|Year : 2021 | Volume
| Issue : 4 | Page : 752-758
|Acute graft-versus-host-disease in acute myeloid leukemia: Clinicopathological correlation based on autopsy findings
Praveen Sharma1, Aditya Jandial2, Amarjit Keisham3, Manish Rohilla4, Neelam Varma1, Pankaj Malhotra2, Bishan Radotra5
1 Department of Hematology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
2 Department of Internal Medicine (Adult Clinical Hematology Division), Postgraduate Institute of Medical Education and Research, Chandigarh, India
3 Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
4 Department of Cytology and Gynaecological Pathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
5 Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
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|Date of Submission||07-May-2020|
|Date of Decision||13-Jun-2020|
|Date of Acceptance||18-Feb-2021|
|Date of Web Publication||20-Oct-2021|
| Abstract|| |
We present a case of acute myeloid leukemia developing acute graft-versus-host-disease (GVHD) in the post transplant phase. The patient had GVHD of skin, liver and gastro-intestinal tract (resolved) with polymicrobial sepsis. The clinical course, treatment and pathological findings on autopsy including the cause of death have been discussed.
Keywords: Acute graft-versus-host-disease, acute myeloid leukemia, autopsy, bone marrow transplant, post-transplant complications
|How to cite this article:|
Sharma P, Jandial A, Keisham A, Rohilla M, Varma N, Malhotra P, Radotra B. Acute graft-versus-host-disease in acute myeloid leukemia: Clinicopathological correlation based on autopsy findings. Indian J Pathol Microbiol 2021;64:752-8
|How to cite this URL:|
Sharma P, Jandial A, Keisham A, Rohilla M, Varma N, Malhotra P, Radotra B. Acute graft-versus-host-disease in acute myeloid leukemia: Clinicopathological correlation based on autopsy findings. Indian J Pathol Microbiol [serial online] 2021 [cited 2021 Nov 28];64:752-8. Available from: https://www.ijpmonline.org/text.asp?2021/64/4/752/328564
| Clinical Presentation|| |
A 25-years-old gentleman, known case of relapsed acute myeloid leukemia (AML) in second complete remission (CR2), was admitted on day +58 following matched unrelated donor (MUD) allogeneic hematopoietic stem cell transplantation (HSCT) and died on day +82. He was admitted with complaints of painless hematuria and increased frequency of micturition of 1 day duration. He had received stem cells from a 10/10 HLA- MUD following reduced intensity conditioning with fludarabine and busulfan; methotrexate and cyclosporine were given as graft-versus-host disease (GVHD) prophylaxis. He had achieved engraftment on D +10. His post-transplantation course was remarkable for grade 4 oral mucositis (day +4), febrile neutropenia with polymicrobial sepsis and fungal pneumonia (day +7) with elevated levels of serum galactomannan (0.85). He received broad-spectrum intravenous (IV) antibiotics and anti-fungals (liposomal amphotericin B and Caspofungin) with which he recovered completely. He was subsequently continued on oral posaconazole as secondary antifungal prophylaxis. On day +14, he had presented with itchy maculopapular rash involving upper back and chest which later on became confluent and extended to bilateral upper and lower limbs. He also developed watery diarrhea along with conjugated hyperbilirubinemia and elevated transaminases from day +17. A clinical diagnosis of acute GVHD (grade 4) was considered and he was started on IV methylprednisolone. The diagnosis of acute GVHD was confirmed on skin biopsy later. The cutaneous and gastrointestinal symptoms gradually resolved by day +32. However, he continued to have deranged liver function tests for which he was further evaluated but work-up was inconclusive. He was discharged from hospital on tapering doses of oral prednisolone on day +55. Unfortunately, he was readmitted 3 days later on day +58 with the above-mentioned complaints. At presentation, he denied history of fever, burning micturition or incontinence. There was no history of facial puffiness or swelling of feet.
