1. Malignant cells are often large, disordered and have bizarre nuclei, usually because the cytoskeleton and nuclear skeleton are unstable and malignant cells often have much more DNA and chromosomes than normal cells (polyploidy and aneuploidy). In this cancer, there is a very large bizarre malignant cell in the centre of the field but all the other cells are also malignant.

Surprisingly, these bizarre cells are often going nowhere, the drivers of cancer growth being those which have a more orderly arrangement and chromosome complement and able to replicate themselves.

These so-called cancer stem cells can be very difficult to identify and hide behind the bizarre cells which are really the end stage of a replication process completely out of control.

2. A curious property of malignant cells is the fact that they are much larger than benign cells.

This may be because their cytoskeleton is disordered. Here, at the same magnification, you can see a comparison between a benign tubule (top) in an inflamed pancreas and a tubule in a pancreatic adenocarcinoma.

3. Here Fluorescence Lifetime Imaging done in conjunction with Prof Paul French’s lab at Imperial College demonstrates metabolic changes in early malignant change within the uterine cervix in the magenta and blue cells, undermining the green normal epithelium.

Our research is aimed at determining whether this technique could be applied in vivo to avoid biopsy and allow surveillance of the tissues.

4. Some very simple stains can really help in a tumour that is difficult to identify on conventional H and E.

Here, alcian blue plus Periodic acid Schiff dyes for mucin (blue and pink respectively) demonstrate some small poorly formed glands in some of the tumour cells which identify it as an adenocarcinoma.

5. In this tissue section, there is some bone with the blue-staining granular calcified bone on the right side of the field being broken up by adenocarcinoma and its associated stroma. The grey material in the spaces within the centre of the glands is mucin-secretion by the tumour cells.

Malignant cells create their own stroma and subvert a blood vessel supply to survive, but this in turn causes breakdown of the bone by releasing enzymes and removing vital nutrients. This explains why patients may get unexpected fractures when tumours spread to bone.

6. Here Fluorescence Lifetime Imaging was performed on liver containing a cancer deposit and clearly shows contrast between the purple tumour the blue normal liver and the edge of the liver where heat has been used to remove the area bloodlessly by RFA (radiofrequency ablation).

This work was done in conjunction with Prof Paul French and his team.

7. Immunohistochemistry is a technique for labelling molecules on a cell-surface using a brown dye linked to antibodies and can be done on routine pathology blocks. Here is an example of a high level of HER2 expression in a breast cancer, which indicates it is likely to respond to Herceptin therapy.

It is important to identify such patients as Herceptin is only effective in tumours with high level expression and does have side effects in some patients.

8. Some patients who are immunosuppressed are susceptible to reactivation of viral infections as the immune system gets distracted. Here is an oesophageal biopsy in a patient undergoing chemotherapy who has reactivated herpes simplex virus.

Viral particles have accumulated in the nuclei giving them the strange “ground glass” appearance which is characteristic of HSV. Confirmation can be obtained by immunohistochemistry where we can specifically stain for the herpes simplex virus (the same virus also causes cold sores, again because the body is distracted by the cold virus).

9. Here is an image of a very poorly differentiated tumour which could not be classified initially but the alcian blue PAS staining demonstrates intracytoplasmic lumina confirming it is an adenocarcinoma.

Notice the crenated appearance to the border of the lumen which is due to coarse microvilli on the surface of the cell.

10. This is an immunohistochemical stain using an antibody to a cell cycle-related protein (Ki67) which marks the stained nuclei out as proliferating. Here there are many cells in this tumour in a proliferative cycle, which often (but not always) correlates with tumours that grow more rapidly.

It is one of the most commonly used antibodies in diagnostic practice to assess the growth potential of tumours and classify them accordingly.

11. This is a biopsy of skin stained by Haematoxylin and Eosin (H&E) demonstrating some dark blue inflammatory cells around blood vessels and a bright red cross section of a cylinder which is also a blood vessel stretching from 7 o’clock towards the centre, the red material being fibrin which has leached from the plasma and deposited in the wall of the blood vessel.

Some dark blue fragments within the lumen indicate inflammatory cells are breaking down (leucocytoclasis) and this is an example of an inflammatory skin condition caused by some drugs and infections called leukocytoclastic vasculitis.

12. This stomach biopsy has been stained with a dye called Cresyl Fast Violet, which demonstrates some dark blue staining bacteria on the surface of the cells. Careful inspection shows they are slightly curved and they also have a subtle spiral shape.

These organisms are called Helicobacter pylori and their discovery by 2 Australian pathologist, Barry Marshall and Robin Warren was one of the most remarkable stories in medical history, culminating in their award of the Nobel Prize in 2005 ( ).

It is important to identify these bacteria as they can be successfully treated with antibiotics, which has resulted in a huge decline in morbidity and mortality from peptic ulcers and to a lesser extent in gastric cancer.

13. Tumours spread through the body by getting into blood vessels and in this case into lymphatics, the channels that drain excess fluid from tissues up to the local filters called lymph nodes.

Seeing this phenomenon means it is important for both pathologist and the clinician to be aware there is a risk that lymph nodes may be involved and follow-up the patient or investigate the lymph nodes more carefully to plan treatment.

14. These are infective organisms known as cryptosporidia which are infecting muscle in this case. Understanding how organisms such as this are detected by and attacked by the immune system helps us create new methods of diagnosis and treatment.

15. This is a cancer cell in the anaphase part of mitosis, where the clumps of chromosomes are pulling apart on an invisible spindle. Ironically, many cells and cancer are so damaged they are incapable of replicating but the ones that are still capable of dividing indefinitely are known as cancer stem cells.

