Vocabulary of Neoplasia General Pathology C603 9-8-2014 T. Davis

Metaplasia METAPLASIA is a reversible change in which one adult cell type is replaced by another adult cell type. Note: the influence that predisposes to change, if persistent, may induce cancer transformation in the metaplastic epithelium. Examples: Columnar-to-squamous (lung, cervix) Squamous-to-columnar (esophagus)

Endocervix with squamous metaplasia

Normal esophagus

Barrett Syndrome

Barrett’s syndrome

Glandular metaplasia

Adenocarcinoma

Dysplasia Term describing cells that have undergone proliferation and atypical cytologic alterations involving cell size, shape, and organization. In models of neoplasia in many organs dysplasia is an antecedent of malignancy (both in-situ cancers and invasive tumors).

Moderate dysplasia (dysplasia)

Carcinoma in-situ (CIS) A preinvasive stage of epithelial malignancy which exhibits the cytologic features of malignancy but has not yet invaded beyond the confines of the native basement membrane.

Carcinoma In Situ of cervix (CIN III)

Carcinoma In Situ- mitoses throughout the epithelium

Early invasion by squamous cell carcinoma through the basement membrane

Pap Smears Normal Low Grade Moderate Severe/CIS

Definitions Neoplasia [G. neos, new + G. plasis, a molding] - The pathologic process that results in the forrmation and growth of a neoplasm. “Abnormal growth that continues”

Neoplasm [neo- + G. plasma, thing formed] “A 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 cessation of the stimuli which evoked the change.” Sir Rupert Willis

-OMA(S) [Greek suffix ‘-oma’ = tumor] Examples of benign tumors: lipoma, fibroma, angioma, leiomyoma, rhabdomyoma, Schwannoma, neuroma, hepatoma

Adenoma [G. aden, gland + -oma] A term applied to benign epithelial neoplasms that form glands, as well as to the tumors derived from glands but not necessarily reproducing glandular patterns. Examples: cystadenoma, papillary cystadenoma, fibroadenoma

Malignant Neoplasms with “oma” Carcinoma Sarcoma Lymphoma Melanoma Mesothelioma Glioma

And: teratoma Tumor with components from 2 or 3 germ cell layers Ovary- usually benign Testis- usually malignant (in adults)

Ovarian Teratoma (“dermoid cyst”

Arrow indicates neural tissue; benign here, but sometimes malignant

Testicular teratoma

Tumors of Mesenchymal Origin BENIGN Fibroma Lipoma Osteoma MALIGNANT (sarcomas) Fibrosarcoma Liposarcoma Osteosarcoma (osteogenic sarcoma)

Tumors of Muscle Origin BENIGN Leiomyoma Rhabdomyoma MALIGNANT Leiomyosarcoma Rhabdomyosarcoma

Smooth muscle tumors of the myometrium

Benign smooth muscle of a leiomyoma

Tumors of Epithelial Origin (Carcinomas) BENIGN Squamous cell papilloma Adenoma Tubular adenoma (adenomatous polyp) Fibroadenoma- breast MALIGNANT Squamous cell carcinoma Adenocarcinoma Colon carcinoma (adenocarcinoma) Adenocarcinoma, (Ductal carcinoma)

Multiple adenomatous polyps

Adenocarcinoma of colon

Invasive adenocarcinoma of colon

Anaplasia Anaplasia = Lack of differentiation = undifferentiated Anaplasia is considered a hallmark of malignant transformation. Anaplastic features include: - Cellular/nuclear pleomorphism - Increased nuclear-cytoplasmic (N/C) ratio - Nuclear hyperchromasia (increased DNA content) - Large nucleoli

Anaplastic rhabdomyosarcoma

Generally, all benign tumors are well-differentiated Malignant neoplasms, in contrast, range from well-differentiated to undifferentiated Well, moderately well, and undifferentiated (poorly differentiated or anaplastic) Grade 1, 2, or 3 (or I, II, III) with 3 the least differentiated)

Other Histologic Features of Malignant Neoplasms Increased/atypical mitotic activity Tumor giant cells Abnormal architecture- sheets or masses of tumor cells growing in an anarchic, disorganized fashion with infiltration and destruction of normal tissues.

Anaplastic tumor with tripolar mitosis

Carcinoma Malignant neoplasms of epithelial cell origin, derived from any of the three germ layers, are called carcinomas. Examples of modifiers include: Squamous cell carcinoma, Adenocarcinoma, Renal cell carcinoma

Bronchogenic CA

Arrow indicates keratin “pearl”

SP SP Squamous cell carcinoma with “squamous pearls” (SP)

* * Intercellular bridges (*)

Pap Stain on sputum cytology: keratinized squamous cell carcinoma

Metastatic adenocarcinoma: immunohistochemistry + for thyroid

Sarcoma Cancers arising within mesenchymal tissue are called sarcomas. Examples of modifiers include: - leiomyosarcoma - osteosarcoma - fibrosarcoma

Osteogenic Sarcoma (osteosarcoma)

Differentiation Differentiation refers to the extent to which parenchymal cells resemble comparable normal cells, both morphologically and functionally.

Differentiation and Tissue of Origin A general rule is that neoplasms differentiate in the direction of their ‘parent’ tissue. - Consider: Transitional cell carcinoma of the urinary bladder is more common than squamous cell carcinoma and adenocarcinoma in this site. Conversely, transitional cell carcinoma arising in the ovary and uterine cervix is quite unusual, though may occur.

