Hidden Markers: Rare Cancer Biomarkers in Diagnostics

Key takeaways

• Rare cancers comprise up to 25% of cases but are often misdiagnosed or detected late, limiting treatment options

• A key challenge is identifying cancer biomarkers that are “hidden” or underrecognized due to limited data, small patient populations and unclear diagnostic pathways

• Immunoassays are highly sensitive tools that detect low-abundance protein biomarkers and complement genomic testing

• These assays enable earlier diagnosis, subtype classification and therapy selection by measuring actual protein levels rather than just genetic changes

• Immunoassays are widely used in rare cancers (e.g., NETs, sarcomas, rare lung cancers) for detecting specific biomarkers and monitoring disease progression or recurrence

• Despite the value of immunoassays, challenges remain, including low awareness, over-reliance on organ-based classification, and the need for the continued development of high-quality diagnostic tests

Rare cancers – generally defined as cancer affecting fewer than 15 out of 100,000 people each year¹ – now account for up to a quarter of all cancer cases.² These cancers pose significant diagnostic challenges, and are prone to misdiagnosis or delayed diagnosis until they reach advanced stages.³ This limits therapy options and makes the cancer harder to treat than in its early stages.³

The challenge of “hidden” biomarkers in cancer 

Lack of clear diagnostic pathways is a significant hurdle to diagnosing rare cancers. While limited data, small patient population and scarce tumor samples may result in clinicians not immediately recognizing a rare tumor marker subtype,^3-5 identifying “hidden” or underrecognized biomarkers is critical for diagnosing rare cancers.

The role of immunoassays

Immunoassay methods like FACTT (Fluorescent Amplification Catalyzed by T7 Polymerase Technique) are highly sensitive for uncovering low-abundance biomarkers.⁶ For example, the use of FACTT-based assays has allowed researchers to detect the appearance of the tumor marker HER2 at a far earlier time point during disease progression than with any other assays.⁶

While DNA/RNA sequencing exposes mutations or fusions, immunohistochemistry (IHC) assays confirm the downstream protein expression and provide fast, scalable results.⁷

How biomarker testing works with immunoassays

Terminology:

A biomarker is a biological molecule – found in the blood and in other bodily fluids or the body’s tissues – that is a sign of either a normal or abnormal process, or an indicator of a disease.⁹

A tumor marker is a substance found in tissue, blood, bone marrow or other bodily fluids that may be a sign of cancer or certain benign (non-cancer) conditions. Many tumor markers are proteins made by both normal cells and cancer cells – however, they are made in higher amounts by cancer cells. Genetic changes in tumor tissue, such as gene mutations, are also used as tumor markers.¹⁰

An immunoassay is a test that uses the binding of antibodies to antigens to identify and measure certain substances and diagnose disease. Test results can provide information about a disease that may help in planning treatment.¹¹

In the context of cancer diagnostics, immunoassays directly measure the biomarkers that tumors produce.¹² This is a powerful complement to molecular (DNA/RNA) testing. For example, a next-generation sequencing (NGS) panel might identify a gene mutation in a tumor, but an immunoassay (like IHC) can assess protein expression,⁷ providing valuable information that often guides therapy selection. Immunoassays are also more accessible in routine practice.

Examples of rare cancer biomarkers detected using immunoassays

Here are a few compelling examples where immunoassays shine for biomarker testing in rare cancers:

Neuroendocrine tumors (NETs) – chromogranin A
NETs are a group of uncommon tumors that originate from hormone-producing cells. A hallmark biomarker for NETs is chromogranin A (CgA), a protein released by neuroendocrine cells. Immunoassays for CgA in blood are widely used to help diagnose and manage NET patients. Because CgA is expressed throughout the neuroendocrine system, it has become a widely accepted biomarker for NETs. Clinicians track CgA levels over time, since elevated or rising CgA can indicate tumor burden or recurrence. 

Even in rare neuroendocrine cancers outside the GI tract, CgA proves useful. Merkel cell carcinoma – a rare neuroendocrine skin cancer – shows CgA expression in tumor cells, and many physicians measure CgA in patient blood as a predictive marker for recurrence of this aggressive cancer. 