| Examination and Investigations|| |
His general physical examination revealed pallor and icterus. Liver was palpable 2 cm below the costal margin (span 16 cm); spleen was not palpable. Cardiovascular, respiratory and nervous system examination was unremarkable. Hemogram revealed normocytic normochromic anemia and thrombocytopenia; total leukocyte count was normal at admission but leukopenia with severe neutropenia developed later in the course of illness [Table 1]. Biochemistry revealed conjugated hyperbilirubinemia, elevated liver transaminases (8 x ULN; SGPT > SGOT) and hypoalbuminemia at admission; hyperbilirubinemia and liver transaminases elevation were noted throughout the hospital stay [Table 2]. Baseline coagulogram and serum creatinine were normal; pre-terminally, he developed coagulopathy and raised serum creatinine [Table 2] and [Table 3]. Urine routine examination revealed 25–30 red blood cells (RBCs)/hpf, 8–10 pus cells/hpf, and no albumin; 24-h urine protein was elevated (1130 mg/TV) and urine for dysmorphic RBCs was positive (10%). Urine culture sent at admission revealed growth of Escherichia coli; urine culture became negative after starting broad spectrum antibiotics. However, urine cultures repeated later in the course of illness (in view of persistent lower urinary tract symptoms) grew Klebsiella pneumoniae and Chrysobacterium indologenes. Assessment for BK virus by quantitative PCR was positive in urine (15 x1011 copies/mL) and blood (18,000 copies/mL); work-up for CMV and adenovirus was inconclusive. Baseline ultrasonography revealed normal sized kidneys with maintained cortico-medullary junction and thickened urinary bladder wall suggestive of cystitis. Ultrasound repeated later in the course of illness revealed enlarged bilateral kidneys and echogenic foci in thickened urinary bladder suggestive of clots. Chest radiograph done at admission revealed non-homogeneous opacification in the left lower zone which concurred with consolidation in the left lower lobe on chest computed tomography (CT) scan. Serum galactomannan was normal (0.32). CT head done pre-terminally was unremarkable.
| Course and Management|| |
He was initially managed as bacterial urinary tract infection with broad-spectrum antibiotics as per urine culture sensitivity; posaconazole was administered in therapeutic doses in view of chest imaging suggestive of fungal pneumonia. It was accompanied by supportive care in the form of packed RBC and platelet transfusion. In view of worsening of symptoms, a possibility of viral hemorrhagic cystitis (HC) was considered and work-up for BK virus, cytomegalovirus and adenovirus was done. Urine and blood samples were found positive for BK virus for which continuous saline irrigation of urinary bladder was started. However, there was no improvement in his urinary symptoms and he continued to have intermittent fever spikes. There was progressive decline in hemoglobin and platelet count for which he required regular transfusion support; profound neutropenia also developed. Antimicrobial therapy was revised in view of growth of K. pneumoniae and Chrysobacterium indologenes on repeat urine and blood cultures showed, respectively. Anidulafungin was added as second antifungal agent but there was no clinical improvement. He developed two episodes of generalized tonic–clonic seizures pre-terminally for which a possibility of intracranial bleed was considered. CT head was normal and fundus examination revealed bilateral retinal hemorrhages. Pre-terminally, he developed respiratory distress and altered sensorium. He continued to deteriorate despite aggressive management and succumbed to his illness on D+82 post-HSCT.
| Final Clinical Diagnosis|| |
Relapsed AML in CR2, post-matched unrelated donor allogeneic HSCT with grade 4 acute GVHD (skin, gut and liver), HC (related to BK virus), complicated UTI (due to gram negative bacteria), healthcare associated pneumonia (bacterial, fungal, and/or CMV), new-onset seizures, and delirium (multifactorial).
Cause of death – refractory septic shock, type 1 respiratory failure.
| Pathology Protocol|| |
External examination: The patient was average built and icteric. There was bilateral lower limb edema. Skin all over the body had parchment-like appearance including ecchymotic patches and petechiae over both the hands.
The serous cavities (pleural and pericardial) were within normal limits, whereas the peritoneal cavity yielded about 1200 ml of hemorrhagic fluid.
Skin: On microscopy, skin biopsy showed evidence of resolving GVHD [Figure 1]. Apoptotic keratinocytes were seen along with focal basal cell vacuolar degenerative changes.
|Figure 1: The epidermis shows apoptotic keratinocytes and vacuolar degeneration of the basal cell layer. No inflammation is seen (H and E; x400)|
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Liver: (Weight-1900 gm). The cut surface was greenish and firm in consistency [Figure 2]a. On microscopic examination, sections from liver showed maintained lobular architecture [Figure 2]b which was highlighted on reticulin stain. Masson trichrome stain did not highlight any portal fibrosis. The bile duct epithelium showed dysplastic changes in form of nuclear atypia with cytoplasmic vacuolation and disordered polarity [Figure 2]c. In addition, many of the bile ducts were damaged due to infiltration by CD3+ lymphocytes [Figure 2]d. Centri-zonal cholestasis was seen on Fouchet's stain and Perls' stain identified prominent peri-portal iron deposition. The findings in liver were consistent with hepatic GVHD.
