NEOPLASIA (TUMORS)

Azerbaijan Medical UniversityDepartment of Pathological Anatomy

Lecture 6

Mushfig Orujov, MD, PhDmushfig.orujov@amu.edu.az

I Part

mailto:mushfig.orujov@amu.edu.az

Plan of the Lecture

• Common information about the tumors• Atypia• Tumor Grading• Tumor Differentiation• Carcinogenesis• Tumor Morphogenesis• Tumor Spread• Classification of tumors: benign and malignant tumors• TNM classification and Cancer Stages• Epithelial tumors

NEOPLASIA

• Lat.: neoplasia – new growth or mass; Greek: oncos – tumor• Neoplasm is an abnormal growth of tissue, and when also forming a

mass is commonly referred to as a tumor.• Oncology is a branch of medicine that deals with the prevention,

diagnosis and treatment of cancer.

Morphological features of neoplastic process:• Autonomy is a tumor cell’s growth independent of controls.• Atypia• Cataplasia and anaplasia

Atypia

•Atypia – is a pathologic term for a structural, functional, metabolic and other abnormalities in a cell.

•Types of atypia:1. Morphological atypia2. Functional atypia3. Biochemical (metabolic) atypia4. Antigenic atypia

• Morphological atypia is a structural difference of tumor cells from its originating normal cells.

MORPHOLOGICAL ATYPIA

HISTOLOGICAL ATYPIA CELLULAR ATYPIA

Destroying of the characteristic structure for the tissue.E.g., disorder of regular arrangement of the fibers

Tumor cells obtain the features of polymorphism, altered nuclear/cytoplasmic (N/C) ratio, the nuclei are hyperchromic and polymorphic

•Antigens of tumors induced by viruses – (e.g., HPV –cervical cancer, EBV – Burkitt lymphoma etc.).

•Antigens of tumors induced by cancerogenicsubstances.

•Transplantation type antigens – oncospecific antigens.•Embryonic antigens – oncofetal antigens. •Heterorgan antigens – formation of protein substances in the tumor tissue belonging to another organ.

Types of the antigenic atypia

Anaplasia(from Ancient Greek: ana, "backward" + plasis, "formation")

• The cells have:– poor cellular differentiation– losing the morphological characteristics of mature cells– losing their orientation with respect to each other and to endothelial cells

– nuclear pleomorphism– altered N/C ratio– presence of nucleoli– high proliferation index

Tumor Grading

• Tumors are often “graded” as to how closely they resemble the normal parent tissue that they are derived from.

• Classification of tumors according on their differentiation:

• Well-differentiated• Moderately differentiated• Poorly differentiated• Undifferentiated (anaplastic)

Tumor Differentiation

• “Well-differentiated” means the cells are very similar in appearance and architectural arrangement to normal tissue of that organ.

• Moderately differentiated cancer cells look and behave somewhere between well-differentiated and undifferentiated cancer cells.

• Most types of cancer have moderately differentiated cancer cells.

Colonic “adenoma” illustrating a “well-differentiated” neoplasm similar to normal colon mucosa

Tumor Differentiation

• “Poorly-differentiated” refers to tumors that show only minimal resemblance to the normal parent tissue they are derived from.

• “Anaplastic” means the tumor shows no obvious similarity to it’s parent tissue, usually associated with aggressive behavior.

• Differentiation often provides clues as to the clinical aggressiveness of the tumor.

• Tumors often lose differentiation features over time as they become more “malignant” and as they acquire more cumulative genetic mutations.

• Differentiation often predicts responsiveness to certain therapies, e.g. estrogen receptors and tamoxifen in breast cancers.

Well-differentiated adenocarcinoma

Moderately differentiated adenocarcinoma

Poorly differentiated adenocarcinoma

Undifferentiated carcinoma (Medullary carcinoma)

Microscopic features of tumors

• Loss of normal architectural arrangement

Microscopic features of tumors

• Pleomorphism – variation in size and shape of cells within the neoplasm

Microscopic features of tumors

• Mitotic activity - increased in more malignant tumors and often abnormal in shape

Causes of Cancer

• Most cancer arises as the result of somatic mutations in the genome resulting from:• Environmental factors – chemical, radiation, viruses• Ageing• Specific geographic zones (E.g., Malignant melanoma affects predominantly fair-skinned Caucasians).

• Professional factors• Obesity• Inherited cancer syndromes – defect in germlineDNA

Radiation

• Ionizing radiation – X-rays, gamma rays, radioactive materials such as Radon gas – all cause a variety of defects to DNA.

