| Web: | mayocliniclabs.com |
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| Email: | mcl@mayo.edu |
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| Web: | mayocliniclabs.com |
|---|---|
| Email: | mcl@mayo.edu |
| Telephone: | 800-533-1710 |
| International: | +1 855-379-3115 |
| Values are valid only on day of printing | |
A 69-year-old man from Wisconsin passed away unexpectedly at home in August. Three weeks prior, he presented with symptoms including hot flashes, sweating, shortness of breath, cough, blurry vision, right eye pain, epigastric pain, right shoulder pain, ankle swelling, redness, a swollen neck lymph node, and loss of balance. He also reported multiple bug bites. His medical history includes hypertension, hyperlipidemia, and type 2 diabetes mellitus. Autopsy findings are shown in the following photos.
The correct answer is ...
Lyme carditis.
This decedent’s gross autopsy showed spotty areas of fibrosis in the heart. Histology showed carditis characterized by interstitial and perivascular lymphoplasmacytic infiltrates with background fibrosis that formed an intersecting curvilinear pattern (“road-map” distribution). The inflammatory infiltrates spanned across the left ventricle, ventricular septum, right ventricle, and the conduction system. Notably, his Lyme antibody modified two-tier test (both IgG and IgM) returned positive. These findings, along with clinical symptoms and geographic location, were consistent with Lyme carditis.
Lyme disease is the most common tick-borne infection in the United States, with an annual report of about 30,000 cases. The spirochetes of Borrelia burgdorferi sensu lato complex are transmitted by ticks (Ixodes ricinus complex), with the peak infection in late spring and summer. Clinical histories can be nonspecific, including viral-like symptoms, malaise, muscle and joint pains, lymphadenopathy, and shortness of breath. Erythema migrans (EM) rash occurs in 70%–80% of patients during the early stage. In the early disseminated phase, cardiovascular symptoms, including atrioventricular block, can occur in about 1.1% of Lyme infection, while fatal myocarditis is rare.
The diagnosis of Lyme carditis is based on clinical history, histology, and serology. Typical autopsy findings include pancarditis with interstitial and perivascular infiltrates, with limited myocyte necrosis. A key differential to hypersensitivity myocarditis is the lack of prominent eosinophilic infiltrates. Warthin-Starry stain (WS), a silver nitrate-based method, is helpful to identify spirochetes, but may have limited sensitivity and specificity due to the low load of the spirochetes and high background staining. Other methods include Borrelia burgdorferi immunohistochemistry (IHC) and nuclear acid detection using polymerase chain reaction (PCR).
Serology testing for Lyme disease includes standard two-tier testing algorism (STTT) and modified two-tier testing algorism (MTTT). For MTTT, enzyme immunoassay (EIA) for total antibody testing against VlsE1 and pepC10 antigens is performed first. If positive, whole cell sonicate (WCS) IgG and IgM testing is performed to confirm the infection. In patients without past Lyme disease, MTTT has been reported to have comparable specificity (≥99%) to STTT, and close to 100% sensitivity for patients with carditis, neuroborreliosis, or arthritis.
It is reasonable to consider arrhythmogenic cardiomyopathy as a potential differential diagnosis for sudden cardiac death. However, the typically gross findings would include fatty or fibrofatty infiltration of the right ventricle with chamber dilation, and histology would show transmural fibrofatty replacement of the myocytes. Given the medical history of hypertension, hyperlipidemia, and diabetes, acute myocardial infarction can be suspected. Autopsy for early infarct may be negative, or demonstrate pale discoloration, hemorrhage, and myocardium softening. Neither of the two scenarios would have pancarditis with extensive lymphoplasmacytic infiltrates.
Yi Zhu, M.D., Ph.D.
Resident, Anatomic Neuropathology
Mayo Clinic
@doctorYiZhu
Ross Zumwalt, M.D.