|Figure 2: a) Organ complex comprises of slice of liver, gallbladder, pancreas and spleen. Liver cut surface is bile stained and firm. No other gross abnormality was identified in any of the organs. b) Section from liver shows maintained lobular architecture (H and E; x100). c) The portal tract shows mild mononuclear cell infiltrate invading and destroying the small bile ducts and ductules. The lining cells exhibit anisonucleosis with mild nuclear atypia and cytoplasmic vacuolations (H and E; x400). d) The portal inflammation is composed of CD3 positive T-cell lymphocytes (immunoperoxidase; x400)|
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Spleen: (Weight-200 gm). Grossly, the spleen was unremarkable. On microscopic study, there was peri-arteriolar white pulp depletion with evidence of secondary iron overload.
Lungs (Weight-900 gm): On gross study, there was evidence of pleuritis. Left upper lobe hemorrhagic infarction was noted [Figure 3]a, which was confirmed microscopically as large areas of alveolar hemorrhage. In addition, a fibro-cavitatory lesion was identified, which was microscopically composed of Gram positive bacterial colonies [Figure 3]b and [Figure 3]c. On Grocott stain, several broad, aseptate acutely branching fungal hyphae, folded unto them were also observed conforming to the morphology of mucormycosis. These fungi were also invading the vessel wall, entering the lumen of blood vessels indicating angio-invasive mucormycosis [Figure 3]d. In addition, at many foci, the alveolar epithelial cells showed presence of basophilic inclusion indicating Cytomegalovirus-induced cytopathic changes. Immunohistochemistry for CMV showed strong nuclear positivity in these cells confirming CMV pneumonitis [Figure 3]e and [Figure 3]f.
|Figure 3: a) Gross photograph of the organ complex comprising of bilateral lungs, trachea and thyroid. The upper lobe of the left lung appears completely hemorrhagic. b) Section from the upper lobe of left lung shows central cavitary lesion containing necro-inflammatory debris and bacterial colonies bordered by fibro-inflammatory tissue (H and E; x200). c) Numerous bacterial colonies are highlighted (Gram's stain; x400). d) Mucor is seen invading the vessel wall and occupying the vascular lumen indicating angio-invasion (Grocott's stain; x400). e) The lung parenchyma shows prominent intra-nuclear basophilic inclusion in the endothelial lining cell that indicates cytomegalovirus inclusions (H and E; x1000). f) Immunohistochemistry for cytomegalovirus showing strong nuclear positivity in endothelial cells (immunoperoxidase; x400)|
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Kidneys: Both the kidneys together weighed 790 gm. Left kidney was enlarged with features of complete hemorrhagic infarction [Figure 4]a, which was confirmed microscopically. Numerous neutrophil rich micro-abscesses were seen in the hemorrhagic renal parenchyma [Figure 4]b. In these areas, Grocott's stain highlighted a few fungal elements within the blood vessels conforming to the Mucor morphology. Additionally, renal tubules showed features of acute tubular necrosis (ATN) with lodged bacterial colonies in the tubular lumen [Figure 4]c. On Gram's stain these bacterial colonies were highlighted and found to be Gram positive. Apart from ATN-related changes, viral cytopathic changes were seen in preserved tubular epithelial cells. IHC for CMV and SV40 showed strong nuclear positivity in these cells indicating CMV infection and BK virus nephropathy, respectively [Figure 4]d.
|Figure 4: a) Gross photograph of the organ complex comprising of the kidneys, the ureters, urinary bladder, and abdominal aorta. The left kidney is grossly enlarged, discolored and hemorrhagic indicative of infarction. The right kidney is normal in size and reveals no significant pathology on gross. Urinary bladder shows hemorrhagic mucosa. b) The left kidney showing large areas of hemorrhagic infarction. Numerous neutrophilic micro-abscesses are seen in the interstitium with intervening preserved renal tissue (H and E; x400). c) Bacterial colonies clogging the tubular lumen of the left kidney are shown (H and E; x400). d) SV40 immunostain showing strong nuclear positivity in the tubular lining epithelium indicative of BK virus nephropathy along with the inset showing positivity for CMV (immunoperoxidase; x400)|
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Urinary bladder showed evidence of HC.
