Diagnosing soft tissue tumors remains challenging, but a new review published by the College of American Pathologists (CAP) offers practical guidance for pathologists. The review outlines how specific immunohistochemical (IHC) markers can serve as reliable surrogates for underlying genetic alterations, supporting earlier, more accurate diagnoses, especially in complex and resource-limited settings.
Here, we connect with Jason L. Hornick, Director of Surgical Pathology and IHC, and Chief of Soft Tissue and Bone Pathology at Brighman and Women’s Hospital, Professor of Pathology at Harvard Medical School, and Consultant at the Dana-Farber Cancer Institute, to discuss the potential of IHC surrogates.
What are the key diagnostic challenges in soft tissue tumor pathology that IHC surrogates help to address?
Sarcomas are rare – accounting for just 1 percent of all cancers – and highly diverse. There are more than 100 types of soft tissue tumors and about 40 distinct sarcomas. In routine practice, pathologists frequently encounter around 20 of these, while many others are so uncommon that they may never be seen. As a result, most pathologists are unfamiliar with these rare tumors and cannot diagnose them using routine histology and standard IHC alone.
Adding to the challenge, tumors with very different clinical behavior – ranging from benign to highly aggressive – can appear histologically similar. Accurate diagnosis is therefore essential for proper prognostication and patient care. While some pathologists turn to advanced techniques like DNA or RNA next-generation sequencing (NGS), these tests are costly, time consuming, and not always accessible. In contrast, IHC is widely available, fast, and affordable. When used as a surrogate for molecular genetic alterations, IHC can help resolve complex differential diagnoses quickly and reliably.
Which tumor types benefit most from IHC surrogate testing, particularly in cases where molecular diagnostics are unavailable?
Soft tissue tumors with genomic alterations that cause a clear change – or “switch” – in protein expression are best suited for IHC-based molecular surrogate testing. This includes gene fusions that lead to the overexpression of proteins normally undetectable by IHC, and tumor suppressor gene losses that result in the absence of proteins typically present in all cells.
Examples of protein upregulation include solitary fibrous tumor (STAT6), epithelioid hemangioendothelioma (CAMTA1), and synovial sarcoma (SS18-SSX). Examples of protein loss include epithelioid sarcoma (INI1), SDH-deficient gastrointestinal stromal tumor (SDHB), and malignant melanotic nerve sheath tumor (PRKAR1A).
How should diagnostic labs balance tissue use when deciding between IHC and NGS in limited biopsy samples?
When possible, it's helpful to divide core needle biopsy samples into two blocks – one for IHC and the other for molecular or cytogenetic testing such as NGS. If this isn’t feasible, cutting a set of unstained slides at the same time as the H&E slide can help preserve limited tissue. Molecular surrogate IHC typically requires only a few slides, provided the pathologist has narrowed the differential diagnosis appropriately – a step that can be challenging in practice.
What are the common pitfalls in interpreting IHC surrogates?
Interpreting loss of protein expression can be difficult when many non-neoplastic inflammatory cells – mainly histiocytes and lymphocytes – are mixed with tumor cells. It’s easy to mistake staining in these normal cells for retained expression in the tumor. It's also essential to confirm an internal positive control before diagnosing loss of expression. Without it, a technical error or poor staining method could falsely appear as loss of a tumor suppressor protein.
You describe IHC as a cost-effective screening tool. In your view, when should IHC surrogates be considered sufficient, and when should they trigger molecular confirmation?
It’s important to understand the published specificity of IHC molecular surrogates. Some markers are nearly 100 percent specific. For example, the SS18-SSX fusion-specific antibody is a highly reliable surrogate for synovial sarcoma (100 percent specificity; 96 percent sensitivity), eliminating the need for further testing when positive. CAMTA1 IHC can similarly serve as a standalone test for epithelioid hemangioendothelioma.
Other IHC surrogates are less specific and may be positive in multiple tumor types. While they can support a diagnosis when used alongside clinical and histologic context, they do not confirm a diagnosis on their own. A good example is INI1 (SMARCB1): loss of this protein is seen in extrarenal rhabdoid tumor, epithelioid sarcoma, poorly differentiated chordoma, and others – such as epithelioid malignant peripheral nerve sheath tumors, where loss occurs in about 70 percent of cases. In these instances, pathologists must carefully consider clinical features, morphology, and additional IHC findings.
Some experts argue that molecular confirmation is essential for certain tumors – like round cell sarcomas – due to their treatment implications. While this is a reasonable view, I believe that, when optimized and interpreted correctly, IHC molecular surrogates can often provide sufficient diagnostic confidence without additional molecular testing.
How do you recommend pathology teams stay updated on validated IHC surrogates as new markers emerge and tumor classifications evolve?
I recommend attendance at CME lectures and courses, as well as keeping abreast of the pathology literature. Excellent review articles that provide important updates in these areas are frequently published.
Do you foresee IHC-based surrogate markers expanding into other difficult-to-diagnose malignancies beyond soft tissue tumors?
Absolutely – and this shift is already well underway. For example, several IHC surrogates are now used to detect tumor suppressor gene inactivation in mesothelioma, including BAP1, MTAP, and NF2. Activating mutations in CTNNB1 lead to abnormal nuclear or cytoplasmic β-catenin expression, which can be detected by IHC. This is diagnostically useful across various tumors, including desmoid fibromatosis, solid pseudopapillary tumor of the pancreas, and glomangiopericytoma of the nasal cavity and sinuses. Neuropathology, too, has been transformed by IHC surrogates of genetic alterations – such as the IDH1 R132H mutation-specific antibody.
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