All these applications depend on sensitive immunoassays (typically ELISA or automated chemiluminescent assays) to detect CgA’s presence. Genomic tests alone could not capture this protein signal.¹³

Sarcomas – protein markers confirming rare subtypes
Sarcomas (malignant tumors of bone or soft tissue) include dozens of subtypes. Many sarcomas are defined by unique protein expressions that IHC can reveal. For example, a gastrointestinal stromal tumor (GIST) is an uncommon sarcoma of the digestive tract. Most GISTs are driven by mutations in the KIT gene, and express the KIT protein (CD117). An IHC stain for KIT is a standard diagnostic test – about 80%–95% of GISTs will show positive KIT staining, confirming the diagnosis.¹⁴

In GISTs that lack KIT expression (KIT-negative), pathologists use Discovered on GIST-1 (DOG1), a protein highly specific to GIST. Immunostaining for DOG1 can unmask GIST tumors that are KIT-negative.¹⁴

Thanks to these antibody tests, patients with unusual GIST variants aren’t misdiagnosed – which is crucial, since GISTs require different treatment to other gastric tumors.¹⁴

Another example is synovial sarcoma, a very rare soft-tissue tumor often affecting young adults. Synovial sarcoma cells characteristically produce an antigen called TLE1. An IHC test for TLE1 has shown ~95% sensitivity for synovial sarcoma, making it a valuable diagnostic marker, especially when the classic gene fusion test is not available. One study showed how adding TLE1 immunostaining to the pathology work-up substantially helped distinguish synovial sarcoma from lookalike tumors.¹⁵

These cases demonstrate how immunoassays pinpoint protein markers to classify rare sarcoma subtypes, ensuring that patients receive the correct diagnosis and therapy.^14,15

Rare lung cancer variants – unusual antigens and fusions 
Immunoassays play a key role in identifying rare lung cancer cases. For example, about 3%–5% of non-small cell lung cancers carry an ALK gene fusion (rearrangement of the ALK gene). This abnormal fusion drives the cancer but isn’t  evident from routine histology. Instead of waiting weeks for an NGS report, pathologists can perform an ALK immunohistochemistry assay on the tumor biopsy. ALK IHC has been shown to be highly accurate – in one comparison it detected ALK-rearranged lung tumors with 86% sensitivity and 100% specificity relative to the genetic fluorescence in situ hybridization (FISH) test.¹⁶ 

Rare gene fusions like NTRK (found in <1% of lung cancers) can be screened using a broad-spectrum TRK antibody immunoassay, ensuring that these uncommon cases are not overlooked.¹⁷

Immunoassays also help track unusual antigen expression in lung cancers. For example, small cell lung carcinoma (SCLC) is an aggressive neuroendocrine lung cancer that accounts for only ~15% of lung malignancies. SCLC tumors secrete markers like pro-gastrin-releasing peptide (ProGRP) and neuron-specific enolase (NSE) into the bloodstream. Both of these can be measured by immunoassays and serve as useful biomarkers. ProGRP is emerging as a superior marker for SCLC and related lung carcinoid tumors; studies report that ProGRP assays can detect SCLC with about 67%–80% sensitivity, and rising ProGRP levels correlate with disease progression or recurrence under therapy.^18,19 

One study in lung carcinoids found that ProGRP outperformed CgA in blood, showing a much higher ability to distinguish active tumors from benign conditions and to reflect tumor burden on follow-up scans.²⁰

Thanks to immunoassays, doctors can identify these rare lung cancer variants early and monitor them over time with simple blood tests – a practical advantage in diseases that often require swift changes in treatment.^16-20

Immunoassays as diagnostic and monitoring tools 

High-performance immunoassays can be used to diagnose rare cancers and track them over time.²¹ When facing a potential rare cancer, clinicians often turn to immunoassay-based tests first, because they are fast and accessible. For example, if a patient has an unusual tumor biopsy, an IHC panel for rare markers can yield answers within a day, while sending the sample for extensive DNA sequencing might take two weeks to return results.²² For urgent clinical decisions – which are common in oncology – this time difference is critical. Immunoassays can be used to guide the initial diagnostic decision-making, while more complex molecular tests run in parallel or later. 

