Category: Clinical Updates

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September 2022: Best Practice for Detecting Hyperhomocysteinemia – Homocysteine Testing—Not MTHFR Genotyping

Best Practice for Detecting Hyperhomocysteinemia: Homocysteine Testing—Not MTHFR Genotyping

There is no conclusive evidence supporting the clinical value of MTHFR polymorphism genotyping.

Practice guidelines from multiple professional societies agree that MTHFR polymorphism genotyping should not be ordered as part of clinical evaluation.

If there is a clinical concern regarding hyperhomocysteinemia, Cleveland Clinic Laboratories recommends Homocysteine testing (HOMCYS) in place of MTHFR genotyping. Homocysteine testing is less expensive, generates a result more quickly, and provides additional actionable information for patient management.

Best Practice

If there is a clinical concern regarding hyperhomocysteinemia (HCC), Cleveland Clinic Laboratories recommends Homocysteine testing (HOMCYS) in place of MTHFR genotyping

Homocysteine (HOMCYS)

Upcoming Changes

November 15, 2022: MTHFR genotyping (MTHFRM) will no longer be available as a send-out test, even if ordered as a miscellaneous test.

March 16, 2021: Homocysteine testing (HOMCYS) will replace MTHFR genotyping at Cleveland Clinic.

HOMCYS Test Overview

Homocysteine (HOMCYS) Test Details

Test Name

Homocysteine

Test Code

HOMCYS

CPT Code

83090

Performing Laboratory

Cleveland Clinic Laboratories

FDA Compliance

In Vitro Diagnostic (IVD)

Methodology

Enzymatic

Days Performed

Sun – Sat

Turnaround Time

8 hours

Specimen Requirements

Type:
Plasma

Volume:
1 mL

Specimen Container:
Light Green Lithium Heparin Plasma Separator Tube (PST)

Transport Temperature:
Refrigerated

Place specimen on ice after draw.

Alternative Specimen Requirements

Type:
Serum

Volume:
1 mL

Specimen Container:
Gold Serum Separation Tube (SST)

Transport Temperature:
Refrigerated

Place specimen on ice after draw.

Special Instructions

• Centrifuge and separate plasma/serum from cells less than one hour after collection.

• If collected in a non-gel separator tube, centrifuge and transfer plasma/serum to a CCL tube and refrigerate.

Stability

Ambient:
4 days

Refrigerated:
4 weeks

Frozen:
10 months

Reference Interval

18-99 Years – Normal:
<15.1 umol/L

MTHFR: Lack of Evidence

Lack of Evidence for MTHFR Polymorphism Genotyping

Recommendation: Test Plasma Homocysteine Levels

Download this Overview (PDF)

There is no conclusive evidence supporting the clinical value of MTHFR polymorphism genotyping.

If there is a clinical concern regarding hyperhomocysteinemia, Cleveland Clinic Laboratories recommends Homocysteine (HOMCYS) testing.

• Multiple practice guidelines agree that MTHFR polymorphism genotyping should not be ordered as part of a clinical evaluation.

• A cheaper, faster, and more accurate way to test for hyperhomocysteinemia is to measure plasma homocysteine levels.

• If plasma homocysteine levels are high, patients can supplement with vitamins such as B6, B12, folate, and folic acid.

• If plasma homocysteine levels are normal, no treatment is indicated—even if there is an MTHFR variant.

Plasma homocysteine levels determine clinical management, regardless of the MTHFR genotype result.

Professional Societies with MTHFR Polymorphism Testing Guidelines:

After reviewing these guidelines,
Cleveland Clinic’s RT-PLMI Section of Molecular Pathology, Genomic Medicine Institute, and Laboratory Stewardship Committee agreed to discontinue MTHFR polymorphism genotyping.

Background

The MTHFR gene (OMIM: 607093) on 1p36.22 encodes the 5,10-methylenetetrahydrofolate reductase enzyme, which converts 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the primary circulatory form of folate. This enzyme is also involved in the metabolism of the amino acid, homocysteine. A deficiency of the enzyme can lead to HHC.

Polymorphisms are common variants within a gene that do not necessarily affect its function, unlike pathogenic or disease-causing variants. Two commonly tested polymorphic variants in MTHFR are:

c.665C>T* (p.Ala222Val)
*Historically referred to as C677T, the ‘thermolabile’ variant

c.1286A>C (p.Glu429Ala)

These variants are so common that approximately 25% of individuals with Hispanic ancestry and 15% of North Americans with European ancestry have two copies of c.665C>T.

