Banff 2022 Liver Group Meeting report: Monitoring long-term allograft health.

The Banff Working Group on Liver Allograft Pathology met in September 2022. Participants included hepatologists, surgeons, pathologists, immunologists, and histocompatibility specialists. Presentations and discussions focused on the evaluation of long-term allograft health, including noninvasive and tissue monitoring, immunosuppression optimization, and long-term structural changes. Potential revision of the rejection classification scheme to better accommodate and communicate late T cell-mediated rejection patterns and related structural changes, such as nodular regenerative hyperplasia, were discussed. Improved stratification of long-term maintenance immunosuppression to match the heterogeneity of patient settings will be central to improving long-term patient survival. Such personalized therapeutics are in turn contingent on a better understanding and monitoring of allograft status within a rational decision-making approach, likely to be facilitated in implementation with emerging decision-support tools. Proposed revisions to rejection classification emerging from the meeting include the incorporation of interface hepatitis and fibrosis staging. These will be opened to online testing, modified accordingly, and subject to consensus discussion leading up to the next Banff conference.

Banff scoring of kidney allograft biopsies: "Manual" application vs software-assisted sign-out.

OBJECTIVES: Pathologists interpreting kidney allograft biopsies using the Banff system usually start by recording component scores (eg, i, t, cg) using histopathologic criteria committed to memory. Component scores are then melded into diagnoses using the same manual/mental processes. This approach to complex Banff rules during routine sign-out produces a lack of fidelity and needs improvement. METHODS: We constructed a web-based "smart template" (software-assisted sign-out) system that uniquely starts with upstream Banff-defined additional diagnostic parameters (eg, infection) and histopathologic criteria (eg, percent interstitial inflammation) collectively referred to as feeder data that is then translated into component scores and integrated into final diagnoses using software-encoded decision trees. RESULTS: Software-assisted sign-out enables pathologists to (1) accurately and uniformly apply Banff rules, thereby eliminating human inconsistencies (present in 25% of the cohort); (2) document areas of improvement; (3) show improved correlation with function; (4) examine t-Distributed Stochastic Neighbor Embedding clustering for diagnosis stratification; and (5) ready upstream incorporation of artificial intelligence-assisted scoring of biopsies. CONCLUSIONS: Compared with the legacy approach, software-assisted sign-out improves Banff accuracy and fidelity, more closely correlates with kidney function, is practical for routine clinical work and translational research studies, facilitates downstream integration with nonpathology data, and readies biopsy scoring for artificial intelligence algorithms.

Immunotactoid hepatopathy: A novel entity with histologically proven recurrence post liver transplantation.

Immunotactoid deposition is a rare fibrillary deposition disease that is primarily seen in the kidney and is associated with paraproteinemia. Here, we report a case of hepatic immunotactoid deposition in a 67-year-old male with a history of smoldering myeloma and chronic kidney disease who underwent liver transplantation for metabolic dysfunction-related cirrhosis. Immunotactoid deposition was first identified in the explanted liver and recurred in the allograft within only 7 weeks following transplantation, presenting as ascites with normal liver function tests. The patient's posttransplant course was complicated by proteinuria and renal failure requiring dialysis. Histologic examination of both native and allograft livers demonstrated pink amorphous material occupying sinusoidal spaces that were Congo-red negative and immunoglobulin M Kappa-restricted. Electron microscopy revealed characteristic deposits of electron-dense bundles of hollow microtubules with a 40 nm diameter within the sinusoids and space of Disse, consistent with immunotactoids. Therapy of the patient's underlying plasma-cell dyscrasia utilizing a daratumumab-based regimen showed decreased serum paraproteins, resolution of ascites, and improved kidney function, no longer requiring dialysis, without inducing rejection. The patient continues to respond to treatment 10 months posttransplant.

Inhibin-Positive "Cholangioblastic" Variant of Intrahepatic Cholangiocarcinoma: Report of 3 New Patients With Review of the Literature.

