Biopsies – tissue is the issue!

First published 19th July 2023. Major update on 6th August 2024 to including key marker and histopathological tissue biomarkers used in Neuroendocrine Neoplasms (NENs).

My diagnostic background

On 19th July 2010, I had a liver biopsy. This followed some low haemoglobin (Hb) and some weight loss reported to my GP surgery in May, I met with a specialist on 8th July and after sending me straight for a CT scan on the same day, the output from that CT confirmed something was drastically wrong.

Clearly CT scans don’t diagnose cancer including grade, so I eventually had to have a liver biopsy on 19th July to confirm the cancer type. I won’t lie and say it was an enjoyable experience. I vividly remember a lot of discomfort including pain. At the time no-one knew I had metastatic Neuroendocrine Tumours; no-one knew I had associated carcinoid syndrome. I suspect that may have played a part in the discomfort of that important procedure. The doctor carrying out the biopsy had several assistants in the room and sent for a nurse whose sole job was to hold my hand and reassure me. It’s not that I was frightened or scared or anxious (not overtly), but my body was reacting to the discomfort despite a mild sedative. I suspect the doctor was worried my discomfort was making me move slightly while he was attempting to carry out this precise procedure, I get that. He used a guided core needle biopsy with 3 attempts.

The biopsy confirmed a grade 2 Neuroendocrine Tumour (NET) in my liver which was considered metastatic. That also confirmed the mass in my mesentery was indicative of a small intestine NET. That has driven my treatment and surveillance since 2010.

I went on to have other biopsy experiences:

1. During recovery in hospital, I had a CT guided FNA fluid removal for a post operative seroma.
2. I had post-surgical tissue samples from my primary surgery and a later lymph node removal/exploratory biopsy (all clearly doubling up as the surgery). Read more here on the latter.
3. I once had a bout of acid reflux and some tissue was taken via endoscopy. Thankfully that was clear.

Biopsies for suspected cancer

Blood tests and scans can really help pin down the location of cancer plus other valuable information. This is true for Neuroendocrine Cancer where it provides diagnostic certainty and is able to measure the aggressiveness of the disease including whether the tumour is well or poorly differentiated. Sometimes, when specialists are certain about the cancer type, and pre-surgical biopsies are difficult/risky, post surgical biopsies are often the first tissue sample to be taken.

Additionally, specific markers can be tested to add diagnostic and prognostic information and molecular tests, while immature as of July 2023, this is an area advancing all the time. See molecular markers below.

Like scans, there are different types of biopsies for different scenarios, and I’ll cover the most common below. I was surprised to find that I have had many of them to date since my initial diagnostics in 2010.

“Liquid biopsies” (a type of blood test) are often hyped in the newspapers and media but mostly remain experimental and in clinical studies. Putting liquid biopsies to one side, most people will continue to have biopsies done in the conventional way for some time. See a paper below about the future of liquid biopsies.

Needle biopsy

Many people will be familiar with this term but “Needle biopsy” is a general phrase for taking samples in easily or fairly easy locations on and in the body. Also known as a percutaneous tissue biopsy. The main types of needle biopsy includes:

Fine-needle aspiration (FNA). During fine-needle aspiration, a long, thin needle is inserted into the suspicious area. A syringe is used to draw out fluid and cells for analysis. An ultrasound is normally used to assist but this is not an image guide procedure (see below).
Core needle biopsy. A larger needle with a cutting tip is used during core needle biopsy to draw a column of tissue out of a suspicious area. An ultrasound is normally used to assist but this is not an image guide procedure (see below).
Vacuum-assisted biopsy. During vacuum-assisted biopsy, a suction device increases the amount of fluid and cells that is extracted through the needle. This can reduce the number of times the needle must be inserted to collect an adequate sample.
Image-guided biopsy. Image-guided biopsy combines an imaging procedure — such as a CT, MRI or ultrasound. Image-guided biopsy allows your team to access suspicious areas that can’t be felt through the skin, such as on the liver, lung or prostate. Using real-time images, your interventional radiologist or surgeon can make sure the needle reaches the intended target.

You may receive a local anaesthetic to dull any pain.

Patients with complications

Transvenous biopsy

Less commonly and to protect those with certain conditions e.g. ascites. A sample tissue from your liver could be taken through a vein in your neck or groin – trans jugular for neck, transfemoral for the groin.

Plugged biopsy

This is a modification of the percutaneous approach that can be used in patients who are at high risk for bleeding (coagulopathy or thrombocytopenia). Although a transvenous biopsy can be obtained in this subset of patients, the plugged approach is used when a larger specimen size is desirable.