The presence of two copies of c.665C>T (homozygosity) may result in decreased MTHFR enzyme activity and mild HHC. Neither of these MTHFR polymorphisms causes severe MTHFR deficiency (<20% enzyme activity).

References

1. Lack of Evidence for MTHFR Polymorphism Testing. ACMG Practice Guideline. Genet Med. 2013;15(2):153-6.
2. Inherited Thrombophilias in Pregnancy. ACOG Practice Bulletin. No. 197. American College of Obstetricians and Gynecologists. Obstet Gynecol. 2018;132:e18–34.
3. Levin BL, Varga E. MTHFR: Addressing Genetic Counseling Dilemmas Using Evidence-Based Literature. J Genet Counsel. 2016;25:901-11.
4. Choosing Wisely® Initiative https://www.choosingwisely.org/
5. Eng, C. A Genetic Test You Don’t Need: Testing MTHFR is usually unnecessary. Cleveland Clinic Health Essentials. https://health.clevelandclinic.org/a-genetic-test-you-dont-need/. Accessed November 19, 2020.

Updating Best Practices

Updating Best Practices

Cleveland Clinic Laboratories encourages providers to incorporate Homocysteine testing (HOMCYS) into their practice in place of MTHFR genotyping.

November 15, 2022: MTHFR genotyping will no longer be available as a send-out test, even if ordered as a miscellaneous test.

March 16, 2021: MTHFR genotyping will no longer be performed in-house at Cleveland Clinic.

Special Communications
Immediate Test Changes
News & Updates
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Pathology Insights: Update on Small Round Cell Tumors with Scott Kilpatrick, MD

Pathology Insights Video Series

Update on Small Round Cell Tumors with Scott Kilpatrick, MD

Presented by Scott Kilpatrick, MD

In this video, Scott Kilpatrick, MD, Director of Orthopedic Pathology at Cleveland Clinic, provides historical context and WHO updates on the evolving classification of undifferentiated round cell sarcomas, including Ewing sarcoma and the so-called Ewing family of sarcomas.

As part of our educational mission for our clients and communities, Cleveland Clinic Laboratories presents the Pathology Insights video series.
These short videos break down information about interesting pathology cases to better inform doctors, laboratory staff, patients, or anyone interested in the field of pathology. Each episode features important cases, methods, and practices that are personally presented by our staff pathologists.
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Estimated Glomerular Filtration Rate (eGFR) Updates

Clinical Update

Estimated Glomerular Filtration Rate (eGFR) Updates

The National Kidney Foundation and American Society of Nephrology joint task force recently released recommendations on including a race variable in eGFR reporting (PMID: 34563581).

Based on these recommendations and internal review, the following changes will occur on February 26, 2022:

Adult eGFR Creatinine Calculation

The adult eGFR creatinine equation will be updated from MDRD to the 2021 CKD-EPI creatinine equation in all blood-based creatinine panels (e.g. BMP).

This equation utilizes creatinine, sex, and age, but does not include a race variable.

The new upper reporting limit will increase from 60 to 150 mL/min/1.73m2.

Adult Cystatin C-Based eGFR

eGFR confirmation with a cystatin C-based calculation is recommended near clinical decision-making thresholds.

Two new equations will be available:

2012 eGFR cystatin C (CYSTC)

  • Variables include cystatin C, age, and sex, but not race.

2021 eGFR creatinine-cystatin C (CRECYS)

  • Variables include creatinine, cystatin C, age, and sex, but not race.

Pediatric eGFR Reporting

The task force recommendations focus on the adult population; however, several changes related to EHR transformation will affect the pediatric population:

– The Bedside Schwartz creatinine factor will no longer be reported. The Bedside Schwartz creatinine equation will be provided as a comment: Bedside Schwartz equation = 0.413 x [height (cm) / serum creatinine (mg/dL)].

– The 2012 Schwartz cystatin C equation will be utilized for patients 2-17 years old when cystatin C (CYSTC) is ordered.

– The 2021 eGFR creatinine-cystatin C equation (CRECYS) is valid for adults only and will not be available to order for patients less than 18 years of age.

Special Communications
Immediate Test Changes
News & Updates
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September 2021: New Test – Beta(β)-D-Glucan Assay

Clinical Update

New Test: Beta(β)-D-Glucan Assay

In-house Beta(β)-D-Glucan (BDG) testing is now available.

The assay diagnoses certain systemic fungal infections, such as Candidemia, and assists in the prognostication and monitoring response to anti-fungal therapy in hospitalized patients.

