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Neoplasmsintroduction

2019

Magdalena Bogdańska

Neoplasia - definition

Neoplasia – new growthA neoplasm is an abnormal mass of tissue the growth of which exceeds and is uncoordinated with that of the normal tissues and persists in the same excessive manner after the cessation of the stimuli which evoked the changes – WillisGenetic changes allow excessive and unregulated proliferation independent of physiologic growth-regulatory stimuli Certain degree of autonomy – some require endocrine support and depend on the host for their nutrition and blood supply

Cancer epidemiology

In 2015, cancer caused over 8.7 million deaths globally and was the second leading cause of death behind cardiovascular diseases

For men, the most common cancer globally was prostate cancer (1.6 million cases). Tracheal, bronchus, and lung cancer was the leading cause of cancer deaths

For women, the most common cancer was breast cancer (2.4 million cases).

Breast cancer was also the leading cause of cancer deaths

JAMAOncology | Special Communication: Global, Regional, and National Cancer Incidence,Mortality, Years of Life Lost, Years LivedWith Disability, and Disability-Adjusted Life-years for 32 Cancer Groups, 1990 to 2015

Cancer epidemiology

cancer incidence is expected to increase in the future

„…the major findings also highlight an unmet need for cancer prevention efforts, including tobacco control, vaccination, and the promotion of physical activity and a healthy diet”

JAMA Oncol. 2017;3(4):524-548. doi:10.1001/jamaoncol.2016.5688

Cancer incidence

Incidence for both sexes increased substantially between 2005 and 2015 for certain cancers

Thyroid cancer cases almost doubled between 2005 and 2015

Neoplasms

Epithelial

Benign

Malignant (carcinomas)

Non-epithelial

Benign

intermediate

Malignant (sarcomas)

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Nomenclature

Benign tumours: by attaching the suffix –oma to the cell type from which the tumor arises

Nonepithelial tumoursFibrous tissue – fibromaBone – osteomaVascular tissue – angiomaCartilage – chondroma

Epithelial tumoursAdenoma: benign epithelial neoplasm producing gland patterns or derived from glands. Cystadenoma: adenoma with cyst formation (ovary)Papilloma: benign epithelial neoplasms growing on any surface and producing finger-like projection

Papilloma benign epithelial neoplasm

Nomenclature

Non neoplastic instances with suffix –oma

Hamartoma: malformation thatpresents a mass of disorganized tissueindigenous to the particular site

Choristoma: congenital anomaly(heterotopic rests)

Some malignant neoplasms: lymphoma, seminoma, melanoma, mesothelioma

NomenclatureMalignant neoplasms

Mesenchymal origin – sarcomas

Fibrous tissue origin – fibrosarcoma

Chondrocytes origin –chondrosarcoma

Vascular origin – angiosarcoma

Epithelial origin – carcinomas

With glandular pattern –adenocarcinoma

With squamous pattern – squamous cell carcinoma

Nomenclature

Mostly – monoclonal origin

Sometimes: divergent differentiation. Mixed tumours

Mixed tumor of the salivary gland(pleomorphic adenoma); Epithelial component and fibrous stroma with cartilage or bone – myoepithelial cells origin

Fibroadenoma of the breast: epithelial component (adenoma) and mesenchymal component (fibro)

Mixed tumor of the salivary gland

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Benign v/s malignant neoplasm

Benign Malignant

Local invasion No Yes

Distant metastases No Yes

Angioinvasion No Yes

Growth Slow Rapid

Capsule Almost always yes No

Local recurrences No Yes

Morphology Well different. Anaplastic

Angiogenesis Small Numerous vessels

Heterogeneity Small Very big

Pathways of disseminating

Lymphatic spread

Hematogenous spread

Seeding within body cavities

Perineural spread

Angioinvasion and distant metastases

Lymphatic (cancers) and hematogenous spread (sarcomas)

Numerous interconnection between lymphatic and vascular system so all forms of cancer may disseminate through either or both systems

Osteogenic sarcoma – pulmonary metastasis

Pediatric Oncology Education Materials

Lymphatic spread

The pattern of lymph node involvement depends principally on the site of the primary neoplasm and natural pathways of lymphatic drainage of the siteLung carcinoma: first regional bronchial, then to tracheobronchial and hilar lymph nodesSometimes: cancer cells seem to traverse the lymphatic channels within the immediately proximate nodes to be trapped in subsequent lymph nodes – skip metastases

Lymph node metastasis of adenocarcinoma

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Sentinal lymph node

First lymph node in a regional lymphatic basin that receives lymph flow from a primary tumour