Immunoassays are also important in treatment monitoring and recurrence tracking. For example, in SCLC, serial ProGRP tests help assess whether the cancer is responding to chemotherapy or starting to grow again – often before changes appear on a scan.²⁰ This monitoring is feasible because immunoassays are scalable and rapid. A lab can process dozens of ELISA tests or run automated immunoassay analyzers daily, but repeated elaborate molecular assays would be impractical due to sample requirements and turnaround time. So, immunoassays act as an ongoing “radar”, continuously providing insights into a patient’s disease course. 

Challenges in rare cancer diagnostics 

Lack of awareness and missed testing 
Because rare cancers appear infrequently, general practitioners and even some specialists may not be familiar with all the niche biomarkers involved. This means a patient with a rare tumor might initially be misdiagnosed as having a more common disease with similar symptoms.³ 

Over-reliance on organ-based classification
Traditional oncology has categorized cancers mostly by their bodily origin (e.g., “lung cancer” or “liver cancer”). While this is still useful, it can mask important distinctions, and rare cancers may not fit the expected mold of their location. 

As an example, until recently, lung cancers were simply classified as “small cell vs. non-small cell”. But today, clinicians know that lung cancers include a variety of biomarker-defined entities, each needing different treatment. The shift toward biomarker-driven classification has opened new therapy avenues but also demands a shift in diagnostic approach, where physicians must look beyond the affected organ.² 

Technical and resource challenges 
Some rare cancer biomarkers simply didn’t have effective tests until recently. Developing a high-quality immunoassay requires investment. This is why IVD raw-material providers like Medix Biochemica are dedicated to producing antibodies and antigens for rare cancer markers, enabling diagnostic kit manufacturers around the globe to build reliable tests.⁸

Frequently asked questions 

1. What are rare tumor markers?
   Rare tumor markers are substances found in tissue, blood, bone marrow or other bodily fluids, that may be a sign of a rare cancer.¹⁰

2. What are some examples of uncommon cancer diagnostics?
   Genome sequencing and multi-omics analysis are advanced diagnostic tools increasingly used for rare (uncommon) cancers. Combined data from genomics, transcriptomics, proteomics and metabolomics can be used to provide a more comprehensive understanding of the complex molecular networks underlying cancer.³

3. How to detect rare cancers?
   Advances in genome testing are making this method increasingly useful in detecting rare cancers, and immunoassays continue to complement these genomics. Certain advanced immunoassay methods are highly sensitive to low-abundance biomarkers, making them useful tools for detecting rare cancers.⁶
   

Partner with Medix Biochemica to create high-performance cancer immunoassays 

Rare cancers no longer have to remain “hidden” diagnoses. The emergence of advanced immunoassays targeting hidden biomarkers has dramatically improved our ability to detect and monitor these uncommon diseases.

With Medix Biochemica’s portfolio of reagents, IVD test manufacturers have access to the critical raw materials needed for cancer marker immunoassay development projects. Many of our raw materials are validated and have been widely used in IVD test development for years, but we also provide a selection of emerging cancer-associated markers.²³

If you’re looking to develop diagnostic tests for rare cancers, get in touch with our expert sales team to discuss your needs.