Brain (Weight-1500 gm): On gross examination, sub-arachnoid hemorrhage was seen in the left frontal lobe. Also, a deep intracerebral hemorrhage was seen extending into the lateral ventricles, third ventricle, and into the fourth ventricle [Figure 5]. Microscopically, the entrapped intra-cerebral vessels in the hemorrhagic areas showed evidence of fibrinoid necrosis. No other significant findings were seen.
|Figure 5: Gross photograph of a coronal section of brain showing large and deep intra-cerebral hemorrhagic area extending into the lateral ventricles and causing contralateral midline shift|
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Intestine: Both large and small intestine were normal on gross examination. Microscopically, no evidence of GVHD was identified.
Stomach and esophagus were grossly and microscopically unremarkable.
Heart: (Weight-250 gm): Grossly, it showed evidence of epicardial hemorrhages. The right and left inflow tract, the right and left outflow tract, the valvulature and coronary arteries were unremarkable. No specific microscopic pathology was identified.
Bone marrow: Post-mortem bone marrow was hypocellular with proportionally represented hematopoietic elements of all the three lineages. There was no evidence of relapse [Figure 6].
|Figure 6: Bone marrow on low magnification showing hypocellularity and reduction in all the three hematopoietic lineage elements. No evidence of relapse is evident (H and E; x100)|
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The adrenals, the thyroid and testes were unremarkable both grossly and microscopically.
| Final Autopsy Diagnosis|| |
A 24-year-old male, case of acute myeloid leukemia, post allogeneic stem cell transplant D+82, the final autopsy diagnosis includes:
- No evidence of relapse
- Evidence of resolving graft-versus-host-disease in skin and liver
- Kidneys-Left kidney hemorrhagic infarction- Mucormycosis; acute tubular necrosis, CMV infection and BK virus nephropathy.
- Lungs- Angioinvasive mucormycosis, superadded Gram positive bacterial and CMV infection, alveolar hemorrhage.
- Brain-deep intracerebral hemorrhage and intraventricular hemorrhage
- Excess iron in liver and spleen.
| Discussion|| |
This gentleman was able to achieve second CR2 after salvage chemotherapy for relapsed AML, but succumbed to the tumultuous course following MUD allogeneic HSCT. Allogeneic HSCT offers the highest chance of cure to patients with relapsed or refractory acute myeloid leukemia. However, this case aptly highlights the other side of the story – the catastrophic complications that can occur following allogeneic HSCT.
He developed polymicrobial sepsis with fungal pneumonia and CMV viremia in the early post-transplantation period. The risk of developing life-threatening opportunistic infections looms large on such patients for a protracted duration, like the hanging “swords of Damocles.” The type of infection varies with the pattern of immune suppression in the different phases (pre-engraftment, early post-engraftment, and late post-engraftment). Profound neutropenia in the pre-engraftment phase increases the risk of bacterial infections and invasive fungal infections. Acute GVHD per se and its treatment with immunosuppressive drugs, and CMV reactivation further enhance the infection risk by causing further immune suppression. He developed severe acute GVHD (grade 4) involving skin, gut, and liver from day +17. About 20 to 60% allogeneic HSCT recipients develop acute GVHD, classically in the first 100 days. Severe acute GVHD is associated with inferior survival and more commonly seen with MUD allogeneic HSCT as compared to matched related donors (59% vs. 39%). Despite improvement in skin and gastrointestinal manifestations of acute GVHD with glucocorticoid therapy, this patient continued to have progressive liver dysfunction. Although acute GVHD is generally diagnosed on the basis of clinical features, histological confirmation is prudent to rule out infectious and non-infectious etiologies that can mimic acute GVHD. Apart from liver GVHD, liver dysfunction in early post-transplantation period can be caused by conditioning toxicity, viral hepatitis (CMV, EBV, HSV, HBV, and HCV), sinusoidal obstruction syndrome, and drug-induced liver injury.