Biopsy of sentinal lymph node allows determination of the extent of spread of tumour and can be used to plan treatment

The JAMA Network

Spread by seeding

Occurs when neoplasms invade natural body cavities

Cancers of the ovary which often widely covers the peritoneal surface

Neoplasms of central nervous system may penetrate the cerebral ventricles and be carried by the cerebrospinal fluid to reimplant on the meningeal surfaces either within the brain or the spinal cord

Neoplastic cells in cerebrospinal fluid

Slide Player

Patient with peritoneal carcinomatosis

World Journal of Surgical Oncology2009 7:5Gabriel Glockzin et al

Peritoneal tumor dissemination arising from colorectal cancer, appendiceal cancer, gastric cancer, gynecologic malignancies or peritoneal mesothelioma is a common sign of advanced tumor stage or disease recurrence and mostly associated with poor prognosis.

A liver with metastatic cancer

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Macroscopic type of growth

*Exophytic

*Mesophytic

*Endophytic

Differentiation and anaplasiaBenign: well differentiated cells that closely resemble their normal counterparts. Mitoses are normal and are extremely scant

Lipoma – mature fat cells

Chondroma – mature cartilage

Differentiation and anaplasia

Malignant: wide range of parenchymal cell differentiation, from surprisingly well differentiated to completely undifferentiated (anaplastic).

Between these two extremes: moderately differentiated

Atlas of Genetics and Cytogenetics in Oncology

THYROID anaplastic (undifferentiated carcinoma)

Atypia and anaplasia

Pleomorphic cells

Extremely hyperchromatic (darkly stained) nuclei

Nuclear-cytoplasmatic ratio 4:1 (normally 1:1)

Giant cells

Bizarre nuclei (large and various in size and in shape)

Coarse and clumped chromatin

Nucleoli

Numerous mitoses

Atypical mitoses

Loss of normal polarity

Atypical mitosesWell differentiated benign neoplasm -

Lipoma

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Well differentiated malignant neoplasm (fibrosarcoma) Well differentiatied squamous cell

carcinoma

Keratin pearl

Adenocarcinoma NOS Not Otherwise Specified

Grading GHistological differentiation

First described by Broders in 1926Establish histological aggressiveness and level of malignancyIs based on the cytological differentiation and the number of mitosesCancers may be classified as grade I, II, III (and IV)Grade I – well differentiated tumour, Grade IV - anaplasticGrading not always correlate with biologic behavior

WHO Classification of Tumors of the Digestive System 2010

The terms “low-grade” and “high-grade” are now favoured for clinical usage owing to the similar behaviour of well- and moderately differentiated carcinomas

Criteria for histological grading of colorectal carcinomas WHO 2010

Criterion Differentiation category

Numerical grade Descriptive grade

>95% with gland formation

Well-differentiated G1 low

50-95% with gland formation

Moderately differentiated

G2 low

0-49% with gland formation

Poorly differentiated

G3 high

High level of microsatellite instability MSI-H

variable variable low

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Low-grade

vs

High- grade

adenocarcinoma

Grading

Is determined by cytologic appearance

Is based on the idea, that behavior and differentiation are related

Poorly differentiated tumours are more aggressive and have a worse prognosis (usually)

Poorly differentiated clustersPDCs- a novel grading system?

Postsurgical Tumor Node Metastasis (pTNM) stage is the main prognostic factor in CRC and it currently drives therapeutic protocols after surgery.

In recent years, the prognostic value of a novel grading system based on the counting of poorly differentiated clusters (PDCs) of neoplastic cells in tumor tissue of colorectal cancer

Tumor budding

Tumor budding is loosely defined by the presence of individual cells and small clusters of tumor cells at the invasive front of carcinomas

Tumor budding

Tumor budding has been shown to be an independent prognostic marker in colorectal carcinomas and the routine reporting of tumor buds is now advocated by using the approach outlined by the ITBCC guidelines. Tumor budding is included in the CAP (College of American Pathologists) protocol as a recommended element. Presence of prominent tumor budding in an adenocarcinoma in a polyp may have implications for management, such as additional resection, while it serves as a prognostic factor in other settings.

https://www.archivesofpathology.org/doi/full/10.5858/arpa.2018-0082-RA

Microsatellite instability (MSI) pathway

Tumours with MSI-H, whether sporadic or Lynch-associated, have morphological differences from tumours with chromosomal instability. They are frequently right-sided, mucinous or occasionally medullary type, associated with a Crohn-like peritumoral lymphocyte infiltrate and an intratumoral lymphocyte infiltrate, devoid of “dirty” necrosis, and better stage-specific prognosis

