CAP Publishes Guidelines for Standardized Amyloidosis Diagnosis, Subtyping

Original from: 360dx

The College of American Pathologists (CAP) on Monday released guidelines for accurate diagnosis of amyloidosis, emphasizing the importance of identifying subtypes of the rare disease caused by hereditary mutations that can be targeted for treatment.

The guidelines, published in Archives of Pathology & Laboratory Medicine on Monday, outline methods for the appropriate tissue testing, protein subtyping, and diagnostic workup for amyloidosis, a rare condition caused by misfolded proteins that aggregate and form insoluble fibrillar deposits that are toxic to tissues and lead to organ damage.

There are 42 recognized forms of amyloidosis that are characterized by the protein that is misfolded, called the amyloid fibril type. Determining the amyloid fibril type in a tissue biopsy distinguishes genetic versus sporadic forms of amyloidosis and can be used to guide treatment. The workup is typically performed using immunohistochemistry (IHC) on tissue biopsies from either the affected organ or a surrogate site, such as the abdominal fat pad.

Currently, the two most common forms of amyloidosis have precision treatments either newly approved or in clinical development: immunoglobulin light chain (AL) amyloidosis and transthyretin (ATTR) amyloidosis. ATTR amyloidosis can also be hereditary, caused by mutations in the TTR gene. For ATTR amyloidosis with cardiomyopathy, Alnylam Pharmaceuticals' small interfering (RNAi) drug Amvuttra (vutrisiran) was approved in the US and Europe this year as a treatment. Alnylam also markets another RNAi drug, Onpattro (patisiran), for the treatment of ATTR amyloidosis patients with polyneuropathy.

Intellia is developing an in vivo CRISPR gene-editing treatment called nexiguran ziclumeran for ATTR amyloidosis, while Immix Biopharma is advancing an autologous CAR T-cell therapy, NXC-201, for treatment of AL amyloidosis.

In the guidelines, the CAP committee said it is good practice for pathologists to determine the fibril protein type for patients with amyloidosis being considered for therapy. "Accurate typing of the amyloid fibrils is essential for optimal patient management as therapies are specific to the type of amyloid," they wrote in the guidelines.

The group recommended that pathologists use mass spectrometry to determine the fibril type in tissue samples in order to optimize tissue use and diagnostic yield for patients being considered for treatment. They explored studies evaluating concordance between IHC and mass spectrometry for amyloid protein typing, finding that overall, mass spectrometry is recommended for subtyping over IHC, "in part because IHC is not available for all types of amyloidosis."

"Many cases yield inconclusive results by IHC, and samples that are not typeable by IHC require subsequent MS to determine the amyloid type," they added.

The committee also laid out methods to standardize the diagnosis of amyloidosis and protein typing by IHC, including the use of Congo red staining, fluorescence microscopy, and mass spectrometry.

The committee concluded after a review of literature that screening cytology samples as an alternative for surgical biopsy samples was acceptable. However, they noted these samples may limit the ability for further testing, including subtyping. They also recommended use of the Congo red staining method or a method that has been validated against Congo red staining and shown equivalency. Finally, they said that adding fluorescence microscopy to polarized light microscopy can help increase sensitivity to detect amyloid in samples.

"Amyloid science is expanding, with advances in diagnostic imaging, fibril typing, and therapies," the CAP guidelines read. "A challenge for pathologists will be to remain abreast of clinical screening techniques for amyloid fibril deposition and the appropriate ancillary testing for protein characterization."

Source: CAP Publishes Guidelines for Standardized Amyloidosis Diagnosis, Subtyping