Cholangiocarcinoma is the second most common primary liver malignant neoplasm. It usually affects older individuals in their seventh decade of life with no gender predilection. Recently, a distinct subtype of cholangiocarcinoma has emerged with 2 proposed names: "cholangioblastic" and "solid tubulocystic." This variant predominantly occurs in younger women who lack the common risk factors for patients diagnosed with cholangiocarcinomas, such as older age and chronic liver disease or cirrhosis. We describe 3 new patients with a cholangioblastic variant of intrahepatic cholangiocarcinoma. At the time of diagnosis, the patients were aged 19-, 46-, and 28-year-old; 2 females and 1 male (the 46-year-old). None of our patients had a history of chronic liver disease or known predisposing factors for liver tumors. Tumor size ranged from 2.3 to 23 cm in greatest dimension. Histological examination of these tumors demonstrated reproducible morphology characterized by trabecular, nested, and multicystic patterns with micro and macro follicles filled with eosinophilic material. The immunohistochemical profile showed that the tumor cells were positive for keratin 7, inhibin, synaptophysin, and albumin in situ hybridization, while negative for HepPar1, arginase, and INSM1. All tumors lacked conventional intrahepatic cholangiocarcinoma/adenocarcinoma morphology. We also review the literature and emphasize that neuroendocrine tumors should be recognized as a major diagnostic pitfall of this variant.

Morphologic and immunophenotypic evaluation of liver allograft biopsies with contemporaneous serum DSA measurements.

BACKGROUND: Acute antibody mediated rejection is increasingly identified in liver allografts as a unique form of alloimmune injury associated with donor specific antibodies (DSA). This manifests pathologically as microvascular injury and C4d uptake. Despite the liver allograft's relative resistance to alloimmune injury, liver allografts are not impervious to cellular and antibody-mediated rejection. METHODS: In this blinded control study, we evaluated CD163 immunohistochemistry and applied the Banff 2016 criteria for diagnosis of acute AMR on a group of indication allograft liver biopsies from DSA positive patients and compared them to indication biopsies from DSA negative controls. RESULTS: Most DSA positive patients were females (75%, p = .027), and underwent transplantation for HCV infection. Significant histopathological predictors of serum DSA positivity were Banff H-score (p = .01), moderate to severe cholestasis (p = .03), and CD163 score > 2 (p = .029). Other morphologic features that showed a trend with DSA positivity include Banff portal C4d-score (p = .06), bile ductular reaction (p = .07), and central perivenulitis (p = .07). The odds of DSA sMFI ≥5000 was 12.5 times higher in those with a C4d score >1 than those with a C4d score ≤ 1 (p = .04). Incidence of definite for aAMR in the DSA positive cohort was 25% (n = 5), and 0% in the DSA negative cohort. A group of 5 DSA positive cases were not classifiable by the current scheme. CONCLUSION: Sinusoidal CD163, Banff H-score, and diffuse C4d are predictors of serum DSA, and facilitate recognition of histopathological features associated with serum DSA and tissue-antibody interaction.

Reversal of Roux-en-Y Gastric Bypass for Successful Salvage of Renal Allograft.

Enteric hyperoxaluria (EH) is a known complication of Roux-en-Y gastric bypass (RYGB) and can lead to nephrolithiasis, oxalate-induced nephropathy, and end-stage renal disease. Recurrent EH-induced renal impairment has been reported after kidney transplantation and may lead to allograft loss. EH occurs in up to one quarter of patients following malabsorption-based bariatric operations. We present a report of medically refractory EH in a renal transplant recipient with allograft dysfunction that was successfully managed with reversal of RYGB. The patient developed renal failure 7 years following gastric bypass requiring renal transplant. Following an uneventful living donor kidney transplant, the patient developed recurrent subacute allograft dysfunction. A diagnosis of oxalate nephropathy was made based on biopsy findings of renal tubular calcium oxalate deposition in conjunction with elevated serum oxalate levels and elevated 24-hr urinary oxalate excretion. Progressive renal failure ensued despite medical management. The patient underwent reversal of her RYGB, which resulted in recovery of allograft function. This report highlights an under-recognized, potentially treatable cause of renal allograft failure in patients with underlying gastrointestinal pathology or history of bariatric surgery and proposes a strategy for management of patients with persistent hyperoxaluria based on a review of the literature.