Speak to Medix Biochemica’s sales team

References

1. Rare cancer. National Cancer Institute. Accessed March 18, 2026. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/rare-cancer.
2. Shifting the paradigm: Challenges, opportunities and methodologies in studying rare cancers. Targeted Oncology. Accessed March 18, 2026. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/rare-cancer.
3. Christyani G, Carswell M, Qin S, et al. An overview of advances in rare cancer diagnosis and treatment. Int J Mol Sci. 2024; 25(2):1201. https://doi.org/10.3390/ijms25021201.
4. Pillai RK, Jayasree K. Rare cancers: Challenges & issues. Indian J Med Res. 2017;145(1):17-27. doi:10.4103/ijmr.IJMR_915_14.
5. Understanding rare cancers: What are they and why do we need to fund research for them?. Conquer Cancer, the ASCO Foundation. Accessed March 18, 2026. https://www.conquer.org/news/understanding-rare-cancers-what-are-they-and-why-do-we-need-fund-research-them.
6. Freudenberg JA, Bembas K, Greene MI, et al. Non-invasive, ultra-sensitive, high-throughput assays to quantify rare biomarkers in the blood. Methods. 2008;46(1):33-38. doi:10.1016/j.ymeth.2008.05.005.
7. Understand protein expression in tissue with immunohistochemistry (IHC). Cell Signaling Technology. Accessed March 18, 2026. https://www.cellsignal.com/applications/immunohistochemistry/protein-expression-immunohistochemistry.
8. Medix Biochemica Tumor Markers Catalog 2022. Medix Biochemica. Accessed March 18, 2026. https://www.medixbiochemica.com/hubfs/Medix%20Biochemica%20Tumor%20Markers%20Catalog%202022_V2-1.pdf.
9. Biomarker. National Cancer Institute. Accessed March 18, 2026. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/biomarker.
10. Tumor marker. National Cancer Institute. Accessed March 18, 2026. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/tumor-marker.
11. Immunoassay. National Cancer Institute. Accessed March 18, 2026. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/immunoassay.
12. Wu J, Fu Z, Yan F, et al. Biomedical and clinical applications of immunoassays and immunosensors for tumor markers. TrAC. 2007;26(7):679-688. doi:10.1016/j.trac.2007.05.007.
13. Gkolfinopoulos S, Tsapakidis K, Papadimitriou K, et al. Chromogranin A as a valid marker in oncology: Clinical application or false hopes? World J Methodol. 2017;7(1):9-15. doi:10.5662/wjm.v7.i1.9.
14. Wada T, Tanabe S, Ishido K, et al. DOG1 is useful for diagnosis of KIT-negative gastrointestinal stromal tumor of stomach. World J Gastroenterol. 2013;19(47):9133-9136. doi:10.3748/wjg.v19.i47.9133.
15. Rekhi B, Basak R, Desai SB, et al. Immunohistochemical validation of TLE1, a novel marker, for synovial sarcomas. Indian J Med Res. 2012;136(5):766-775. PMID: 23287123; PMCID: PMC3573597.
16. Le Quesne J, Maurya M, Yancheva SG, et al. A comparison of immunohistochemical assays and FISH in detecting the ALK translocation in diagnostic histological and cytological lung tumor material. J Thorac Oncol. 2014;9(6):769-774. doi:10.1097/JTO.0000000000000157.
17. NTRK and lung cancer. American Lung Association. Accessed March 18, 2026. https://www.lung.org/lung-health-diseases/lung-disease-lookup/lung-cancer/symptoms-diagnosis/biomarker-testing/ntrk-and-lung-cancer.
18. Wojcik E, Kulpa JK. Pro-gastrin-releasing peptide (ProGRP) as a biomarker in small-cell lung cancer diagnosis, monitoring and evaluation of treatment response. Lung Cancer (Auckl). 2017;8:231-240. doi:10.2147/LCTT.S149516.
19. Holdenrieder S, von Pawel J, Dankelmann E, et al. Nucleosomes, ProGRP, NSE, CYFRA 21-1, and CEA in monitoring first-line chemotherapy of small cell lung cancer. Clin Cancer Res (2008) 14 (23): 7813–7821. https://doi.org/10.1158/1078-0432.CCR-08-0678.
20. Nisman B, Oleinikov K, Nechushtan H, et al. Plasma progastrin-releasing peptide and chromogranin assays for diagnosing and monitoring lung well-differentiated neuroendocrine tumors: A brief report. J Thor Oncol. 2023;18(3):369-376. doi:10.1016/j.jtho.2022.11.021.
21. Next-generation immunoassays for diagnosis. Nature. Accessed March 23, 2026. https://www.nature.com/articles/d42473-024-00342-6.
22. Improved turnaround times for NGS wait on improved technology. ILCN. Accessed March 23, 2026. https://www.ilcn.org/improved-turnaround-times-for-ngs-wait-on-improved-technology/.
23. Tumor markers. Medix Biochemica. Accessed March 23, 2026. https://info.medixbiochemica.com/tumor-markers.