MSI-H morphology and clinical behaviour

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Staging

Staging is based on the size of the primarytumour (T), its extent of spread to regionallymph nodes (N) and presence or absence of metastases (M).T1, T2, T3, T4 describe the increasing size of the primary lesionN0, N1, N2, N3 indicate progressivelyadvancing node involvementM0 and M1 absence or presence of distantmetastasesStaging has greater clinical value thangrading

TNM classification -staging

Nature Reviews Disease Primers 3, Article number: 17048 (2017)

TNM classification (breast cancer)TNM classification of tumors of the

colon and rectum. 2018

Tis – carcinoma in situ: intraepithelial or invasion of lamina propria (no extension through the muscularis mucosa)T1 – tumor invade submucosaT2 – tumor invades muscularis propriaT3 – tumor invades subserosa or into non-peritonealized pericolic or perirectal tissusesT4a – tumor perforates visceral peritoneumT4b – directly invades other organs or structures

Benign v/s malignant

Benign resemble the tissue of origin and are well differentiated; malignant are poorly or completely undifferentiatedBenign are slow growing; malignant tumours generally grow fasterBenign are well circumscribed and have the capsule; malignant are poorly circumscribed and invade the surrounding normal tissueBenign tumours are localized to the site of origin; malignant are locally invasive and they metastasize to distant sites

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Benign v/s malignant neoplasm Neoplasms with local malignancy

Def: Tumour with invasive local growth (destruction and penetration of the surrounding tissues) but without metastases

Basal cell carcinoma of the skin, pleomorphic adenoma of the salivary gland.

Often with local recurrences

Basal cell carcinomaPreneoplastic disorders

Def: Clinical condition with well-recognized predispositions to the development of malignant neoplasia

Persistent regenerative cell replication: squamous cell ca in the margin of the skin wound, liver cell ca in cirrhosis

Hyperplastic and dysplastic proliferations: endometrial ca in atypical endometrial hyperplasia

Chronic atrophy gastritis: in pernicious anemia or following long standing H. pylori infection

Chronic ulcerative colitis

Leukoplakia of the oral cavity, vulva or penis

Villous adenoma of the colon

Are benign tumours precancerous?

What is the risk of malignant transformation in benign neoplasm?

In general minimal but with exceptions

Better to say: each type of benign tumour is associated with particular level of risk ranging from high to virtually nonexistent

Villous adenoma of the colon may undergo malignant transformation in 50% of cases

Malignant change in leiomyoma are extremely rare

WHO classification of tumors of the colon and rectum 2018

Benign epithelial tumors and precursors

Conventional colorectal adenoma (benign neoplsm, composed of dysplastic epithelium; the descriptor „conventional” distinguishes this from lesions in the serrated pathway)

Subtypes: tubular, villous, tubulovillous with low grade or high grade dysplasia

The likehood of carcinoma is greater with higher number, larger size, higher proportion of villous architecture and more extensive HGD (high grade dysplasia)

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Dysplasia= Intraepithelial neoplasia

Principally in the epithelia

Architectural disarrangment

Loss of the uniformity of the individual cells

Dysplastic cells are abnormally large, pleomorphic with hyperchromatic nuclei

More abundant mitotic figures, frequently in abnormal location

Dysplasia

Dysplasias do not necessarily progress to cancer

Low grade

High grade

Carcinoma in situ: when dysplastic changes are marked and involve the entire thickness of the epithelium

High-grade dysplasia= carcinoma in situ (preinvasive carcinoma)

Pathology Outlines

Dysplasia in the colonic epithelium

Clinical aspects

All neoplasms may cause problems due to:

Location and impingement of the adjacent tissues and structures

Functional activity (hormone synthesis, paraneoplastic syndromes)

Bleeding or infection (ulceration)

Symptoms that result from rupture or infarction

Cachexia

Location

Crucial in both benign and malignant tumours

Small benign tumour: pituitary adenoma can compress the surrounding gland and lead to hypopituitarism; Small leiomyoma in renal arteries – renal ischemia and hypertension

Small malignant tumours: small bile duct carcinoma may lead to jaundice

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Hormone production

In both benign and malignant neoplasms

More likely connected with a well differentiated benign tumour than with a corresponding carcinoma

Most frequently in endocrine organs tumours (adrenal cortex, pancreatic islet)

Cancer cachexia

Def: Progressive loss of body fat and lean body mass, accompanied by profound weakness, anorexia and anemia

Not caused by reduced food intake but by cytokines released by the tumour or host

