Activated macrophages growth factors extensive fobrosis and loss of organ structure and functionWinter 13A Jalan14What are the characteristics of chronic transplant rejection? Caused predominantly by vascular changes (intimal fibrosis) accompanied by ischemia and loss of parenchymal cellsGradual and progressive decline in transplanted organ function over a period of months and years

Chronic rejectionIrreversibleOccur over a period of months to yearsExtensive fibrosis and loss of organ structure characterize the histologic findings in the transplantActivated macrophages release growth factors that stimulate fibroblasts to deposit collagenThere is also chronic ischemia secondary to antibody-mediated damage to the vessels

14Means to increase graft survivalABO group compatibilityMost important factorAbsence of preformed antibodies against donor HLA antigensHLA matching between donor and recipient

Winter 13A Jalan15Means to increase graft survivalImunosuppressive therapyCyclosporine ABlocks T cell activation, IL-2 production.Mycophenolate and azathioprine:Blocks T cell proliferationCorticosteroids:Blocks inflammationAnti-T ell antibodies:Cause T cell destructionPlasmapheresis or anti B cell therapy

Winter 13A Jalan16Graft-versus-host disease(GVHD)Causes:Occurs as a complication of BM and liver transplantsPathogenesis:Donor lymphocytes produce interleukin-2 activation of NK cells (primary effector cells in acute GVH reactions) produce extensive epithelial cell necrosis in the biliary tract (jaundice), skin (maculopapular rash), and GI tract (diarrhea)

Winter 13A Jalan17What is graft versus host disease (GVH)? Occurs when donor T lymphocytes recognize the recipient's HLA antigens as foreign and react against them.Occurs with both bone marrow transplantation and solid organ transplantation, especially when these organs contain numerous lymphoid cells.In acute GVH (occurring within the first 90 days), donor T lymphocytes attack the host's skin, biliary tract epithelium, and gut epithelium. This clinically manifests as maculopapular rash, secretory diarrhea, and signs of cholestasis.The diagnosis is confirmed by a colon biopsy showing characteristic "exploding crypt lesions" (extensive death of epithelium of the crypts).In chronic GVH (between 90 and 400 days), destruction of skin appendages, fibrosis of the dermis, and cholestatic jaundice are seen.

17Graft-versus-host diseaseClinical findings:Dermatitis rashBile duct necrosis jaundiceGIT mucosa ulceration bloody diarrhea, abdominal crampsDiagnosis:Confirmed by colon biopsy shows characteristic "exploding crypt lesions" (extensive death of epithelium of the crypts).Winter 13A Jalan18Winter 13A Jalan19

Graft-versus-host disease (GVHD) is a complication that can occur after a stem cell or bone marrow transplant in which the newly transplanted material attacks the transplant recipient's body.See also: Transplant rejection CausesGVHD occurs in a bone marrow or stem cell transplant involving a donor and a recipient. The bone marrow is the soft tissue inside bones that helps form blood cells, including white cells that are responsible for the immune response. Stem cells are normall found inside bone marrow.Since only identical twins have identical tissue types, a donor's bone marrow is normally a close, but not perfect, match to the recipient's tissues. See: Histocompatibility antigen test The differences between the donor's cells and recipient's tissues often cause T cells (a type of white blood cells) from the donor to recognize the recipient's body tissues as foreign. When this happens, the newly transplanted cells attack the transplant recipient's body.Acute GVHD usually happens within the first 3 months after transplant. Chronic GVHD usually starts more than 3 months after transplant, and can last a lifetime.Rates of GVHD vary from between 30 - 40% among related donors and recipients to 60 - 80% between unrelated donors and recipients. The greater the mismatch between donor and recipient, the greater the risk of GVHD. After a transplant, the recipient usually takes drugs that suppress the immune system, which helps reduce the chances (or severity) of GVHD.SymptomsSymptoms in both acute and chronic GVHD range from mild to severe.Common acute symptoms include:Abdominal pain or cramps Diarrhea Fever Jaundice Skin rash Vomiting Weight loss Chronic symptoms may include:Dry eyes and dry mouth Hair loss Hepatitis Lung and digestive tract disorders Skin rash Skin thickening In both acute and chronic GVHD, the patient is very vulnerable to infections.Exams and TestsThe tests done usually depend on the symptoms, but may include:Gastrointestinal endoscopy, with or without a biopsy Liver function tests (AST, ALP, and bilirubin levels will be increased) Liver biopsy (if the patient only has liver symptoms) Lung x-rays Skin biopsy TreatmentThe goal of treatment is to suppress the immune response without damaging the new cells. Medicines commonly used include methotrexate, cyclosporine, tacrolimus, sirolimus, ATG, and alemtuzumab either alone or in combination.High-dose corticosteroids are the most effective treatment for acute GVHD. Antibodies to T cells and other medicines are given to patients who do not respond to steroids.Treatment of chronic GVHD includes prednisone (a steroid) with or without cyclosporine. Other treatments include mycophenolate mofetil (CellCept), sirolimus (Rapamycin), and tacrolimus (Prograf).Outlook (Prognosis)How well a person does depends on the severity of the condition. Some cases of GVHD can lead to death.Many cases, whether acute or chronic, can be treated successfully. Sometimes treatment of the condition can lead to severe complications.Successful treatment of GVHD does not guarantee that the transplant itself will succeed in treating the original disease.Possible ComplicationsCholestasis Death Moderate to severe damage to the liver, lung, or digestive tract Severe infection Severe lung disease When to Contact a Medical ProfessionalIf you have had a bone marrow or stem cell transplant, call your health care provider immediately if any unusual symptoms appear, including:Diarrhea Difficulty breathing Skin rash Stomach cramps Yellowing of the skin or eyes (jaundice) PreventionBefore a transplant, your blood type and tissue type will be carefully matched with eligible donors. This matching will reduce the risk of GVHD. Whenever possible, donations from closely matched family members can further decrease the risk of this problem. Absolute prevention of GVHD is not possible, and it is a risk when receiving a transplant from anyone else.Alternative NamesGVHD

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Inset- Crypts show many apoptotic bodies (for higher magnification of the crypt with arrow see figure 1B ). B. Magnified crypt shown in the inset of figure 1A : The crypt shows "popcorn" lesions (arrows) with occasional muciphages (arrowhead) in LP.. This phenomenon has been labeled variously as "exploding crypt cells"20ID/CCA 45 year old male with refractory acute myeloid leukemia is brought to the emergency room with fever, a generalized rash, jaundice, right upper quadrant pain, severe diarrhea, and dyspnea; two months ago, he underwent an apparently uncomplicated bone marrow transplantation.HPIPrior to the transplant, he received radiotherapy and chemotherapy as well as broad-spectrum antibioticsPEVS: normal blood pressure. PE: cachexia; moderate dehydration; 2+ jaundice; violaceous and erythematous macules as well as papules and bullae with scale formation over extremitiesLabsElevated IgE level. CBC/PBS: falling blood counts; relative eosinophilia. Elevated direct serum bilirubin and transaminases, no infectious agents on stool examWinter 1321A JalanImmunopathologyThe EndWinter 13A Jalan22