• UV light (non-ionizing) – primarily sun-exposure and T-T dimerization – skin cancers.

Common features of viral carcinogenesis

• Oncogenic viruses typically integrate their genomes into host cells and enter a period of “latency”.

• May be of DNA or RNA type.• DNA viruses include EBV, HPV and Hepatitis B virus.• RNA viruses include retroviruses like HTLV-1 and indirectly HIV.

Viral carcinogenesis

Human papilloma virus (HPV) prototype• Cause warts (HPV 6/11 genotype)• Some genotypes have stronger cancer causing associations,

esp. 16 and 18 with cervical carcinoma – Pap smears of cervix can detect precursor lesions of infection.

• Viral genes interact with human genes concerned with cell division.

Other oncogenic viruses • Epstein-Barr virus (EBV) associated with some lymphomas

and nasopharyngeal carcinoma.• Hepatitis B virus associated with malignant liver tumors.

Theories of Cancerogenesis

• Viral-genetic theory (Silber’s) • Physicochemical (“stimulation”) theory (Virchow’s)• Dysontogenetic theory (dysis - “disturbation”, ontogenesis -“individual development”) (Conheim’s)• Polyethiologic theory (Petrov’s)

Tumor Morphogenesis

1. Pre-tumor conditions:- Atrophy- Hyperplasia- Sclerosis- Chronic inflammation- Metaplasia- Dysplasia- Dyshormonal processes- Metabolic disorders etc.• These precancerogen processes subdivide into 2 groups:1) obligatory (absolute)2) facultative (relative)

Tumor Morphogenesis

2. Tumor formation• Initiation or mutation period – mutation in the genetic apparatus of the cell.• Expression or modification period –proliferation, malignization, autonomic growth of the cell etc.

3. Tumor growth patterns

Expansive Invasive AppositionalPeritumoral tissues are compressed and capsule is formed.Usually characteristic of benign tumors.

Surrounding tissues are destroyed, there is no capsule around the tumor.Usually characteristic of malignant tumors.

Mutagenic effect of tumor cell to normal cell is caused by the tumor transformation.

According to the attitude of the lumen of cavitary organs

Exophytic Endophytic

Tumor grows expansively toward the lumen.

Tumor grows invasively into the wall of a hollow organ.The wall of organ is thickened.

Expansive Growth pattern (offered by Song W.Wong)

Invasive growth pattern

Periods of Tumor Morphogenesis

• Destroying of regeneration.• Appearance of pretumoral changes such as hyperplasia and dysplasia.• Malignization and proliferation of cells.• Formation of tumor bud.• Progression and growth of tumor.

Classification of tumorsaccording their clinical-morphological features

Benign Malignant Carcinoma in situ

TUMORS

Terms to know about when discussing neoplasia

•Benign – typically refers to those tumors incapable of metastasis and having a good clinical outcome (prognosis)

•Malignant – those tumors capable of invasive growth and/or metastasis, often fatal if not treated effectively

Gross (macroscopic) features of two breast neoplasms

Benign – circumscribed, often encapsulated, pushes normal tissue aside

Malignant – infiltrative growth, no capsule, destructive of normal tissues

DIFFERENCES BETWEENBENIGN AND MALIGNANT NEOPLASMS

• Size• Growth characteristics• Vascularity/necrosis• Function• Invasion/metastasis

DIFFERENCES BETWEEN BENIGN AND MALIGNANT NEOPLASMS

BENIGN

Nuclear variation in size and shape minimal

Diploid

Low mitotic count, normal mitosis

Retention of specialisation

MALIGNANT

Nuclear variation in size and shape minimal to marked, often variable

Range of ploidy

Low to high mitotic count, abnormal mitosis

Loss of specialisation

DIFFERENCES BETWEEN BENIGN AND MALIGNANT NEOPLASMS

BENIGN

Structural differentiation retained

Organised

Functional differentiation usually

MALIGNANT

Structural differentiation shows wide range of changes

Not organised

Functional differentiation often lost

Tumor Spread• The spread is a characteristic of malignant tumors.

(1) Local invasion• Malignant tumor cells invade, penetrate local tissuefissure progressively.

(2) Metastasis

• Spread of a malignant tumor from one site to another via blood or lymph.

METASTASIS OF TUMORS

Lymphatic

Hematogenous

Contact and implantation

Mixed

Directions of metastasisOrtogradeRetrogradeParadoxal

① Lymphatic metastasis

a. This is the most common pathway for initialdissemination of carcinoma.

b. Tumor cells gain access to an afferent lymphaticchannel and carried to the regional lymph nodes.

