Neoplasia is characterized by uncontrolled cellular growth owing to increased cellular proliferation and/or decreased apoptosis. If the neoplasm grows without invading its stroma and surrounding tissues ,it is of benign nature and the disease is local. If the growing neoplasm invades its stroma and surrounding tissues gaining access to lymph vessels or blood vessels, it acquires metastatic potential so the disease is potentially systemic, not only local.  When we examine all neoplasms microscopically, we look for signs of differentiation ie, their resemblance to   normal tissues so as to define their histogenesis and classify them , since the tissue towards which a neoplasm differentiates is generally  identical to the tissue from which it derives. Only in malignant tumours,  the degree of differentiation is reported as the histologic grade of malignancy. In benign tumors which are not fully differentiated and exhibit some degree of cellular atypia , we grade their degree of cellular dysplasia. Benign tumors are not staged since, due to their benign nature  , they are incapable of metastasizing . On the contrary, malignant tumours are staged according to the extent of their dissemination at the time of their diagnosis.

1. Histology  of normal appearing endocervical type cylindrical-glandular epithelium. Note the basal orientation of the nuclei of the cylindrical epithelial cells, close to the basement membrane (black arrows). This could correspond to normal endocervix. However , this image derives from a section of a well – circumscribed ovarian multi-cystic tumour.  The expanding, non infiltrating margin of the tumour and the complete lack of cellular-nuclear atypia are consistent with a benign tumour . Taking the glandular differentiation of   neoplastic cells into account, we diagnose this benign  tumour as an “adenoma”. Due to the mucous secreting ability of these cells  and the cystic configuration of the tumour, we can further categorize it as a ”mucinous cystadenoma” of the ovary. This is a case of a benign tumour  which is completely differentiated i.e. closely mimicking a normal tissue ( endocervix epithelium in this case).

2. This is an image of a normal breast duct. Note the lumen (asterisk) , the cylindrical epithelial cells (white arrows) and the myoepithelial cells (pink arrows) ,  close to the basement membrane.

3. We observe the regular transition of  normal breast tissue  to a neoplasm which is well-circumscribed and its expansive margin forms a pseudocapsule (white arrows). The glandular differentiation of the neoplastic cells is evident in the form of lumen forming structures (blue arrows). The neoplastic cells closely resemble to each other; there is lack of nuclear atypia/pleomorphism.

4. The neoplastic cells’ nuclei  are similar with regard to their shape and size .  Due to its benign nature and glandular differentiation , this neoplasm is diagnosed as an “adenoma” and furthermore as a “fibroadenoma” due to the increased amount of fibrous tissue (orange asterisks) which is responsible for the firm consistency of this type of breast tumour. This is another example of a benign tumor with complete differentiation; this is proven by the presence of myoepithelial cells (pink arrows) in the neoplastic glandular structures, just like in the normal ducts of the surrounding breast tissue.

5&6. In contrast to the previous benign tumour (ie fibroadenoma), note the infiltrating  type of tumour margin of the present malignant tumour (brown arrows). Atypical neoplastic cells with pleomorphic, often hyperchromatic nuclei , invade the adipose (fat) tissue (yellow circles) of normal breast . Malignant neoplasms are generally characterized by nuclear atypia and invasiveness. The present tumour is a ductal invasive (adeno)carcinoma of the breast . In the first of the two images, apart from the invasive component of the cancer within fat cells, we can notice the pre-invasive component of the tumour ie, atypical neoplastic cells being confined within three ducts  (purple asterisks) and not yet having broken the basement membranes of these ducts like the invasive cells have done. This precursor state of invasiveness is called “in situ” carcinoma and has no metastatic potential since neoplastic cells cannot reach and invade lymph or blood vessels.

7. This is an image of normal mature adipose tissue. The nuclei of mature fat cells are small and inconspicuous ; they can sometimes be noticed at the cells’ periphery (black arrows). The cytoplasm with its characteristic “empty”/vacuolated appearance (yellow circles) predominates. This histologic image corresponds to a section taken from a macroscopically well circumscribed yellowish tumour surrounded by a fibrous capsule. This tumour is benign due to its smooth contour and the lack of cellular atypia . Taking into account its differentiation to mature adipose tissue , we can diagnose a “lipoma” ; its differentiation is complete.