This FDA-approved test is a protease zymogen-based colorimetric assay (FUNGITELL® ASSAY) based on a modification of the Limulus Amebocyte Lysate (LAL) pathway in which BDG, where present in the sample, binds Factor G. Activated Factor G turns a proclotting enzyme to clotting enzyme. The latter cleaves an artificial chromogenic substrate (a short peptide) to generate a color. The reaction occurs at 37°C and is kinetically read by a spectrophotometer to generate a standard curve and sample readouts that are subsequently converted to BDG concentrations in pg/ml.

It is important to note that certain fungi, such as the genus Cryptococcus that produces very low levels of BDG, may not result in serum BDG levels sufficiently elevated to be detected by the assay. Infections with fungi of the order Mucorales, such as Absidia, Mucor, and Rhizopus, that are not known to produce BDG can also yield non-detectable serum BDG levels. In addition, the yeast phase of Blastomyces dermatitidis produces little BDG and may not be detected by the assay. Furthermore, positive BDG results have been seen in hemodialysis patients, those who received certain fractionated blood products (such as albumin, IVIg), and those exposed to glucan-containing gauze or surgical sponges.

The sample should be centrifuged within 2 hours of collection to separate the serum from the cells.

Separated samples or serum should be stored refrigerated pending delivery to the testing laboratory.

Heel and fingerprick collections are unacceptable.

Test Name
(1,3) B-D Glucan

Test Code
BDGLUC

CPT Code
87449

Methodology
Protease zymogen-based colorimetric assay (FUNGITELL® ASSAY)

Specimen Requirements
Type: Serum
Volume: 0.5 mL
Container: Gold BD Hemogard™ Serum Separation Tubes (SST)™
Transport Temperature: Refrigerated

Stability
Ambient: Unacceptable
Refrigerated: 7 days
Frozen: 1 year

Reference Range
Negative; <60 pg/mL

Reportable Range
31 to 500 pg/mL

Days Performed
Monday, Wednesday, Friday

Special Communications
Immediate Test Changes
News & Updates
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September 2021: Ziad Peerwani, MD Appointed as Medical Director of Cleveland Clinic Laboratories

Clinical Update

Ziad Peerwani, MD Appointed as Medical Director of Cleveland Clinic Laboratories

Ziad Peerwani, MD has been appointed as the new Medical Director for Cleveland Clinic Laboratories, effective September 1, 2021.

Dr. Peerwani was most recently CEO of Union71, based in Abu Dhabi, where he oversaw 17 laboratories, outpatient phlebotomy services, and the performance of more than 15 million lab tests per year.

“We look forward to the experience Dr. Peerwani brings to leading and growing our outreach laboratory services,” says Brian Rubin, MD, PhD, Chair of Cleveland Clinic’s Robert J. Tomsich Pathology & Laboratory Medicine Institute.

Ziad Peerwani, MDD

Ziad Peerwani, MD

About Dr. Peerwani:

In August 2020, Dr. Peerwani was appointed to carve out all laboratory services from SEHA, the government-owned health care system in Abu Dhabi, into an independent company while minimizing the impact on patient care and operations.

After successfully establishing the new business—Union71—Dr. Peerwani was appointed as its first CEO on October 4, 2020. During Union71’s first year, Dr. Peerwani stabilized and grew the laboratory while substantially outperforming Year 1 projections. Eventually, in March 2021, Union71 merged into PureHealth, with Dr. Peerwani supporting another transition.

Before serving as Union71’s CEO, Dr. Peerwani was Chairman of Pathology & Laboratory Medicine at Tawam Hospital, the regional cancer center for SEHA.  He was also the section chief of hematopathology and flow cytometry, providing the majority of clinical sign-out over the years.

Prior to joining Tawam in 2014, Dr. Peerwani practiced general anatomic and clinical pathology at Baylor Scott & White All Saints Medical Center — Fort Worth.

Dr. Peerwani completed his residency and fellowship in Anatomic Pathology, Clinical Pathology, and Hematopathology at Cleveland Clinic.

Special Communications
Immediate Test Changes
News & Updates
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Pathology Insights – Mammary Myofibroblastoma: A Practical Approach with Miglena Komforti, DO

Pathology Insights Video Series

Mammary Myofibroblastoma: A Practical Approach to Pathologic Diagnosis on Core Needle Biopsy

Presented by Miglena Komforti, DO

Myofibroblastoma is an uncommon benign neoplasm of the breast.

Dr. Miglena Komforti, a staff member of Cleveland Clinic’s Breast Pathology Section, discusses the histopathologic findings, ancillary immunohistochemical stains, molecular alterations, and clinical significance of mammary myofibroblastoma.