Endoscopic biopsy

This comprises a thin, flexible tube (endoscope) with a light on the end to see structures inside your body. Special tools are passed through the tube to take a small sample of tissue to be analysed. For lung investigations, this is often called a bronchoscopy.

What type of endoscopic biopsy you undergo depends on where the suspicious area is located. The endoscope can be inserted through your mouth, rectum, urinary tract or a small incision in your skin.

Examples of endoscopic biopsy procedures include cystoscopy to collect tissue from inside your bladder, bronchoscopy to get tissue from inside your lung and colonoscopy to collect tissue from inside your colon. Depending on the type of endoscopic biopsy you undergo, you may receive a sedative or anaesthetic before the procedure.

There is also an endoscopic ultrasound capability, In NET, this is commonly used for the pancreas and known as EUS. An endoscopic tube may also have a small needle to remove fluid or tissue samples (biopsy) for examination in a lab. This procedure is called EUS-guided fine-needle aspiration or EUS-guided fine-needle biopsy. The EUS is also able to provide detailed images of the digestive tract and surrounding organs and tissues, including the lungs, gall bladder, liver and lymph nodes.

Surgical biopsy

Sometimes due to the location, your doctor may recommend a surgical biopsy if the cells in question can’t be accessed with other biopsy procedures or if other biopsy results have been inconclusive. Where possible, this is normally carried out by ‘keyhole’ surgery (laparoscopy).

During a surgical biopsy, a surgeon makes an incision in your skin to access the suspicious area of cells. Examples of surgical biopsy procedures include surgery to remove a breast lump for a possible breast cancer diagnosis and surgery to remove a lymph node for a possible lymphoma diagnosis. Sometimes a surgical biopsy may remove all of the cells.

You may receive local anaesthetics to numb the area of the biopsy. Some surgical biopsy procedures require general anaesthetics to put you to sleep.

Following a planned surgery to remove tumours, a tissue sample may be taken from the removed tumours to clarify or update the tumour grading and/or staging.

Miscellaneous biopsies

Other biopsies are available but less commonly in NET.

Skin biopsy – A skin biopsy removes cells from the surface of your body. A skin biopsy is used most often to diagnose skin conditions, including melanoma and other cancers. The type of skin biopsy you undergo will depend on the type of cancer suspected and the extent of the suspicious cells. This could include a type of Neuroendocrine Carcinoma known as Merkel Cell Carcinoma. Different types of skin biopsies are used for specific purposes.
- Shave biopsy. Uses a tool similar to a razor to scrape the surface of your skin.
- Punch biopsy. A circular tool removes a small section of your skin’s deeper layers.
- Incisional biopsy. Involves the use of a scalpel to remove a small area of skin. Whether you receive stitches to close the biopsy site depends on the amount of skin removed.
- Excisional biopsy. During an excisional biopsy, an entire lump or area of skin that appears suspicious is removed. You’ll likely receive stitches to close the biopsy site.
Bone marrow biopsy – this type is normally recommended based on your blood test results or if your provider suspects cancer is affecting your bone marrow which is inside some of your larger bones where blood cells are made. Analysing a sample of bone marrow may reveal what’s causing your blood problem. A bone marrow biopsy is commonly used to diagnose a variety of blood problems, both cancerous and not cancerous. A bone marrow biopsy can diagnose blood cancers, such as leukaemia, lymphoma and multiple myeloma. It can also detect cancers that started elsewhere and travelled to the bone marrow. You’ll receive a local anaesthetic or other medicine to minimize discomfort during the procedure.

Do biopsies make cancer spread?

Correlation does not always mean causation.

Myth vs. Fact: The fear that biopsies spread cancer is a persistent myth, though the benefits of the procedure significantly outweigh the theoretical risk.

Biopsy vs. Natural Progression: The intrinsic ability of cancer cells to invade and spread is what leads to metastasis, not the biopsy itself.

If there was any truth in this claim, imagine what the risk would be undergoing surgery? Here is my research.

The chance of cancer spreading from a biopsy is extremely low, and the benefits of a biopsy for accurate diagnosis and treatment planning far outweigh this minimal risk. Medical professionals take extensive precautions to prevent cancer cell spread during biopsies, using specialized techniques and instruments. While the possibility of “tumour seeding” (cancer cells spreading along the biopsy site) is a concern, it is not well-supported by evidence, and the intrinsic behaviour of the cancer itself is the primary driver of spread.

Why Biopsies Are Necessary

Definitive Diagnosis: Biopsies are the most reliable way to confirm a cancer diagnosis by examining suspicious cells under a microscope. Treatment Planning: They help determine the type and stage of cancer, which is crucial for developing the most effective treatment plan.