Senior Associate Consultant, Anatomic Pathology
Mayo Clinic
In your capacity as the lead physician of a healthcare facility, your team has grappled with enhancing the patient journey experience during laboratory visits. To address this, your data science unit devised a machine-learning (ML) model that can potentially identify patients who might go through unsatisfactory experiences during their visit to the lab. Your research team describes their model to be at the level of proof of concept, with a clinical research use case, and real-world representative data, the data pipeline is a prototype–caliber pipeline, and they identified users from a clinical user experienced perspective. Yet, they haven’t started stakeholder analysis or product caliber specifications. The team provided you with a model card to communicate their work so far.
The correct answer is ...
MLTRL4.
In this vignette, we introduce two central concepts: the AI lifecycle framework and model cards. These concepts are pivotal for evaluating the maturity of a Machine Learning (ML) system. Our vignette focuses on an ML system devised within a multifaceted healthcare system, with anticipation of its integration into the prevailing software landscape. To ascertain the maturity of this AI technology, exploring the Machine Learning Technology Readiness Level (MLTRL) framework may be warranted. This framework considers the obligations of an ML system and emphasizes other crucial aspects like fairness, ethics, reliability, and robustness.
Drawing from experiences with ML systems across diverse sectors — including aerospace, defense, and civil engineering — Lavin, et al. delineated processes, and testing standards. This has enabled a structured approach for assessing the maturity of ML systems suited for real-world applications.
The objective of the MLTRL framework is to cultivate and launch ML systems that are robust, reliable, and responsible. This framework streamlines workflows and bolsters communication across teams at various AI system development stages. Its design mirrors the stages of AI product evolution, spanning research and development, productization, and deployment.
For instance, MLTRL4 serves as a proof of concept, showcasing the model's real-world data performance. However, at this juncture, the ML system hasn't advanced sufficiently to align with the requirements of data governance, product standards, code integrity, and regulatory compliance, as seen in MLTRL5,6. On the other hand, MLTRL1 denotes goal-oriented research, marking the nascent stages of ML model development. MLTRL9 signifies the culmination of this framework, where an ML system's deployment is continually monitored and refined.
Our vignette also underscores the importance of the MLTRL model card within the MLTRL framework. These model cards document and elucidate the performance attributes of an ML model, making them vital for both individual and functional communication. They serve to relay project updates and facilitate team member onboarding. Beyond this, they act as gauges for maturity, helping determine a model's position on the continuum between foundational research and deployment. By fostering communication across stakeholders and transcending the development phase, these cards distill some of the intrinsic knowledge embedded in the process. We propose that MLTRL cards act as foundational pillars supporting other tools, such as model cards, data cards, and ethical/responsibility parameters.
MLTRL model cards are cohesive and transferable documents, linking an ML system with its present milieu and its maturity journey. The external environment is portrayed via project data, overarching requirements, intended applications, and tacit knowledge. In contrast, the system's intrinsic attributes are conveyed through details on the model algorithm, testing status, potential biases, technical knowledge debt, and MLTRL stage debriefings. An intermediary layer exists between the internal and external domains, emphasizing data-related considerations like acquisition, sharing, privacy, and ethics.
The MLTRL model cards aren't merely standalone documents but community resources complementing tools like pivotal for documentation and data provenance. For instance, our choice was to adopt datasheets for datasets proposed by Google, given their transparency and ease of implementation. Additionally, MLTRL model cards can be synchronized with data cards using DVC (data version control), reinforcing best practices in ML system development.
Lastly, MLTRL model cards champion transparency and thoroughness, especially in AI clinical trials. Researchers can harness these cards to craft clinical trial protocols, aligning seamlessly with frameworks like SPIRIT-AI and CONSORT-AI. Moreover, these model cards pinpoint potential biases within an ML system, an aspect not inherently addressed in AI clinical trials. Effective reporting in AI trials commences with comprehensive documentation of ML system development. SPIRIT-AI clinical trial protocols, for example, can be augmented using TRL cards, enriching sections like title, background, interventions, and potential harms.
EzzAddin Al Wahsh, M.D., M.B.A.
Fellow, Clinical Informatics
Mayo Clinic
Christopher Garcia, M.D.
Senior Associate Consultant, Computational Pathology and AI
Mayo Clinic
A 60-year-old man with a history of drug and alcohol abuse recently presented to the ER with active upper gastrointestinal bleeding, hypovolemic shock, and possible sepsis. The present liver biopsy was performed seven days after the ER presentation due to the persistently elevated liver enzymes, especially the alkaline phosphatase of over 400 units/L.