As part of our educational mission for our clients and communities, Cleveland Clinic Laboratories presents the Pathology Insights video series.
These short videos break down information about interesting pathology cases to better inform doctors, laboratory staff, patients, or anyone interested in the field of pathology. Each episode features important cases, methods, and practices that are personally presented by our staff pathologists.
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July 2021: Test Menu Optimization & Discontinuations – MGLESE, MYSGRV, PARSYN

Special Communication

Test Menu Optimization & Discontinuations: MGLESE, MYSGRV, & PARSYN

Cleveland Clinic regularly updates its clinical practices to align with the latest testing practices as a part of our Continuous Improvement efforts.

A recent review has identified tests that will be discontinued in favor of more simple, focused, and cost-effective testing options.

Please refer to the test information below or contact Client Services for assistance.

Test Discontinuations

Effective August 3, 2021.

Myasthenia Gravis (MG)/Lambert-Eaton Syndrome (LES) Evaluation, Serum (MGLESE)

Alternative Tests:

Acetylcholine Receptor Binding Antibody Test (ACHRAB)*

ACHRAB Clinical Info:
Anti-acetylcholine receptor binding antibody test is used as an aid in the diagnosis of myasthenia gravis. A negative result cannot exclude myasthenia gravis. Clinical correlation is required.

*Note: Acetylcholine Receptor Modulating Antibody (ACEMOD) and Muscle-Specific Kinase Antibody (MUSK) can be ordered separately if clinically indicated.

P/Q-Type Voltage-Gated Calcium Channel (VGCC) Antibody Test (VOLTCA)

VOLTCA Clinical Info:
Aids in the evaluation of muscle weakness in the context of neuromuscular junction disorder with or without cancer, or the diagnosis of paraneoplastic neurological syndromes.

Myasthenia Gravis Evaluation with Muscle-Specific Kinase (MuSK) Reflex, Serum (MYSGRV)

Alternative Tests:

Acetylcholine Receptor Binding Antibody Test (ACHRAB)*

ACHRAB Clinical Info:
Anti-acetylcholine receptor binding antibody test is used as an aid in the diagnosis of myasthenia gravis. A negative result cannot exclude myasthenia gravis. Clinical correlation is required.

*Note: Acetylcholine Receptor Modulating Antibody (ACEMOD) and Muscle-Specific Kinase Antibody (MUSK) can be ordered separately if clinically indicated.

Paraneoplastic Syndrome Ab Panel with Reflex (PARSYN)

Alternative Tests:

Paraneoplastic Autoantibody Evaluation, Serum (PARNEO)

PARNEO Clinical Info:
This supplemental testing is recommended in cases of chorea, vision loss, cranial neuropathy, and myelopathy.

Special Communications
Immediate Test Changes
News & Updates
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Pathology Insights – Diagnosis of Oncocytic Salivary Gland Tumors with Mobeen Rahman, MD

Pathology Insights Video Series

Diagnosis of Oncocytic Salivary Gland Tumors

Presented by Mobeen Rahman, MD

The diagnosis of oncocytic salivary gland tumors can be challenging, especially on core needle biopsies.

Dr. Mobeen Rahman, staff Head & Neck pathologist, discusses an interesting case that explores this issue.

As part of our educational mission for our clients and communities, Cleveland Clinic Laboratories presents the Pathology Insights video series.
These short videos break down information about interesting pathology cases to better inform doctors, laboratory staff, patients, or anyone interested in the field of pathology. Each episode features important cases, methods, and practices that are personally presented by our staff pathologists.
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CC-SIGN® Head & Neck Gene Fusion Next-Generation Sequencing Panel

CC-SIGN® Head & Neck Gene Fusion Next-Generation Sequencing Panel

This customized, 30-gene Next-Generation Sequencing (NGS)-based laboratory-developed test is intended for use in the diagnosis and management of benign and malignant tumors of the head and neck.

In particular, salivary gland neoplasms are broadly covered by this panel—which also covers select mesenchymal tumors and other lesions arising in head and neck sites.

The CC-SIGN® Head & Neck Gene Fusion NGS Panel is available as part of a comprehensive, diagnostic consultation or as a stand-alone test. This laboratory-developed test interrogates gene targets associated with known translocations in salivary gland and other solid tumors. Additionally, this panel identifies the corresponding fusion partner which may be helpful in the selection of treatment targets in some cases.

Results are delivered within 14 days of specimen receipt, allowing for a timely, definitive diagnosis in difficult salivary gland tumors and other head and neck lesions in a stand-alone fashion or with the support of our expert pathologists.