Evidence and Medical Practice Low Risk: Studies have shown the risk of cancer spread from a biopsy is extremely low. Precautions: Doctors use techniques like using different surgical tools for different areas, guided imaging (ultrasound, CT scans) to precisely target the area, and minimizing tissue manipulation.Tumor Seeding: While some tumors cannot be safely biopsied without the risk of seeding, doctors avoid core biopsies in these cases, opting for complete removal.Immune Response: Dislodged cancer cells are often cleared by the body’s immune cells.

Updates in histopathological classification and tissue biomarkers of neuroendocrine neoplasms (NENs)

In all the documents I have read about tissue sampling for Neuroendocrine Neoplasms, one thing I learned is despite being a scientific subject, it is not total 100% science! Some biopsies are pretty much clear on what is being diagnosed based on the tissue sample but like everything else in NENs, tumour heterogeneity plays a part. I often see that one pathological biomarker can be indicative for a particular type of NET or NEC but there is very often not 100% certainty. Often other markers are used for backup and corroboration, sometimes they are looking for negative markers markers in that regard. The Pathologist’s job is so important but often it can be so tough. Particularly when the tissue sample is borderline adequate or less. However, this may help some of you decode your pathology reports, many of which you post in my private group!

Earlier this year I let you know about the first ever dedicated WHO classifiicaton of Neuroendocrine Neoplasms. These documents are published by a committee comprising many pathologists. It defines what things should be called and what makes up grade and differentiation. When you dig into the detail, you find details of the tissue biomarkers used by pathologists to make their diagnoses. I wanted to provide you with a summary of that output (the whole output is not only extremely complicated but extremely long! I wanted to cover the following terms as some seem interchangeable but they are not.

1. Histology – “the study of tissues and cells under a microscope.”

2. Immunohistochemistry. “A laboratory method that uses antibodies to check for certain antigens (markers) in a sample of tissue. The antibodies are usually linked to an enzyme or a fluorescent dye. After the antibodies bind to the antigen in the tissue sample, the enzyme or dye is activated, and the antigen can then be seen under a microscope. Immunohistochemistry is used to help diagnose diseases, such as cancer. It may also be used to help tell the difference between different types of cancer.”

You may see this abbreviated to IHC and it is the sort of info you would see on a biopsy report.

3. Molecular Marker. “A biological molecule found in blood, other body fluids, or tissues that is a sign of a normal or abnormal process, or of a condition or disease. A molecular marker may be used to see how well the body responds to a treatment for a disease or condition. Also called biomarker and signature molecule.”

This is relatively new and now appearing in WHO classifications. Some work has been conducted in NENs but has only really been deemed good enough to become part of the latest NEN series 2022. But it is early days and not everyone will benefit from the work which is mainly in the gastroenteropancreatic NENs (GEPNENs) area, particularly in Pancreatic NENs. It may also be the sort of thing that liquid biopsies show more of but be aware of this statement from a known pathology NEN expert who said “……However, at this point it should be recognized that, notwithstanding the plethora of information about the genomic landscape of NEN, the gathered data represent a good foundation but are still not definitely sufficient for a robust molecular classification of digestive NEN.” (see Reference 9).

4. Epithelial tissue. “Epithelial tissue is one of the four main types of body tissue found in your organs and covers internal and external surfaces in your body. It has several different structures and functions depending on where it is in your body.”

This is esoteric pathology stuff but important to distinguish Neuroendocrine Neoplasms which are from epithelial or non-epithelial cells. To simply this, all NENs other than pheochromocytoma and paraganglioma are from epithelial cells.

A Summary of IHC and Molecular Markers commonly used in NEN – what it “might” mean

to follow – a work in progress

“Liquid Biopsies” – the non-invasive future?

This is a really complex issue. There is much information online about this subject but nothing to confirm that liquid biopsies are anywhere near become a reality in Neuroendocrine Neoplasms anytime soon. I said “non-invasive” above but clearly a blood test sample is required and I guess that is somewhat invasive – but not as invasive as (say) a percutaneous liver biopsy. However, as most cancer patients are doing blood tests all the time, the data could be there al. But as these tests are potentially diagnostic, clearly they could also become screening tools and testing tools when a patient is being worked up for an as yet undiagnosed condition. These tools could also potentially be used in surveillance, particularly on the basis that some markers might be able to predict which cancer patients will likely recur after initial diagnosis and treatment.

On that basis, I will leave you to read this summary. Click on Reference 9 below.

Resources Used

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