7.6 about 24 minDeep Learning viewL7 p.22–24, 26

Diagnosis, grade and stage

Tissue makes the diagnosis. Grade says how abnormal the cells look; stage says how far the tumor has gone. Stains and serum markers support an answer, they do not replace the histology or the clinical picture.

Getting the tissue: biopsy, FNA, frozen section, cytology

L7 p.22

The lecture's rule is blunt: biopsy or excision is generally required before a tumor can be classified as benign or malignant with certainty, because some benign tumors grow in a malignant-looking way and some malignant tumors look circumscribed. Each sampling method answers a different question.

How tissue is obtainedL7 p.14, 22Ref. · Robbins: laboratory diagnosis

  • Core or incisional biopsy

    What it gives
    Intact tissue: architecture and the relation to the basement membrane
    Best for
    Deciding invasive versus in situ; grading; running stains
    Limits
    Sampling error if the needle misses the lesion

  • Fine-needle aspiration (FNA)

    What it gives
    Cells only, no architecture
    Best for
    Quick assessment of a palpable mass: thyroid nodule, breast lump, lymph node
    Limits
    Cannot usually show invasion, because the basement membrane is not visible

  • Frozen section (during surgery)

    What it gives
    A rapid diagnosis in minutes
    Best for
    Is the lesion malignant? Are the margins clear? Is the sentinel node involved?
    Limits
    Freezing distorts the cells; always confirmed on permanent sections

  • Exfoliative cytology (Pap smear, effusion fluid)

    What it gives
    Shed cells
    Best for
    Screening (cervix) and detecting malignant cells in fluid
    Limits
    Shows atypia, not invasion

  • Excision

    What it gives
    The whole lesion
    Best for
    Definitive diagnosis, grade, stage, margins
    Limits
    An operation

Grade versus stage

L7 p.24Ch. VII cases p.4

Grade describes the tumor cells: how closely they still resemble the normal tissue of origin (differentiation), together with nuclear atypia and mitotic activity. Grades run low, intermediate, high (anaplastic). Stage describes the tumor's extent: how large or deep the primary is, whether regional nodes are involved, and whether there are distant metastases. Everything about the cells is grade; everything about distance travelled is stage.

Teaching schematic

Grade: what the cells look like

Differentiation, pleomorphism, mitoses. Low → high (anaplastic). Answered down the microscope.

T · primaryN · nodesM · distantStage answers: how far has it gone?

Stage: how far it has gone

T size or depth, N nodes, M metastases. The strongest prognostic factor for survival.

Grade looks down the microscope at the cells; stage looks at the patient. The same grade can occur at any stage, and the same stage with any grade.L7 p.24

Sorting facts into grade or stageL7 p.24

  • Cells resemble the normal tissue of origin

    Grade or stage?
    Grade
    Why
    Differentiation

  • Marked nuclear pleomorphism and 25 mitoses per high-power field

    Grade or stage?
    Grade
    Why
    Cytologic abnormality

  • Tumor invades 8 mm into the bowel wall

    Grade or stage?
    Stage (T)
    Why
    Extent of the primary

  • 3 of 14 axillary nodes contain tumor

    Grade or stage?
    Stage (N)
    Why
    Regional spread

  • Nodules in both lungs

    Grade or stage?
    Stage (M)
    Why
    Distant metastasis

  • Tumor extends through the prostatic capsule

    Grade or stage?
    Stage (T)
    Why
    Local extent

  • Gleason pattern: fused, poorly formed glands

    Grade or stage?
    Grade
    Why
    Architecture of the tumor cells themselves

Lecture slide

Lecture diagram of TNM: T0–T3 primary tumor size, N0–N2 local and distant node involvement, M0, M1 and MX for distant metastases.
The lecture's TNM scheme. T scores the size or depth of the primary tumor (T0–T3 or T4), N the involvement of local and more distant nodes (N0–N2 or N3), M distant metastases (M0, M1; MX when they cannot be assessed).L7 p.24

Core activity · Almost Twins

Almost Twins

Two look-alikes side by side. Decide what they share, then pick the clue that separates them and say why it works.

Look-alike A

Grade

Grade: what the cells look like

Differentiation, pleomorphism, mitoses. Low → high (anaplastic). Answered down the microscope.

What the pathologist sees down the microscope.
  • Carries prognostic information
  • Describes the cells: differentiation, pleomorphism, mitoses, necrosis
  • Determined on the slide alone
  • Low, intermediate, high (anaplastic)

Step 1 · What they share

What do grade and stage share?

Select every feature that both show.

Immunohistochemistry: asking the cell what it is

L7 p.23

When a tumor is too poorly differentiated to name by morphology, immunohistochemistry answers with antibodies against proteins that each lineage still makes. Intermediate filaments are the backbone of the panel because every cell type keeps its own.