Request a Pathology Consult
Molecular Pathology at Cleveland Clinic

Test Overview

Test Name

Head and Neck Next Generation Sequencing (HDNK)

CPT Codes

81445
88381

Turnaround Time

14 days (upon specimen receipt)

Specimen Requirements

Formalin-fixed, paraffin-embedded (FFPE) tissue
• Ten (10) unstained, 4 μM sections of FFPE on charged, unbaked slides
• One (1) H&E stained slide with best tumor area* circled by a pathologist

*minimum of 20% tumor content for best results

Transport Temperature

Room (ambient) temperature

Specimen Shipping Address

Cleveland Clinic Laboratories
2119 E. 93rd Street, L15
Cleveland, OH 44106

Specimens must be sent via UPS, FedEx, or DHL – review our Shipping Information for more details.

Clinical Indications

This test is intended for the diagnosis of benign or malignant mesenchymal tumors (sarcomas & their mimics) as well as other solid tumors.

Targeted Gene Regions

Genes interrogated, including relevant transcripts and exons, are listed in alphabetical order.

A

Gene, Transcript, Exons

ALK
NM_004304
2, 4, 6, 10, 16-23, 25, 26

B

Gene, Transcript, Exons

BRAF
NM_004333
Exons 1-5, 7-16, 18

C

Gene, Transcript, Exons

CAMTA1
NM_015215
Exons 3, 8-10

CRTC1
NM_015321
Exons 1-4

E

Gene, Transcript, Exons

ETV6
NM_001987
Exons 1-7

EWSR1
NM_005243
Exons 4-14

F

Gene, Transcript, Exons

FOS
NM_005252
Exon 4

FOSB
NM_006732
Exons 1, 2

FOXO1
NM_002015
Exons 1-3

FUS
NM_004960
Exons 3-11, 13, 14

G

Gene, Transcript, Exons

GLI1
NM_005269
Exons 4-7

H

Gene, Transcript, Exons

HMGA2
NM_003483
Exons 1-5

M

Gene, Transcript, Exons

MAML2
NM_032427
Exons 2, 3

MKL2
NM_014048
Exons 11-13

MYB
NM_001130173
Exons 7-9, 11-16

N

Gene, Transcript, Exons

NCOA1
NM_147223
Exons 12-15

NR4A3
NM_006981
Exon 2

NR4A3
NM_173200
Exons 3, 4

NTRK1*
NM_002529
Exons 2, 4, 6, 8, 10-14

NTRK2*
NM_006180
Exons 5, 7, 9, 11-18

NTRK3*
NM_001007156
Exon 15

NTRK3*
NM_002530
Exons 4, 7, 10, 12-16

NUTM1
NM_175741
Exons 2-4, 6

*A specimen positive for a fusion in one of these genes makes the patient a candidate for larotrectinib treatment.
Standalone NTRK testing is also available via the CC-SIGN® NTRK Gene Fusion NGS Panel.

P

Gene, Transcript, Exons

PAX3
NM_181459
Exons 6-8

PAX7
NM_002584
Exons 6-8

PLAG1
NM_002655
Exons 1-4

PRKD1
NM_002742
Exons 10-13

R

Gene, Transcript, Exons

RET
NM_020630
Exons 2, 4, 6, 11, 15, 16

RET
NM_020975
Exons 8-14

S

Gene, Transcript, Exons

SS18
NM_001007559
Exons 2-6, 8-11

SS18
NM_005637
Exons 2, 3

STAT6
NM_001178078
Exons 1-7, 15-20

T

Gene, Transcript, Exons

TFE3
NM_006521
Exons 2-8

Y

Gene, Transcript, Exons

YAP1
NM_001130145
Exons 1-9

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Pathology Insights – NUT Carcinoma with Sanjay Mukhopadhyay, MD

Pathology Insights Video Series

NUT Carcinoma

Presented by Sanjay Mukhopadhyay, MD

In this video, Sanjay Mukhopadhyay, MD, Director of Pulmonary Pathology at Cleveland Clinic, highlights a rare, aggressive, malignant tumor and draws attention to a distinctive immunohistochemical profile that can serve as a tip-off to the correct diagnosis.

As part of our educational mission for our clients and communities, Cleveland Clinic Laboratories presents the Pathology Insights video series.
These short videos break down information about interesting pathology cases to better inform doctors, laboratory staff, patients, or anyone interested in the field of pathology. Each episode features important cases, methods, and practices that are personally presented by our staff pathologists.