Hematuria and lower urinary tract symptoms were definitely caused by BK virus-related HC, which undoubtedly dominated the clinical picture. Etiology of HC among HSCT recipients varies depending on the timing of onset. Early-onset HC (<72 h) is generally attributed to the chemotherapeutic drugs used in conditioning (cyclophosphamide, busulfan, fludarabine, etc.). Contrarily, viral infections (like BK virus, cytomegalovirus, and adenovirus) are most commonly implicated for the late-onset HC (>72 h). Other predisposing factors for late-onset HC include older age, presence of GVHD, steroid use, thrombocytopenia, and coagulopathy. Moreover, the incidence of HC is higher after MUD transplant (40%) vis-à-vis matched related donor transplant (16%). The co-existing urinary tract infection due to gram negative bacteria probably caused accentuation of local symptoms. The renal involvement in this case is suggested by dysmorphic RBCs in urine, proteinuria, renal enlargement (on ultrasound), and raised serum creatinine. Renal dysfunction in this setting is often attributed to infections and nephrotoxic drugs; however, glomerular proliferative lesions with proteinuria have been uncommonly described as manifestations of renal GVHD.
Autopsy revealed hemorrhagic infarcts in lungs as well as kidneys with histopathological features of angio-invasive mucormycosis. The recipients of solid organ and hematopoietic stem cell transplantation are at increased risk of this life-threatening opportunistic fungal disease. Invasive mucormycosis is caused by the pathogenic Mucorales, most frequent being Rhizopus, Mucor, Lichtheimia, Rhizomucor, and Cunninghamella species. It can present in the form of non-specific clinical features and lack reliable biomarkers for identification. In one of the prospective studies, invasive mucormycosis accounted for 8% of all the cases of invasive fungal infections among HSCT recipients and the median time to mucormycosis in these patients was 123 days. The incidence of mucormycosis in the studies reported from the developed countries varies from 0.1% to 2%., The occurrence of grade 4 acute GVHD, prolonged treatment with high dose corticosteroids, concomitant cytomegalovirus, and iron excess (on autopsy) are the likely factors that predisposed the index patient to develop invasive mucormycosis early in the post-transplant period. As per literature, among HSCT recipients, those with GVHD are specifically known to exhibit highest risk for invasive mucormycosis., In one of the case series, mucormycosis in HSCT recipients was preceded by other invasive fungal infection in 35% cases. This patient had also developed fungal pneumonia with elevated serum galactomannan (suggesting invasive aspergillosis) early in the post-transplant course (on day +7) which completely resolved with antifungal therapy (liposomal amphotericin B and caspofungin). An important learning point here is that posaconazole does not provide universal protection against Mucorales; despite receiving posaconazole this patient developed invasive mucormycosis. It should be kept in mind that poor absorption, drug interactions, and variable compliance are known to affect posaconazole pharmacokinetics and can potentially lead to breakthrough mucormycosis. Unfortunately, the trough posaconazole concentrations were not available in index case.
Early-onset pulmonary complications in such patients can be due to opportunistic infections or non-infectious etiologies. Considering the setting of prolonged neutropenia, immunosuppressive treatment for acute GVHD, and consolidation on chest imaging, it was not surprising to find opportunistic pathogens (bacterial, fungal, and CMV) dominating the lung pathology in this case. However, non-infectious complications like diffuse alveolar hemorrhage, idiopathic pulmonary syndrome, and chemotherapy-associated pneumonitis are other complications that can occur in such patients.
The progressive decline in hemoglobin, TLC, and platelets can be explained by sepsis, CMV infection, or hemophagocytosis. Pre-terminally, he developed generalized tonic–clonic seizures followed by altered sensorium. Neurological complications in allogeneic HSCT recipients most commonly result from cerebrovascular bleeding and opportunistic infections (fungal, toxoplasmosis, CMV). Given the unremarkable CT head, the possibility of intracranial bleed and opportunistic CNS infections seems less likely. However, the possibility of CNS microbleeds cannot be ruled out. Other potential causes include regimen-related toxicity (fludarabine), hypoxic-ischemic encephalopathy, hepatic encephalopathy, and septic encephalopathy.
Early diagnosis and treatment of GVHD along with supportive care has improved the outcome in patients with acute GVHD. The role of a pathologist in the management of transplant candidates is important, especially in the post-transplant settings for the detection of various complications. Histopathological features of acute GVHD in various organs are challenging to identify.,, However, a thorough knowledge of the pathological spectrum and proper interpretation of findings with clinical correlation are necessary for accurate diagnosis and improved management of these patients.
Compliance with ethical standards
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. A detailed informed consent from the parents was taken for publication purposes.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh - 160 012
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2], [Table 3]
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