• In lymph nodes, initially tumor cell are confined to the subcapsular sinus; with the time, the architecture of the nodes may be entirely destroyed and replaced by tumor.

Lymphatic metastasis

① Lymphatic metastasis

c. Through the efferent lymphatic channels tumor maystill be carried to distanced lymph node, and enter thebloodstream by the way of the thoracic duct finally.

d. Destruction of the capsule or infiltration to neighboring lymph nodes eventually causes these nodes to become firm, enlarged and matted together.

② Hematogenous metastasis

a. This pathway is typical of sarcoma, but is alsoused by carcinoma.b. Process: tumor cells → small blood vessels →

tumor emboli → distant parts → adheres to theendothelium of the vessel → invasive the wall of thevessel → proliferate in the adjacent tissue →establish a new metastatic tumor.

c. Follow the direction of blood flow. Tumor cellsentering the superior or inferior vena cava will becarried to the lungs; tumor cells entering the portalsystem will metastasize to the liver.d. Some cancers have preferential sites for metastases:

• Lung cancer often metastasize to the brain, bones, andadrenal glands.

• Prostate cancer frequently metastasize to the bones.e. Morphologic features of metastasis tumors:

multiple, circle, scatter.

Portal vein system

Systemic veins

Pulmonary vein system

Liver

Lung

Other organs

Hematogenous metastases

http://www.pathologyoutlines.com/topic/thyroidfollicular.html

http://www.pathologyoutlines.com/topic/thyroidfollicular.html

Cancer Stages

• The TNM classification of a cancer usually correlates to one of the following five stages.

• Stage 0: This refers to cancer that is "in situ," meaning that cancerous cells are confined to their site of origin. This type of cancer has not spread and is not invading other tissues.

• Stage I – Stage III: These higher stages of cancer correspond to larger tumors and/or greater extent of disease. Cancers in these stages may have spread beyond the site of origin to invade regional lymph nodes, tissues, or organs.

• Stage IV: This type of cancer has spread to distant lymph nodes, tissues, or organs in the body far away from the site of origin.

Carcinoma in situ

Epithelial neoplasm with features of malignancy:• Altered cell growth• Cytological atypia with tissue atypia• Altered differentiation• Microscopically appears as malignant tumor

• No invasion through basement membrane.• Don’t metastases

Common systemic effect of malignant tumors

•Loss of appetite•Cancer cachexia: anorexia and weight loss due to effects on appetite

and taste, the metabolic rate goes up in cancer patients, exacerbating the syndrome.

•Fever: likely due to pyrogen release (Hodgkin’s lymphoma, renal cell carcinoma, osteosarcoma).

•General fatigue•Anemia: bleeding, pure red cell aplasia (thymoma), autoimmune

hemolytic anemia (B-cell leukemias and lymphomas, solid tumors), anemia of chronic disease (many patients with advanced malignancy).

•Pain•Muscular weakness

Secondary changes in the tumor tissue

• In benign tumors:- inflammation- mucinosis- calcinosis• In malignant tumors:- inflammation- mucinosis- necrosis- foci of hemorrhage

CLASSIFICAION OF NEOPLASMS

1. Epithelial tumors without specific localization2. Specific localized or organ-specific epithelial tumors3. Mesenchymal (Soft Tissue and Bone) tumors 4. Tumors of melanin-forming tissue5. Tumors of nervous system and brain6. Tumors of hemopoietic and lymphoid tissues7. Teratomas (germ cell tumors)

Epithelial tumors without specific localization

• Another name is common epithelial tumors.• Develop from squamous, transitional, glandular and columnar

epithelium.• Found in the epidermis, mucosa of digestive, respiratory, urogenital

systems etc.Divided into 2 groups

Benign Malignant•Papilloma•Adenoma

•Carcinoma- squamous cell carcinoma- adenocarcinoma

BENIGN COMMON EPITHELIAL TUMORS

Papilloma• A papilloma is growing exophytically (outwardly

projecting) in nipple-like and often finger-like fronds. • When used without context, it frequently refers to

infections (squamous cell papilloma) caused by human papillomavirus (HPV genotype 6/11), such as warts.

• Develops from the covering epithelium of skin and mucosa of some organs: oral cavity, esophagus, urinary tract, vagina etc.

• Tumor consist of the central fibrovascular core surrounded epithelial parenchyma.

Papilloma

• Macroscopical features:• Spherical shaped, whitish-gray colored, cauliflower-like

appearance.• Surface is irregular.• Microscopical features:1. Tumor tissue consist of abundant papillae. 2. Tumor has expansive growing base.3. In the epithelium of papillae develops the hyperkeratosis associated with the hyperfunction.