8. This tumor also demonstrates some degree of vacuolation in its cells; there is evidence of some degree of fat tissue differentiation ,  not complete however, since some neoplastic cells show more than one vacuoles in their cytoplasm (green arrows) . The neoplastic cells’ nuclei are easily noticeable due to their increased size by comparison to the benign adipocytes of the previous image and furthermore , there is nuclear pleomorhism ie, the nuclei do not generally look like each other with respect to their size or shape. This tumour was located in the retroperitoneum and could not be completely excised by surgery due to its infiltrating margins. As this tumor is characterized by invasiveness and cellular atypia , it must be malignant. Due to its fat tissue differentiation it is classified as a “liposarcoma”. The vacuolated malignant cells with some degree of fat tissue differentiation are called “lipoblasts” (green arrows). A malignant tumour cannot be expected to be completely differentiated in a way a benign tumour can be.

9.Here is an example of a benign tumour which , in contrast to the previous benign tumors we studied, is not fully differentiated ie, it shows some degree of cellular dysplasia. In the lower left of the image, we notice some normal crypts of colon mucosa (white arrows) while in the rest of the image we notice a basophilic, darker staining tissue because of the increased number of nuclei (blue arrows) . This is a neoplasm protruding from the colon mucosa into the lumen of the colon and thus can be endoscopically be described as a polyp. There are no signs of invasiveness ; so it’s still a benign tumour and there is glandular differentiation of the neoplastic tissue ; so this neoplasm can be classified as an “adenoma”.

10. Nevertheless, this still benign neoplasm is not fully differentiated since its cells are quite different by comparison to normal colonocytes – goblet cells (white arrows). There is pseudostratification of the nuclei towards the luminal surface (blue arrow); brisk mitotic activity is noticed (black arrows) ,well above the proliferation zone of colon mucosa and there is evident mucus depletion because these cells can no longer function as normal colonocytes. These neoplastic cells with this distinctive morphology  have malignant potential; however, invasion is yet absent,basement membranes are still intact   and thus these cells  are classified as “dysplastic cells”.  This condition can be described as “intraepithelial neoplasia” or “cellular dysplasia” and is one reason why benign tumors are excised; if left untreated, invasion through the basement membrane can occur.

11. Cellular dysplasia is graded as  low or  high, the latter being close to “in situ” cancer . Low grade dysplasia can regress or evolve to high grade dysplasia. High grade dysplasia frequently leads to cancer ( invasion through the basement membrane); however , there’s a possibility that cancer evolves on a background of low grade dysplasia or even of normal appearing morphology. As a rule though, cancer evolves on a background of high grade cellular dysplasia – in situ cancer / high grade intraepithelial neoplasia.

Cellular dysplasia, low-grade in particular , must be distinguised from two other forms of cellular atypia ie, regenerative atypia due to inflammation and degenerative atypia due to stressful stimuli effect on cells ( radiotherary-chemotherapy effects).

In the above image of a colon adenoma/adenomatous polyp, we can notice areas of normal colonic crypts (white arrows) , areas of low grade dysplasia (orange arrows) and areas of high grade dysplasia (red arrows) ; in most of the latter, there is  such severe abnormality in the glandular architecture (cribriform configuration) that the basement membrane is not likely to be retained. In such areas invasion of the lamina propria has probably developed so neoplasia is no longer intaepithelial / in situ; an intramucosal carcinoma has probably developed.

12. In order to diagnose malignant neoplasia , two basic criteria must be fulfilled as a rule: invasion and cellular atypia. In the present image we notice normally appearing glandular endometrial epithelium (white arrows)  surrounded by its characteristic stroma (white asterisks) extending through the muscular bundles of the myometrium (pink circles) . This ectopic development of normal tissue cannot be considered as invasion and the whole process is not neoplastic in nature; this is a case of adenomyosis.

13. In contrast, in this image we notice extension of atypical cells forming glandular structures  (blue arrows) in the fat tissue (yellow circles) of the bowel subserosa . This is true invasion and thus this is a malignant neoplasm. Due to the glandular differentiation of the atypical cells, this malignant neoplasm is classified as an “adenocarcinoma” and the degree of invasion at its primary site is mentioned in the T category of the TNM staging system.

14. In this image we notice the cancerous glands of the previous colon adenocarcinoma (blue arrows) invading through the subcapsular area of a regional lymph node into its parenchyme (purple asterisks). This is nodal metastasis and it is taken into account to report the N status of TNM staging system.

15. Here we notice vascular cancerous emboli (blue arrows) at the primary site of a serous ovarian cancer . The possibility of systemic, distant metastatic spread of this cancer is serious; the radiologic and pathologic findings in the patient’s liver or lungs, if consistent with metastatic disease, should be mentioned in the M category of the TNM staging system.

16. This is an image of non-neoplastic liver tissue. Notice the hepatic sinusoids (red circles)  with their  lining of endothelial cells and Kupffer cells (black arrows).