The correct answer is ...
Amyloid deposition.
The biopsy shows liver parenchyma with acellular eosinophilic amorphous material deposition within the sinusoidal spaces with atrophy of the hepatocytes, characteristic of amyloidosis. Confirmatory Congo Red special stain demonstrated salmon-colored deposits, which showed apple green-birefringence under polarization, confirming amyloid deposits. The subsequent mass-spectrometry analysis identified the deposits to be AL-amyloid.
Amyloidosis is a systemic disorder characterized by extracellular amyloid protein deposition commonly involving the liver.1 Autopsy studies have shown up to 95% of patients with amyloidosis to have hepatic involvement.2
Clinically, patients present with hepatomegaly and elevated serum alkaline phosphatase as the most common laboratory finding associated with hepatic amyloidosis.3
The five most common systemic forms of amyloid that involve the liver are amyloid light chain (AL), acquired amyloidosis (AA), B2 microglobulin amyloidosis (Abeta2M), and the two types of transthyretin amyloidosis (ATTR) (hereditary and non-hereditary). The present subtype, AL-amyloid, is associated with plasma cell dyscrasias, multiple myeloma, B-cell lymphoma, or Waldenstrom disease. The precursor proteins can be Kappa or Lambda immunoglobulin light chains derived from plasma cells.
Amyloid deposits in the liver show similar morphologic findings as other organ sites, as it presents as an acellular eosinophilic amorphous material, which may deposit in the sinusoids, portal tracts, vessel walls, or any mix of the mentioned sites.
Specific subtypes of amyloid may show different patterns of deposition within the liver. For example, some studies have demonstrated that AA amyloidosis shows deposits primarily in the blood vessels of the portal tracts, whereas AL amyloidosis usually shows a “sinusoidal” pattern. However, the distribution pattern alone is not used clinically to subtype amyloid.4 Additionally, the deposit morphology may also help determine the subtypes of amyloid deposits as large round eosinophilic globular deposits within the hepatocytes or reticuloendothelial cells characterize the “globular amyloid deposits,” which are highly specific for leukocyte chemotactic factor (LECT2)-associated amyloidosis.5
Previously, immunostains were utilized to subtype the amyloid. However, due to their challenges in interpretation, laser microdissection with mass spectrometry is now the preferred method that is both sensitive and specific for identifying all amyloid subtypes.6
The differential diagnosis for hepatic amyloid is the presence of other extracellular deposits that can look similar on H&E, such as dense collagen deposits, collection of red blood cells, or light chain deposition. The application of Congo Red Trichrome stain can be helpful for their distinction.
The Light chain deposition disease is a rare monoclonal plasma cell proliferative disorder characterized by the deposition of light chains in the basement membranes. It primarily affects the kidneys, and the liver is the most common site of extrarenal involvement. These typically deposit within the sinusoidal spaces similar to amyloid but are Congo Red stain negative.7
Byoung Uk Park, M.D.
Fellow, Gastrointestinal & Liver Pathology
Mayo Clinic
Chady Meroueh, M.D.
Consultant, Anatomic Pathology
Mayo Clinic
Assistant Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science
A 17-year-old girl presents to her primary care physician with episodic watery diarrhea, nausea, and crampy abdominal pains. She is up to date on her vaccinations and denies any recent travels or changes in her diet. Family history and past medical history are both unremarkable; moreover, physical exam is only significant for mild, diffuse abdominal tenderness. Upper GI endoscopy demonstrates diffuse nodular mucosa in the fundus. A fundic biopsy is taken and shown below.
The correct answer is ...
Anemia and upper gastrointestinal bleeding symptoms are more common in younger patients.