Clinical, histological and molecular profiling of different stages of alcohol-related liver disease.

OBJECTIVE: Alcohol-related liver disease (ALD) ranges from never-decompensated ALD (ndALD) to the life-threatening decompensated phenotype, known as alcohol-related hepatitis (AH). A multidimensional study of the clinical, histological and molecular features of these subtypes is lacking. DESIGN: Two large cohorts of patients were recruited in an international, observational multicentre study: a retrospective cohort of patients with ndALD (n=110) and a prospective cohort of patients with AH (n=225). Clinical, analytical, immunohistochemistry and hepatic RNA microarray analysis of both disease phenotypes were performed. RESULTS: Age and mean alcohol intake were similar in both groups. AH patients had greater aspartate amino transferase/alanine amino transferase ratio and lower gamma-glutamyl transferase levels than in ndALD patients. Patients with AH demonstrated profound liver failure and increased mortality. One-year mortality was 10% in ndALD and 50% in AH. Histologically, steatosis grade, ballooning and pericellular fibrosis were similar in both groups, while advanced fibrosis, Mallory-Denk bodies, bilirubinostasis, severe neutrophil infiltration and ductular reaction were more frequent among AH patients. Transcriptome analysis revealed a profound gene dysregulation within both phenotypes when compare to controls. While ndALD was characterised by deregulated expression of genes involved in matrisome and immune response, the development of AH resulted in a marked deregulation of genes involved in hepatocyte reprogramming and bile acid metabolism. CONCLUSIONS: Despite comparable alcohol intake, AH patients presented with worse liver function compared with ndALD patients. Bilirubinostasis, severe fibrosis and ductular reaction were prominent features of AH. AH patients exhibited a more profound deregulation of gene expression compared with ndALD patients.

Alcoholic hepatitis masquerading as tumor infiltration: Reversibility after abstinence.

A subset of patients with alcoholic hepatitis present with atypical imaging resembling hepatic tumor infiltration. Our case involves a patient who was initially thought to have multiple large hepatic metastases, ultimately found to have alcoholic hepatitis. It is essential to ask about alcohol use when clinical suspicion is high.

Esophageal Carcinoma Cuniculatum Associated with Non-Necrotizing Granulomatous Inflammation and Lymphadenopathy: Clinicopathologic Features and Diagnostic Challenges.

BACKGROUND Esophageal carcinoma cuniculatum (CC) is an exceptionally rare, well-differentiated squamous cell carcinoma (SCC) with initial microscopic evaluation often yielding inconclusive diagnoses due to its characteristically bland histomorphologic appearance on superficial endoscopic biopsy. This can lead to delayed diagnosis and pose challenges in further management of these cases. CASE REPORT We present the case of a 52-year-old man with symptoms of dysphagia and odynophagia. The initial chest CT scan showed gastroesophageal (GE) junction wall thickening and regional lymphadenopathy. Esophagogastroduodenoscopy (EGD) revealed an esophageal mass, but the mucosal biopsies were inconclusive. Repeat endoscopic biopsies also failed to yield a definitive diagnosis. Under strong clinical suspicion for malignancy, an esophagogastrectomy was performed, which yielded the diagnosis of CC, and the associated enlarged lymph nodes revealed non-necrotizing granulomatous lymphadenitis. CONCLUSIONS Only 15 cases of esophageal CC have been described in the literature. This particular case is unique due to the associated abundant lymphoplasmacytic and granulomatous inflammation and involvement of regional lymph nodes by non-necrotizing granulomas not previously described.

Can Medullary Thyroid Carcinoma Arise in Thyroglossal Duct Cysts? A Search for Parafollicular C-cells in 41 Resected Cases.