Liposarcoma

Additional Concepts Rate of Growth In general, the growth rate of tumors correlates with their level of diffferentiation, and thus most malignant tumors grow more rapidly than do benign lesions. High grade malignant tumors (Grade 3) are more aggressive Local Invasion Most benign tumors are well circumscribed, while cancers grow by progressive infiltration, invasion, and destruction of the surrounding tissue.

GRADING TUMORS Malignant tumors only Degree of differentiation and mitotic rate Grades I-IV (higher grades are more anaplastic) Important for some tumors: breast, prostate, endometrium, astocytomas Dysplasias of the cervix are “graded” Grading is done by Pathologists

STAGING TUMORS How far has the tumor spread? Malignant tumors only Based on tumor size (T), lymph node involvement (N), distant metastases (M) Staging often involves: the Pathologist, radiology or other imaging, lab tests (tumor markers) CIS is often referred to as Stage Zero

Pathways of Spread Seeding of Body Cavities and Surfaces: carcinoma, mesothelioma, and thymoma Lymphatic Spread: initial route of spread for carcinomas Hematogenous Spread: utilized by sarcomas and carcinomas

Fibroadenoma of Breast Benign; rubbery, well-demarcated No invasion No metastasis

Fibroadenoma

Benign ducts of a fibroadenoma

FIBROADENOMA Benign ducts of fibroadenoma

Ductal Carcinoma In Situ DCIS

DCIS (Ductal Carcinoma In Situ) Surgery Meds. Watch Invasive (10 yrs.) 3% 17% 30% Die Brest CA (10 yrs.) 0.3% 2% 3%

DCIS- “A Rose is Not a Rose” 400 “Healthy” Women Surveyed for choice of treatment if DIAGNOSIS IS “DCIS” but other term used “non-invasive breast CA”- 53%: no surgery “Breast lesion”- 66%: no surgery “Abnormal cells”- 69%: no surgery

Invasive

Invasive Ductal Carcinoma Mammogram with carcinoma

Vascular invasion by invasive ductal carcinoma

BREAST CARCINOMA GRADING Bloom and Richardson Tubules present (1-3 points) Nuclear atypia (1-3 points) Mitoses (1-3 points) Total score 3-5: Grade I (Well differentiated) Total score 6,7: Grade II (Moderately differentiated) Total score 8,9: Grade III (Poorly differentiated)

Well differentiated: Tubules Small nuclei (Well Diff.)

Moderately differentiated: Rare tubules/solid nests Pleomorphic nuclei (Mod. Diff.)

Poorly differentiated: No tubules; pleomorphic Many mitoses (Poorly Diff.)

BREAST CARCINOMA STAGING Stage 0 (in situ or CIS): 5-year 92% Stage I. (<2 cm & LN-): 5-year 87% Stage II. (2-5 cm & 0-3 LN+): 5-year 75% *Stage III. (>5 cm & >4 LN+): 5-year 46% Stage IV. Distant metastases: 5-year 13%

BREAST CARCINOMA OTHER Estrogen receptor (+): tumor is stimulated by estrogen and can be treated with the “anti-estrogen” tamoxifen. This is palliation. HER-2 Neu amplification: by immunostaining or FISH is seen in 20% of cases. If HER-2 Neu is amplified in the invasive tumor, the patient can be treated with Herceptin (Trastuzumab) or Tykerb (Lapatinib) . This is very expensive and tends to be used in high grade/high stage lesions that are HER-2 Neu positive. Triple Negative Breast Carcinoma- negative for estrogen and progesterone recptors and no overexpression of HER-2-Neu (recently reviewed in NEJM 363: 1938-1948)

ER (+)

HER-2 Neu (+)

COLON CANCER Grading is not very helpful STAGING: predicts clinical outcome (TNM) No penetration of the muscularis mucosa (Tis); 100% cure rate Penetration of muscularis propria (and maybe serosa too) but lymph nodes negative (T3); 70% cure rate 1-3 (+) lymph nodes (N1); 30% cure rate Distant metastases (M1); rare cures

COLON CANCER OTHER 50% of colorectal carcinomas show “ras” mutations; 50% of adenomas > 1cm also show ras mutations CEA (carcinoembryonic Ag) can be used to follow patients after surgery Deeply infiltrating tumors cause desmoplasia (fibrosis) and “apple core/ napkin-ring” appearance. Desmoplasia is also seen in breast carcinoma

Adenomatous polyps

Adenoma: Crowded glands but no atypia

Molecular model for colorectal adenocarcinoma

TNM Staging System

Colon adenocarcinoma

Metastases: Metastases are tumor implants discontinuous with the primary tumor. *METASTASIS unequivocally marks a tumor as malignant because benign neoplasms do not metastasize.

Liver with metastatic carcinoma

Metastatic melanoma in liver and bone marrow

2 additional Terms Choristoma: An ectopic rest of ‘normal’ tissue. Normal tissue in an abnormal location. Examples include glial tissue in the tongue, breast tissue in the “milk line”, nodules of pancreas in the small bowel, and adrenal rests in the uterine broad ligament or spermatic cord. Hamartoma: Mass of disorganized but mature specialized cells or tissue indigenous to the particular site. Hamartoma of lung is classically a mass of benign cartilage with or without, blood vessels, adipose tissue, etc. Hemangiomas are also called hamartomas.