Squamous papilloma of the hard palate

• http://www.jisppd.com/articles/2013/31/4/images/JIndianSocPedodPrevDent_2013_31_4_279_121833_f1.jpg

Squamous papilloma

• http://www.brown.edu/Courses/Digital_Path/systemic_path/hn/papilloma_OC.jpg

Adenoma (Greek: aden – “gland”)

• Adenoma derived from the glands but not necessarily reproducing glandular patterns.

• Most common tumor type.• Exophytically grows toward the lumen.• Capsulated, soft consistency, whitish-pink colored.• Has broad pedicle, usually prevail the parenchyme.• Also co-called as adenomatous polyps.• Precancerogen process.

BENIGN COMMON EPITHELIAL TUMORS

TYPES OF ADENOMA

• Adenomatous polyp or glandular polyp - present in the mucosa.

• Fibroadenoma – stroma is prevailed, consistency relatively is harder.

• Alveolar (acinar) adenoma - arises from acinary structures of glands.

• Tubular adenoma – develops from the epithelium of glandular ducts.

• Trabecular adenoma – has a trabecular pattern.

• Solid adenoma (Latin: solidus – “full”, “hard”) or cribrous adenoma –there is no spaces in the big glandular structures.

• Papilllary adenoma or cystadenoma

• Mixed adenoma

Adenomatous polyp

• http://library.med.utah.edu/WebPath/GIHTML/GI113.html

Adenomatous tubulo-villous polyp, pedunculated (colon)

• http://www.pathologyatlas.ro/pathology_atlas_imagini/tubulovillous_adenoma_pedunculated_polyp_colon.jpg

Mammary fibroadenoma

• http://www.humpath.com/IMG/jpg_mammary_fibroadenoma_12_1a.jpg• http://www.humpath.com/IMG/jpg_mammary_fibroadenoma_12_2a.jpg

• https://secure.health.utas.edu.au/intranet/cds/pathprac/Files/Cases/Breast/Case63/Pictures63/M2.jpg

Hyalinizing trabecular adenoma of the thyroid

• https://icytology.files.wordpress.com/2011/12/ich0061.jpg• https://icytology.files.wordpress.com/2011/12/ich0062.jpg

Ovarian Mucinous Cystadenoma

• http://www.webpathology.com/slides-13/slides/Ovary_MucinousCystadenomaGross2.jpg• http://www.pathpedia.com/education/eatlas/histopathology/ovary/mucinous_cystadenoma/mucinous-

cystadenoma-ovary-[6-ov024-5].jpeg?Width=600&Height=450&Format=4

MALIGNANT COMMON EPITHELAL TUMORS

• The malignant tumor of the epithelial tissue is called the cancer or carcinoma.

• Degrees of the differentiation:- undifferentiated- poorly differentiated- moderately differentiated - well differentiated

• This tumors mainly metastases by lymphatic spread.

Types of the carcinomas

1. Squamous cell carcinoma (SCC):keratinizing and non-keratinizing

2. Adenocarcinoma:acinar, tubular, papillary

3. Colloid cancer – mucinous cancer4. SOLID cancer 5. MEDULLARY cancer 6. FIBROUS (Scirr) cancer 7. SMALL CELL cancer8. Carcinoma in situ9. DIMORPHIC cancer – Mixed cancer• Small cell, colloid and medullary cancers are anaplastic cancers.

Cutaneous squamous cell carcinoma • Cutaneous squamous cell carcinoma is a malignancy of epidermal

keratinocytes that displays variable degrees of differentiation and cytological features.

• Most often in sun exposed areas• Scalp, ear, lip, nose, eyelid are high risk anatomic sites• Gross description:• Often hyperkeratotic scaly plaque• May have induration, ulceration, hemorrhage• Microscopic (histologic) description:• Carcinoma of keratinocytes that infiltrates the dermis• An associated precursor lesion (actinic keratosis / keratinocytic dysplasia

/ squamous cell carcinoma in situ) is often present• Spectrum of histologic features; all share downward growth below level of

adjacent or overlying epidermis• The keratin pearl is a keratinized structure found in regions where

abnormal squamous cells form concentric layers.