Thyroglossal duct cysts (TGDCs) are present in ~7% of adults and develop from the midline migratory tract between the foramen cecum and anatomic location of the thyroid. Thyroid tissue can be identified in 2/3 of TGDCs, and up to 1% develop associated malignancy, 90% of which are papillary thyroid carcinoma. Cases of follicular and anaplastic carcinoma have been documented, but there are no reports of medullary thyroid carcinoma arising in a TGDC. This is presumably due to the distinct embryologic origin of parafollicular C-cells, from which medullary carcinoma arises. The goal of this study is to determine whether parafollicular C-cells are present in TGDCs. H&E sections from 41 TGDC cases were examined for thyroid tissue, thyroglossal duct remnants, ultimobranchial remnants, and parafollicular C-cells. Immunohistochemistry was performed for TTF-1 and calcitonin. Eighty three percent (34/41) of cases contained thyroid tissue on H&E and by TTF-1. No cases (0/41) had ultimobranchial remnants or parafollicular C-cells on H&E or with calcitonin. One case of papillary carcinoma in a TGDC was identified. These cases illustrate that although TGDCs often contain thyroid tissue, parafollicular C-cells are absent. Therefore, unlike other thyroid neoplasms, there is no evidence to support the possibility of medullary carcinoma arising in a TGDC.

Comparison of GATA-3, mammaglobin, GCDFP-15 expression in breast carcinoma in serous effusions: A cell-block micro-array study.

BACKGROUND: GATA-3 is a potential marker for detection of metastatic breast carcinoma, reportedly more sensitive than mammaglobin (MAM) and GCDFP-15. We aim to compare the sensitivity of GATA-3, MAM and GCDFP-15 in determining the breast origin of malignant effusions. METHODS: Cell blocks from 27 cases of serous effusions positive for metastatic breast cancer were retrieved. Immunohistochemistry for GATA-3, MAM, gross cystic disease fluid protein 15 (GCDFP-15), estrogen receptor (ER) and progesterone receptor (PR) was performed on cell-block micro-array. Statistical analysis using two ways Chi square, one-way ANOVA and multiple regression was performed. RESULTS: The detection rate of breast cancer in serous fluid was significantly higher with GATA-3 (88.8 %, X2=15.9, p=0.00034) than with MAM (51.8 %) and GCDFP-15 (37.0 %). All ER positive cases (19) were GATA-3 positive. Conversely, all GATA-3 negative cases (3) were ER negative. The intensity of stain and percentage of positive cells were significantly higher with GATA-3 (p<0.0001) than with MAM and GCDFP-15. The intensity and percentage of positive cells score of GATA-3 were statistically associated with ER stain intensity and percentage of positive cell scores. CONCLUSIONS: GATA3 is a sensitive marker, superior to MAM and GCDFP-15 in determining the breast origin of metastatic adenocarcinoma. It is also strongly associated with ER expression.

Utility of GATA-3 in the work-Up of breast adenocarcinoma and its differential diagnosis in serous effusions:: A Cell-Block Microarray Study.

BACKGROUND: GATA-3 is a transcription factor involved in human tissue growth and differentiation. It is a potential marker for breast carcinoma origin in metastasis and predictive of good prognosis. We aim to evaluate the role of GATA3 in determining the breast origin of metastatic adenocarcinoma in malignant effusions using immunohistochemistry on cell-block microarray in comparison with ER and PR results. METHODS: Cell blocks from 100 cases of malignant and reactive serous effusions with confirmed diagnosis were selected; 28 mammary carcinomas, 64 extra-mammary adenocarcinomas (gastrointestinal, pulmonary, gynecologic), and 8 reactive mesothelium proliferation as control. Immunohistochemistry on cell-block microarray was used. Microarray slides were stained for GATA-3, ER and PR. Nuclear staining of >1% was considered positive. RESULTS: GATA3, ER and PR were positive in 25 (89%), 20 (71%) and 16 (57%) of breast carcinoma cases, respectively. All non-breast cancer cases were negative for GATA-3 with the exception of one Müllerian adenocarcinoma (1.6%). The calculated sensitivity, specificity and positive predictive value (PPV) of GATA3 reactivity in determining the breast origin of metastatic adenocarcinoma was 89.3% (95% CI: 71.7-97.7%), 98.6% (95% CI: 91.6-99.9%) and 96.2% (95% CI: 80.4-99.9%), respectively. GATA3 positivity was associated with ER or PR positivity in 84% of cases. CONCLUSIONS: GATA3 is a useful marker in determining the breast origin of metastatic adenocarcinoma in malignant serous effusions. Reactivity to GATA3 may indicate good prognosis. Diagn. Cytopathol. 2016;44:731-736. © 2016 Wiley Periodicals, Inc.