TNF: suppresses appetite, inhibits the action of lipoprotein lipase

Protein-mobilizing factor (proteolysis-inducing factor): break down of skeletal muscle proteins by the ubiquitin-proteosome pathway

Other cytokines with lypolytic action

No satisfactory treatment

Paraneoplastic syndromes

Def: Symptoms complexes that occur in patients with cancer and cannot be readily explained by local or distant spread of the tumour nor by the elaboration of hormones indigenous to the tissue of origin of the tumour

10 – 15% of patients with cancer

Paraneoplastic syndromes

May represent early manifestation of occult neoplasm

May represent significant clinical problem and may even be lethal

May mimic metastatic disease and confound treatment

Paraneoplastic syndromesMechanisms

Abnormal hormones production

Immunologic response

Hypercoagulability

Unknown

Abnormal hormone production

Cushing syndrome (ACTH, ACTH-like substance) –small cell ca of the lung, pancreatic ca, neural tumoursHypoglycemia (insulin, insulin-like substance) -hepatocellular ca, mesenchymal sarcomas, fibrosarcomasHypercalcemia (parathyroid hormone-related protein, TNF alfa factor which activates osteoclasts, IL-1, TGF alfa) – squamous cell ca of the lung, breast ca, renal ca, ovarian ca, adult T-cell leukemia/lymphomaPolycythemia (erythropoietin) – renal ca, hepatocellular ca, cerebellar haemangiomaCarcinoid syndrome (serotonin, bradykinin) –bronchial adenoma, pancreatic ca, gastric ca

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Immunologic mechanism

Nephrotic syndrome – various cancers

Dermatomyositis – bronchogenic ca, breast ca

Acanthosis nigricans – gastric ca, lung ca, uterin ca

Myasthenia – bronchogenic ca

Disorders in the peripheral and central nervous system – breast ca

Acanthosis nigricans

Acanthosis nigricans is a skin condition characterized by areas of dark, velvety discoloration in body folds and creases. The affected skin can become thickened. Most often, acanthosis nigricans affects armpits, groin and neck.

The skin changes of acanthosis nigricans occur as a paraneoplastic syndrome or in people who are obese or have diabetes.

Paraneoplastic syndromesMechanisms

Hypercoagulability

Nonbacterial thrombotic endocarditis –various cancers

Venous thrombosis (Trousseau phenomenon) – pancreatic ca, lung ca, others

Unknown mechanism

Anemia – thymic neoplasms

Hypertrophic osteoarthropathy and clubbing of the fingers – bronchogenic ca

Tumour markers

Biochemical assays for tumour-associated enzymes, hormones and other markers in the blood

They cannot be utilized for definitive diagnosis, as they can be elevated in benign disorders and non-neoplastic conditions and can be low in cancers. They have low sensitivity and specificity

To screen some neoplasms, for detection of recurrences, for predicting their behavior

Tumour markers

CEA – carcinomas of the colon, pancreas, stomach, breastAFP – Yolk sac tumor, hepatocellular caBeta hCG – chorioncarcinomaNSE – small cell ca of the lungPSA – prostatic adenocarcinomaCalcitonin – medullary carcinoma of the thyroid glandCatecholamines – pheochromocytomaImmunoglobulins – multiplex myelomaCA15-3 – breast caCA19-9 – ductal adenocarcinomasCA125 – ovarian cancersTdT – leukemias

Immunohistochemistry

In 1941 Albert Coons first described this method

Powerful adjunct to routine histology

Detection of typical cells substances (proteins) by monoclonal antibodies

The possibility to define the neoplasms origin

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Cytokeratis (keratins)

Are intermediate filament proteins and are found within the cytoplasm of all epithelial cells (both: normal and neoplastic)

They form the cytosceleton of all the epithelial cells, along with microfilaments

Are numbered in a sequence contrary to their molecular weight (e.g. lower molecular weight keratins such as CK 19

Immunohistochemical positive reaction (brown): cytokeratins labeling

squamous epithelium

CK19

Immunohistochemistry

Marker Carcinoma Lymphoma Sarcoma Melanoma

CK + - -/+ -/+

Vimentine -/+ + + +

LCA - + - -

HMB45 -/+ - - +

S100 -/+ - - +

EMA + -/+ -/+ -

Immunohistochemistry

Origin Markers

Epithelial Cytokeratins, EMA, PSA

Lymphoid LCA

Melanocytic HMB45, MelanA, S100

Muscle Desmin, actin

Glial GFAP, S100

Neuroendocrine Chromogranin A, synaptophysin, insulin

Vascular CD34, CD31, FVIII

Histiocytic CD68

Embryonal antigens AFP, CEA

Vimentin, diffuse strong positivity