Collagenous gastritis is described in the literature has having a bimodal distribution: a pediatric subtype and an adult subtype. The pediatric variant of the condition is more likely to present with anemia and upper GI bleeds. The bleeding episodes are thought to be due to entrapment of blood vessels within the subepithelial collagen plate (please review the biopsy image and note the many vessels within said collagen). The adult form of the condition, while less likely to be associated with anemia/UGIBs, often presents within the setting of other comorbidities, such as lymphocytic gastritis, celiac sprue, autoimmune disorders (e.g., Hashimoto thyroiditis, polymyositis), as well as collagenous colitis.1 There has also been a case report of collagenous gastritis in a patient with systemic lupus erythematosus, but more research needs to be done to conclusively determine whether or not there is an association between the two clinical entities.2 It is also worth noting that this dichotomy is merely a trend and not definitive; for instance, anemia and bleeding symptoms have been reported in some adult patients as well, though it appears to be a more common presentation in the younger population.
The subepithelial space will stain with Congo red.
While the subepithelial material may resemble amyloid deposits, it is important to allow the patient presentation and history to guide the diagnosis. While amyloidosis is certainly worth placing in the differential given the biopsy specimen, amyloidosis is much more common in the setting of other comorbidities. For instance, primary amyloidosis (AL amyloidosis) is typically secondary to the overproduction of immunoglobulin light chains in the setting of a plasma cell dyscrasia — such as multiple myeloma or Waldenström macroglobulinemia. Moreover, secondary amyloidosis (AA amyloidosis) is due to deposition of serum amyloid A protein. This is seen in chronic inflammatory conditions such as rheumatoid arthritis, as well as juvenile rheumatoid arthritis. Another class of amyloidosis worth mentioning involves the deposition of transthyretin within liver and cardiac tissue. These patients tend to present with symptoms of heart failure.3
Definitive therapy is a combination of PPI and antibiotics.
To date, no definitive therapy has been agreed upon. An important concept to keep in mind for this entire case (and any case for that matter) is that, while we learn textbook cases, we generally do not live textbook lives. Still, we hope that our medical tomes might at least guide us towards piecing together some clinicopathologic gestalt. But what should we do when the textbook is still being written? Collagenous gastritis, as a clinical entity, was first described in 1989 by Colletti and Trainer.4 As such, this condition is relatively new in its description in the literature; consequently, there is currently no definitive cure or treatment for this condition. Varying therapies — such as PPIs, H2 blockers, sucralfate, misoprostol, 5-aminosalicylates, and corticosteroids — have been tried with variable success. Topical, targeted budesonide administration has shown promising results for managing symptoms; that said, a standard of care has yet to be definitively defined for collagenous gastritis.5 Antibiotics are only used when there is an underlying infectious etiology, which is not the case in majority of reported cases.
Biopsy of nodules on endoscopy will demonstrate diagnostic pathology.
This may seem counterintuitive, but the raised, polyp-like areas of nodularity actually demonstrate normal stomach histology. It is actually the areas of depression around these nodules which are best for biopsy, as these depressed areas evince subepithelial collagenous thickening. Think of it another way: the nodular areas are normal histologically but appear more salient grossly because they are surrounded by areas of collagen deposition.6
Other information regarding collagenous gastritis:
This is a very rare condition. There may be around 300 cases described worldwide, though this is a somewhat liberal estimate, with some experts claiming even fewer cases globally. So far, there does not appear to be a geographic preference. Additionally, some studies suggest there may be a slight female preponderance, though other studies have reported no gender preference. Presenting symptoms may include nausea, vomiting, recurrent crampy abdominal pain, and watery diarrhea. To date, there have been no reported cases of dysplasia or carcinoma arising from or as a consequence of collagenous gastritis. The pathogenesis is unclear, but it is thought that an inciting inflammatory process occurs, which results in subsequent collagen deposition.7
Dustin Parsons, M.D.
Resident, Anatomic & Clinical Pathology
Mayo Clinic
Eric Chen, M.D., Ph.D.
Consultant, Anatomic Pathology
Mayo Clinic
Associate Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science
A 72-year-old woman presents with vaginal bleeding and is subsequently diagnosed with endometrioid adenocarcinoma (FIGO grade 2/3) (Figure 1). Immunohistochemistry (IHC) for mismatch repair (MMR) proteins is notable for an absence of MLH1, PMS2, MSH2, and MSH6 expression (Figure 2).
The correct answer is ...