Utility of TTF-1 and Napsin-A in the work-up of malignant effusions.

BACKGROUND: Similar to TTF-1, Napsin-A is recently used increasingly to differentiate between pulmonary adenocarcinoma (P-ADC) and extra-pulmonary adenocarcinoma (EP-ADC). The aim of this study was to compare the performance of TTF-1 and Napsin-A in determining the primary origin of adenocarcinoma in malignant serous effusion. METHODS: Following IRB approval, cellblocks from 139 cases of malignant serous effusions of histologically or clinically determined origin including: 26 P-ADC, 108 EP-ADC, 2 pulmonary squamous cell carcinoma (P-SQC), and 3 pulmonary small cell carcinoma (P-SCC) were retrieved. Each case was stained with Napsin-A and TTF-1 and evaluated for positivity and intensity of staining. RESULTS: Napsin-A and TTF-1 stained positive in 17/26 (65%) and 14/26 (54%) of P-ADC and in 2/108 (1.8%) and 0/108 (0%) of EP-ADC with a PPV of 89 and 100%, respectively. In combination, they positively stained 18/26 (70%) of P-ADC with a PPV of 90%. Out of 9 poorly differentiated P-ADC, 7 (78%) stained positive for Napsin-A, while 4 (45%) were reactive for TTF-1. Both Napsin-A and TTF-1 were negative in P-SQC, while P-SCC reacted positively for TTF-1 in 2/3 (66%) of cases and none for Napsin-A. CONCLUSION: Napsin-A and TTF-1 are both useful markers in distinguishing P-ADC from EP-ADC. However, Napsin-A performed better in poorly differentiated P-ADC and its mimickers. The nuclear staining of TTF-1 is crispier and much easier to interpret than Napsin-A cytoplasmic stain. An antibody panel including TTF-1 and Napsin-A or a dual stain will be very helpful in determining the origin of metastatic adenocarcinoma in serous effusion.

Solid Ehrlich tumor growth treatment by magnetic waves.

In this work the retardation of Ehrlich tumor growth implanted in mice was studied by employing 4.5 Hz magnetic field. Eighty female Balb/c mice were used, twenty as normal group; the other sixty mice were inoculated with Ehrlich tumor, then they were divided equally into three groups namely A, B and C. Group A (control group) animals were not exposed to the magnetic field. The tumors in the thigh of the animals of group B were exposed to 4.5 Hz, 2 Gauss square wave magnetic field by using a small solenoid connected to a power square wave generator. Group C animals were whole body exposed inside a large solenoid to 4.5 Hz, 2 Gauss square wave magnetic field. Both groups B and C were exposed for a period of 2 weeks at a rate 2 hours per day. Tumor volume, survival period, histological examination and dielectric relaxation of the tumor were measured to investigate the activity of the tumor of the exposed and the unexposed animals. The results indicated that exposing the tumor tissue to 4.5 Hz square wave magnetic field for 2 weeks at a rate 2 hours/day inhibited tumor growth and increased the survival period of the animals. However, group B showed more improvements than did group C. This was attributed to some distortions in the square waveform in the large solenoid (group C). By comparing data from current and previous work, it was concluded that the use of magnetic waves showed better results over previously published work using amplitude modulated electromagnetic waves with the same frequency.