Just being in division doesn’t qualify cell as a stem cell but many treatments are directed towards stopping excessive division of cells. Unfortunately, the side effects of this treatment sometimes affect normal cells which replace themselves every day, such as those in the skin, hair, gut and bone marrow, so oncologists have to be careful to monitor the side effects of treatments designed to stop cells dividing.

16.  This striking image is of a nodule on the skin of a young patient which is due to a pox virus, molluscum contagiosum, more commonly known as “water warts”.

The dark purple objects are nuclei vastly expanded by accumulation of the virus particles. The individual viruses cannot be resolved with the light microscope however.

This condition is innocuous and clears up once the immune system learns to eliminate the virus.

17. Lung cancers are often divided into so-called small cell carcinoma and a group known as non-small cell carcinoma.

This is not as simplistic as it sounds, as it provides the 1st line of decision-making for treatment. Many lung cancers, like this one, very poorly differentiated (differentiation is the extent to which it resembles the normal cell counterpart) and difficult to classify.

In fact although the cells are rather “wild” and thus difficult to recognise, their true nature is given away by the clear spaces which are intracytoplasmic lumina (which can be highlighted by Alcian blue PAS as shown elsewhere on the site).

18. This is a liver condition where fat builds up in the liver cells causing this foamy appearance (when we take tissue through the processes in the laboratory, we remove the fat content and replace it with wax in order to enable us to take a section for the microscope).

So-called fatty change in the liver can be caused by a variety of toxins including as in this case chemotherapy treatment, but in some people alcohol, disturbed fat metabolism in diabetes or in severe obesity can produce the same effect. The condition can be treated.

19. This is another tumour where we are looking for a potential target for treatment. In this case it is a relatively newly identified antigen on the cell surface, marked out by the brown lines, called PD-L1, a receptor which binds to T cells and stops the lymphocyte destroying the cell.

If there are high levels of expression, there are new therapies available (such as Pembrolizumab) which can block PD-L1 and restore the immune killing function (see ).

20. This spectacular image is a ball of fungus in a lung, stained by a technique (Grocott’s) which employs dissolved silver which is precipitated onto the fungal hyphae outlining them.

Some of the hyphae are branching and occasional septa are present.

21. This is a section of a very distinctive benign tumour of the salivary glands called an adenolymphoma or “Warthin’s tumour”.

It has this distinctive 2 layers of nuclei, the inner of which has nuclei lining up resembling a fence palisade.

These tumours are easily cured by surgery.

22. Here is a distinctive tumour of the thyroid gland, so-called papillary thyroid carcinoma. Papillae are fingerlike projections of stroma carrying blood vessels, and here are covered by columnar cells with very distinctive nuclei which have some subtle grooves and clearing of the chromatin with a pale centre and dark ring, resembling the eyes of a cartoon character called Orphan Annie.

We still don’t know quite why this phenomenon is peculiar to this tumour type but it is very helpful for pathologists to identify and distinguish it from other tumours.

23. This was a tumour-like lump near the elbow in a patient who had arthritis. The central area is pink and blue due to the breakdown products of collagen, DNA and some fibrin leaking from blood vessels, and around the margin there are macrophages which are attempting to scavenge the debris and fibroblasts laying down new scar collagen outside them.

This makes it fairly hard and is often worrying to patients but it is a benign rheumatoid nodule, easily diagnosed when you have knowledge of the clinical history.

24. Some cancers are very difficult for pathologists to see. The signet ring cell cancer of the stomach and the invasive lobular carcinoma of the breast both lack an important molecule which sticks cells to each other, E Cadherin, due to a mutation and hence they tend to invade singularly.

This makes them look like macrophages and can be easily missed. Here, there are gastric glands stained with Alcian blue PAS, but the “camouflaged” tumour cells in the stroma are highlighted as a result.

A simple and quick technique to resolve what can otherwise be an almost impossible diagnosis.

25. Malignant melanoma of the skin is becoming more common due to our increased exposure to UV irradiation, which can damage DNA and lead to mutations. Here, the pigment forming cells of the skin of acquired mutations and began to proliferate, and instead of residing at the base of the epithelium where they normally live, they have migrated towards the basket weave type corneal layer as they have lost their sense of position due to the damage to their DNA and cytoskeleton.

Also note that they are irregular in shape, size and nuclear outline, characteristics which allow us to identify this as a potentially malignant proliferation.

26. This was a very interesting finding inside an unusual tumour of an ovary. The ovary contains precursor cells which usually remain dormant but sometimes they undergo a change so they become capable of starting to grow and dividing into all sorts of mature tissues found in the body (technically termed a teratoma, a tumour forming many different tissue types).

We usually find skin and hair in the cysts, together with some teeth, but this was 1 of the oddest findings where a small stomach, complete with the acid secreting glandular lining in the centre, the layer beneath it which is the submucosa and the muscular wall has formed!

Fortunately most ovarian teratomas are benign although it is best to remove them as occasionally they can undergo malignant transformation.

27. This is a biopsy taken from a skin rash in a young adult which had proved difficult to diagnose. The expert dermatologist eventually referred to wondered if this might be syphilis, and we were able to test for this by immunohistochemically staining for the organism, seen here as brown spiral organisms (spirochetes) confirming this diagnosis.

Syphilis, which was once controlled by antibiotics, seems to be making a return and this it can masquerade as other diseases so increased clinical awareness is needed.


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