MLH1 promoter hypermethylation and MSH2 pathogenic alteration (c.560T>C, p.Leu187Pro).
MLH1 promoter hypermethylation leads to silencing of MLH1 gene expression thus preventing subsequent protein formation. Consistent with the patient’s age, this form of epigenetic inactivation occurs most commonly in the context of sporadic (versus hereditary) tumor development. Loss of MLH1 would also account for the loss of PMS2 protein expression given the existence of the two proteins as a dimer. Independently, a pathogenic missense variant in MSH2 resulting from the instability created by MLH1/PMS2 loss would lead to the loss of MSH2, which would in turn lead to concomitant loss of MSH6 expression.
POLE alteration (variant of undetermined significance) and PMS2 pathogenic alteration
Although a POLE pathogenic alteration could, in theory, result in additional downstream alterations (including in the MMR genes) that could, in turn, result in loss of IHC staining for all MMR proteins. However, only a VUS was identified in POLE and the overall mutation spectrum of the tumor was not hypermutated. In addition, there is limited evidence available to support this theory. Although a PMS2 pathogenic alteration could explain the loss of PMS2 by IHC, not all PMS2 mutations cause the loss of MLH1. The PMS2 mutation would not explain the loss of MSH2/MSH6.
MLH1 promoter hypermethylation and MSH6 alteration (variant of undetermined significance, VUS)
MLH1 promoter hypermethylation would explain the loss of MLH1 and PMS2 by IHC. However, a VUS in MSH6 would not necessarily explain the loss of MSH6. Furthermore, MSH2 can be expressed by IHC in the absence of MSH6.
Failure of IHC positive control
Although a failure of the positive control can certainly explain the loss of any protein by IHC, background staining of non-neoplastic cells (stroma/lymphocytes) in this case rules out this possibility (Figure 2).
Mazen Atiq, M.B.B.S.
Fellow, Molecular Genetic Pathology
Mayo Clinic
Kevin Halling, M.D., Ph.D.
Consultant, Laboratory Genetics and Genomics
Mayo Clinic
Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science
Ande Rumilla, M.D.
Consultant, Laboratory Genetics and Genomics
Mayo Clinic
Assistant Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science
A 25-year-old woman with a twin gestation complicated by twin-to-twin transfusion syndrome underwent an amniocentesis procedure, and amniotic fluid from Twin A was obtained. There were no other anomalies or complications noted with the pregnancy. A chromosomal microarray study performed on cultured cells from the amniotic fluid showed mosaic trisomy 6 as displayed on the figure below. Maternal cell contamination was ruled out.
The correct answer is ...
The microarray result may represent pseudo-mosaicism due to culture artifact. Additional cytogenetic studies should be performed on an independent culture to confirm or refute this finding.
Mosaicism is defined as the presence of two or more populations of cells with differing genetic complements. When a mosaic finding is observed in prenatal specimens, several possibilities are important to consider when assessing if this represents true fetal mosaicism. In prenatal results from cultured amniotic fluid cells, apparent mosaicism may represent true fetal mosaicism, maternal cell contamination, or pseudomosaicism due to culture artifact. Since decisions regarding termination or continuation of a pregnancy can be influenced by these results, it is imperative to determine whether true fetal mosaicism is present or not.
In this case, since maternal cell contamination has been ruled out, and low-level mosaicism could be present in a fetus with no obvious abnormalities by ultrasound, additional studies are required (karyotype, fluorescence in situ hybridization, or repeat microarray studies) to determine if true fetal mosaicism is present. These studies can either be performed on residual uncultured amniotic fluid specimen (if available) or on independent cultures derived from the same amniotic fluid sample that was received. If true fetal mosaicism is present, trisomy 6 cells should be detected in two or more independent cultures. If pseudomosaicism due to culture artifact is the cause of the mosaic trisomy 6, then the abnormality will only be present in the culture that was used for the chromosomal microarray study.
Sharri Cyrus, M.B.B.S.
Fellow, Laboratory Genetics and Genomics
Mayo Clinic
Nicole Hoppman, Ph.D.
Consultant, Laboratory Genetics and Genomics
Mayo Clinic
Associate Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science