The lecture's panelL7 p.23

  • Cytokeratin

    Positive in
    Epithelium
    Use
    Carcinoma (any epithelial tumor)

  • Vimentin

    Positive in
    Mesenchyme
    Use
    Sarcoma (and many other non-epithelial cells)

  • Desmin

    Positive in
    Muscle
    Use
    Leiomyosarcoma, rhabdomyosarcoma

  • GFAP

    Positive in
    Neuroglia
    Use
    Astrocytoma, ependymoma

  • Neurofilament

    Positive in
    Neurons
    Use
    Neuronal tumors, neuroblastoma

  • Chromogranin (and synaptophysin)

    Positive in
    Neuroendocrine cells
    Use
    Small cell carcinoma of lung, carcinoid

  • S-100

    Positive in
    Melanocytes, Schwann cells, Langerhans cells
    Use
    Melanoma, schwannoma, Langerhans cell histiocytosis

  • PSA

    Positive in
    Prostatic epithelium
    Use
    Confirms a prostatic origin in a metastasis

  • ER (estrogen receptor)

    Positive in
    Breast epithelium
    Use
    Breast origin; predicts response to hormonal therapy

  • Thyroglobulin

    Positive in
    Thyroid follicular cells
    Use
    Follicular and papillary thyroid carcinoma

Markers not on the lecture slide but used constantly: CD45 (leukocyte common antigen) for lymphoma, HMB-45 for melanoma (more specific than S-100), and TTF-1 for lung adenocarcinoma and thyroid.

Worked case · A panel in practice

A 62-year-old woman has a 4-cm mass in the neck. The biopsy shows sheets of discohesive large cells with no glands, no keratin and no pigment. Nothing can be named on H&E.

Which panel would you run, and how would you read it?

L7 p.23

Serum tumor markers

L7 p.26

Serum markers are substances a tumor releases into the blood. Their great strength is following a known cancer: a marker that falls after resection and then rises again signals recurrence long before imaging does. Their weakness is that benign conditions raise them too, so they are poor screening tests on their own.

Markers in the lectureL7 p.25–26

  • AFP

    Associated tumors
    Hepatocellular carcinoma; yolk sac (endodermal sinus) tumor of ovary or testis
    Notes
    Also raised in pregnancy and cirrhosis

  • β-hCG

    Associated tumors
    Choriocarcinoma, hydatidiform mole; testicular tumors with syncytiotrophoblast
    Notes
    Also the pregnancy test; can cause gynecomastia or hyperthyroidism

  • PSA

    Associated tumors
    Prostate carcinoma
    Notes
    Also raised in benign prostatic hyperplasia and prostatitis

  • CEA

    Associated tumors
    Colorectal and pancreatic carcinoma; also lung, stomach, breast
    Notes
    Mainly used to monitor for recurrence after colon cancer surgery

  • CA-125

    Associated tumors
    Surface-derived ovarian carcinoma (serous cystadenocarcinoma)
    Notes
    Helps separate benign from malignant adnexal masses; raised in endometriosis and peritonitis too

  • CA 19-9

    Associated tumors
    Pancreatic and colorectal carcinoma
    Notes
    Also raised in cholestasis

  • CA 15-3

    Associated tumors
    Breast cancer
    Notes
    Monitoring, not diagnosis

  • LDH

    Associated tumors
    Malignant lymphoma (and many other tumors)
    Notes
    A measure of tumor burden and turnover; prognostic

  • Neuron-specific enolase

    Associated tumors
    Small cell carcinoma of the lung (and neuroblastoma)
    Notes
    Neuroendocrine

  • Bence Jones protein (free light chains in urine)

    Associated tumors
    Multiple myeloma, Waldenström macroglobulinemia
    Notes
    Monoclonal light chains, the clonality idea from 7.1

  • Calcitonin

    Associated tumors
    Medullary carcinoma of the thyroid
    Notes
    Used for diagnosis, monitoring and family screening in MEN 2

Knowledge check · 7.6

Answer, read why, and try again whenever you like. Answers are kept in both study modes.

0 of 5 correct
  1. Q1IHC: cytokeratin identifies carcinomaCh. VII cases p.5L7 p.23

    A 60-year-old man who has smoked two packs a day for 40 years has 4 months of weight loss, wheezing and breathlessness. A chest radiograph shows a 10-cm left lung mass and bronchoscopy shows obstruction of the left main bronchus. The biopsy is shown.

    Bronchial biopsy: irregular nests of atypical squamous cells in stroma; one nest surrounds a bright pink, concentric whorl of keratin.

    Immunohistochemistry of this biopsy would most likely show strong expression of which marker?

  2. Q2Grade versus stageCh. VII cases p.4L7 p.24

    An 80-year-old man has lower abdominal pain, weakness and 7 kg of weight loss over 6 months. PSA is 8.5 ng/mL and the prostate is enlarged and nodular. Needle biopsy shows invasive prostatic adenocarcinoma.

    Histologic grading of this carcinoma is based primarily on which criterion?

  3. Q3Stage outweighs gradeL7 p.24

    Two women have invasive ductal carcinoma of the breast. Patient A has a high-grade (poorly differentiated) 1.2-cm tumor with no involved nodes and no metastases. Patient B has a low-grade (well-differentiated) 1.2-cm tumor with 9 involved axillary nodes and two liver metastases.

    Who has the worse prognosis, and why?

  4. Q4Reading an IHC panelL7 p.23

    A 58-year-old woman has a 3-cm axillary mass. Biopsy shows sheets of large, discohesive, poorly differentiated cells. Immunohistochemistry is negative for cytokeratin and for S-100, and strongly positive for CD45.

    What is the most likely diagnosis?

  5. Q5Tumor markers monitor diseaseL7 p.26

    After resection of a colonic adenocarcinoma, a patient's CEA falls from 42 to 3 ng/mL. Eight months later, with no symptoms, it is 29 ng/mL.

    What is the best interpretation?

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