17. This is an image of a malignant neoplasm in the liver . The distinction of its primary or metastatic  nature is of vital importance. Most malignant neoplasms in the liver are metastatic and the same is true as far as malignant lung and bone tumours are concerned. The differentiation of the present tumor will help us answer this question . The malignant cells which are characterized by some degree of nuclear pleomorphism, form trabeculae like normal hepatocytes do; however, these trabeculae are thicker and the cells forming them demonstrate atypia ( nuclear pleomorphism and hyperchromasia , brisk mitotic activity ). Most importantly, the sinusoidal pattern of blood circulation is retained (red circles) and endothelial cells / Kupffer cells are noticeable (black arrows) ; in other words, there is evidence of liver tissue differentiation in this malignant neoplasm of the liver which thus has to derive from hepatocytes. This is a hepatocellular carcinoma . Malignant tumours are graded according to their degree of differentiation  ie, how closely they look like the normal tissue they probably come from. The present hepatocellular carcinoma, in which liver architecture is quite well preserved by the malignant cells, belongs to low histologic grade of malignancy ie, high degree of differentiation. However, we should point out that histologic grade of malignancy does not necessarily represent the degree of biological agressiveness of the tumour. Highly differentiated malignant tumours -like this one- do have metastatic potential as all malignant tumours do.

18. Here is a case of a malignant tumour clearly invading the muscular layer of the gastric wall (pink circles) . The neoplastic cells (grey arrows), however, are not characterized by significant nuclear atypia, since all nuclei have homogenous characteristics (lack of nuclear pleomorphism).  These are tumours of neuroendocrine differentiation  and such tumors with high degree of differentiation, as the present gastric tumour,  were formerly known as carcinoids.

19. Here is another case where we can suspect malignancy because of the invasive growth of a cell population. We notice small lymphocytes with no significant morphologic abnormalities extending out of the parenchyme of a  lymph node and invading the adjacent fat tissue (yellow circles).  It’s a case of  lymphocytic lymphoma ie,  a malignant tumor of lymphocytic origin and the histologic grade of malignancy is low due to the small size of lymphomatous cells.

20. Here is a tumour of the skin with an exophytic pattern of growth (white double arrow). Normal epidermis is noticeable on the right. There is no evidence of invasion in the dermis (pink arrows) . A tumour with a totally exophytic configuration is probably benign , especially when the neoplastic cells are fully differentiated as in the present case; their majority  is morphologically identical to basal cells of normal epidermis . This is a basal cell papilloma of the skin.

21. In this image we notice significant  atypia in a considerable number of epidermal cells ( nuclear pleomorphism , hyperchromasia, black arrows). In reaction to this, there is neovascularization (red arrows) and a dense immune lymphocytic response in the dermis (blue asterisks) . Due to the severe nuclear abnormalities,this condition can be described as a high grade dysplasia or intraepidermal “in situ” squamous cell carcinoma, despite the fact that the whole thickness of the epidermis does not appear to be involved. In general , cellular dysplasia in stratified squamous epithelia is graded with respect to the thickness of the epithelium being occupied by the atypical cells. Furthermore, in the present case, the sharp margin (brown arrow) of a downward invagination of highly atypical squamous cells is arguably consistent with microinvasion of the papillary dermis. Microinvasive neoplastic disease is generally treated as in situ cancer, ie with conservative resection of the lesion at a safe distance from surrounding tissues.

22. In this case the irregular islands of atypical cells (blue arrows) extend much deeper in the dermis approaching the eccrine glands of the skin (white triangles). The tumour margin is of the infiltrative type.

23. On higher magnification, there is considerable nuclear pleomorphism (brown arrows). Both general criteria of malignant neoplasia ( ie, invasive growth and cellular atypia) are fulfilled; so now we must look for signs of differentiation so as to name this malignant tumour.  Despite the increased nuclear /cytoplasmic ratio, some malignant cells possess a fair amount of pink staining cytoplasm (pink circles). Intercellular bridges appear to join one malignant cell to the other (black arrows) . There is evidence of keratinization in individual cells (pink asterisk). All these are signs of squamous cell differentiation; so this malignant tumour is classified as a squamous cell carcinoma of the skin.

24. In the present squamous cell carcinoma , there is some evidence of maturation in the malignant squamous cells which appear to have abundant cytoplasm (pink circle). On the other hand there is a sign of definite cellular atypia in the form of an atypical mitosis (black arrow). Atypical mitoses characterize only malignant cells.

25. Squamous cell carcinomas are generally graded according to their extent of keratinization (keratin follicles , pink circles).This  widely keratinizing squamous cell carcinoma is of low histologic grade / high degree of differentiation because it closely resembles the keratinizing epithelium of normal epidermis.

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