Cutaneous squamous cell carcinoma

• http://trialx.com/curetalk/wp-content/blogs.dir/7/files/2011/02/skincancer.jpg• http://www.pathologyoutlines.com/topic/skintumornonmelanocyticscc.html

http://trialx.com/curetalk/wp-content/blogs.dir/7/files/2011/02/skincancer.jpghttp://www.pathologyoutlines.com/topic/skintumornonmelanocyticscc.html

SCC, Keratin pearls

• http://www.geocities.ws/m4pathology/Osce/Slides/histsch63a.jpg

Squamous Cell Carcinoma (SCC) of the Uterine Cervix

https://tulane.edu/som/departments/pathology/images/Slide008_1.jpghttps://secure.health.utas.edu.au/intranet/cds/pathprac/Files/Cases/Female/Case56/Pictures56/M1.jpg

Adenocarcinoma of the Sigmoid colon

• https://farm7.staticflickr.com/6155/6167498131_1a49619658_b.jpg

• http://www.pathologyatlas.ro/pathology_atlas_imagini/moderatelly_differentiated_adenocarcinoma_colon.jpg

Colorectal cancer

• http://www.frontiersin.org/files/Articles/134001/fmed-02-00011-HTML/image_m/fmed-02-00011-g001.jpg

A. H&E

B.Pancytokeratin immunostain

Mucinous gastric carcinoma (mucus lakes)

• http://2.bp.blogspot.com/-EL4BVn8T_d8/T6oq9YF5dnI/AAAAAAAAHi8/rB4qa05f3dY/s1600/gastric_carcinoma_diffuse_type_mucinous_detail.jpg

Small cell breast carcinoma

• http://webpathology.com/slides-13/slides/Breast_Carcinoma_SmallCell1.jpg

CIS of the urothelium

• https://openi.nlm.nih.gov/imgs/512/265/2766363/2766363_1746-1596-4-35-2.png

A – H&EB – p53+

C – H&ED – CK20+

Anaplastic Carcinoma of the Thyroid

• http://www.surgicalpathologyatlas.com/glfusion/mediagallery/mediaobjects/disp/c/c_anaplastic.jpg

Signet cell carcinoma

NEOPLASIA (TUMORS)Plan of the LectureNEOPLASIAСлайд номер 4Atypia Слайд номер 6Слайд номер 7Anaplasia��(from Ancient Greek: ana, "backward" + plasis, "formation") Tumor GradingTumor DifferentiationСлайд номер 11Tumor DifferentiationСлайд номер 13Well-differentiated adenocarcinomaModerately differentiated adenocarcinomaPoorly differentiated adenocarcinomaUndifferentiated carcinoma (Medullary carcinoma)Microscopic features of tumorsMicroscopic features of tumorsMicroscopic features of tumorsCauses of CancerRadiationCommon features of viral carcinogenesisViral carcinogenesisСлайд номер 25Theories of CancerogenesisTumor MorphogenesisTumor MorphogenesisСлайд номер 29Слайд номер 30Слайд номер 31Periods of Tumor MorphogenesisClassification of tumors�according their clinical-morphological features Terms to know about when discussing neoplasia Слайд номер 35Слайд номер 36Слайд номер 37DIFFERENCES BETWEEN�BENIGN AND MALIGNANT NEOPLASMSDIFFERENCES BETWEEN BENIGN AND MALIGNANT NEOPLASMSDIFFERENCES BETWEEN BENIGN AND MALIGNANT NEOPLASMSСлайд номер 41Tumor SpreadMETASTASIS OF TUMORSСлайд номер 44Слайд номер 45Слайд номер 46Слайд номер 47Слайд номер 48Слайд номер 49Слайд номер 50Слайд номер 51Cancer StagesCarcinoma in situСлайд номер 54Common systemic effect of malignant tumorsSecondary changes in the tumor tissueCLASSIFICAION OF NEOPLASMSEpithelial tumors without specific localizationBENIGN COMMON EPITHELIAL TUMORSPapillomaSquamous papilloma of the hard palateSquamous papillomaAdenoma (Greek: aden – “gland”)TYPES OF ADENOMAAdenomatous polypAdenomatous tubulo-villous polyp, pedunculated (colon)Mammary fibroadenomaСлайд номер 68Hyalinizing trabecular adenoma of the thyroid Ovarian Mucinous CystadenomaMALIGNANT COMMON EPITHELAL TUMORS Types of the carcinomasCutaneous squamous cell carcinoma Cutaneous squamous cell carcinoma SCC, Keratin pearlsSquamous Cell Carcinoma (SCC) of the Uterine CervixAdenocarcinoma of the Sigmoid colonColorectal cancerMucinous gastric carcinoma (mucus lakes)Small cell breast carcinomaCIS of the urotheliumAnaplastic Carcinoma of the ThyroidSignet cell carcinoma