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Quick Reference Handbook for Surgical Pathologists > Chapter 1: Immunostains - Introduction > Flashcards

Chapter 1: Immunostains - Introduction Flashcards

1
Q

Name some immunostains that can differentiate carcinomas/lymphomas/melanomas.

A

Carcinoma: Cytokeratins

Lymphoma: CD45

Melanoma: S100, MelanA, HMB45

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2
Q

Name some general prognostic markers.

Name some germane to breast cancer, and CLL.

A

Ki67 (MIB1) and p53

Her2 (adverse prognosis in breast cancer)

CD38 (adverse prognosis in CLL)

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3
Q

Name some predictive markers in breast and other cancers.

A

ER/PR (predicts tamoxifen response in breast)

Her2 (predicts trastuzumab response in breast)

c-Kit (predicts imatinib response in general)

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4
Q

Why is p53 overexpressed in p53-mutated tumors?

A

Inactivating mutations in p53 also disable protein degradation, resulting in overexpression.

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5
Q

What types of antigens should be nuclear in localization?

A

Transcription factors (TTF-1, CDK2, Myogenin, WT1, p53), steroid hormone receptors (ER, PR), and Ki67 (except in hyalinizing trabecular adenoma of thyroid)

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6
Q

What types of antigens should be cytoplasmic in localization?

A

The vast majority, including all intermediate filaments, contractile proteins, melanosome-associated proteins, secretory products, and other functional molecules.

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7
Q

What types of antigens should be membranous in localization?

A

Receptors, adhesion molecules, virtually all CD (cluster of differentiation) antigens. Be careful to distinguish from cytoplasmic, especially in Her2 & EGFR.

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8
Q

Name some antigens that have characteristic combined nuclear and cytoplasmic reactivity.

A

S-100, calretinin, and beta-catenin (with mutations in APC pathway, eg deep fibromatosis and colon cancer.)

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9
Q

What is granular immunoreactivity indicate? Examples?

A

Localization to cytoplasmic organelles. For example, racemase (mitochondrial/peroxisomal), P501S (golgi), and Napsin A (lysosomal).

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10
Q

What does punctate immunoreactivity indicate? Example?

A

Represents some antigens that aggregate in the cytoplasm, eg CK tangles that form in neuroendocrine carcinomas.

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11
Q

Name some examples in which loss of immunoreactivity is diagnostic.

A

DPC4 loss in pancreatic carcinoma

E-cadherin loss in lobular breast carcinoma

INI-1 loss in rhabdoid tumors and AT/RT

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12
Q

How are cytokeratins classified and stratified?

A

Moll’s catalogue, in which they are separated based on gel electrophoresis.

CK1-8 are basic, CK9-20 are acidic.

CK1-6 and 9-17 are HMW, 7-8 and 18-20 are LMW.

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13
Q

Distinguish the distribution of HMWCKs, LMWCKs, and intermediate weight CKs.

A

HMWCKs: Expressed in squamous epithelia. Called “tonofilaments” ultrastructurally.

LMWCKs: Loosely distributed in the cytoplasm and unable to bundle. Found in visceral organs.

Intermediate: Usually 5, 6, and 17. Found in basal cells.

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14
Q

Why are certain pairs of CKs expressed jointly? Name some examples.

A

Keratins are heterodimers consisting of an acidic and basic heterodimer. Classic pairs include 1+10 and 8+18.

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15
Q

What do the following cytokeratin cocktails detect?

  1. AE1
  2. AE3
  3. Cam5.2
  4. CK5/6
  5. CK903
A
  1. All acidic CKs except 9/12/17/18
  2. All basic cytokeratins (1-8)
  3. LMWCKs (8, 18)
  4. HMWCKs (5>6)
  5. HMWCKs (1, 5, 10, 14)
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16
Q

How are HMWCKs and LMWCKs differently expresses in carcinomas?

A

Squamous cell carcinomas express HMWCKs (but poorly-differentiated may co-express LMWCKs)

Adenocarcinomas and carcinoma of visceral epithelia express LMWCKs (but eg Pancreas, endometrium, breast, urothelial will co-express HWMCKs)

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17
Q

What carcinomas will not stain AE1/AE3?

A

HCC (expresses CK18)

RCC (can be CK-negative in general)

Neuroendocrine carcinomas (variable, Cam5.2 is better?)

Adrenocortical neoplasms (often CK negative)

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18
Q

What roles do EMA, CEA, and p63 have in the context of cytokeratin IHC?

A

EMA and CEA can be thought of as “LMWCK-equivalents” in glandular epithelia, with p63 as a “HMWCK-equivalent” in squamous, urothelial, and basal cells.

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19
Q

What three classes of non-carcinomas can be cytokeratin positive?

A
  1. Tumors with true epithelial differentiation (eg epithelioid sarcomas, germ cell tumors, chordoma, mesothelioma)
  2. High-grade cancers with aberrant epithelial reactivity (usually focal, with Cam5.2)
  3. Gliomas and reactive astrocytes (may cross react with AE1/AE3).
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20
Q

How can Bowen’s disease (SqIS) be distinguished from Paget’s disease?

A

Paget’s is Cam5.2+ (LMWCK).

Bowen’s disease is CK903 (or CK5/6)+.

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21
Q

What are some uses for CK903 and CK5/6?

A

Urothelial (CK903+) vs prostate (CK903-)
Mesothelioma (CK5/6+) vs adenocarcinoma (CK5/6-)
UDH (CK903+) vs DCIS (CK903-)

Identifying basal cells in prostatic lesions (CK903+)
Identifing metaplastic breast cancer (CK903+)

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22
Q

What is the utility of Ber-EP4?

A

Reacts with majority of adenocarcinomas. Mostly used to distinguish lung adenocarcinoma (+) from mesothelioma (-). Especially useful in cytology of effusions.

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23
Q

Which organs are CK7+, CK20-?

A

Above the diaphragm organs (lung & mesothelioma, breast, thyroid, salivary gland) and the gyne tract (uterus, non-mucinous ovary).

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24
Q

Which organs are CK7-, CK20+?

A

Below the diaphragm GI tract (colorectal) and Merkel cell carcinoma

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25
Q

Which organs are CK7+, CK20+?

A

Peridiaphragmatic GI organs (pancreaticobiliary, stomach) and bladder, as well as mucinous ovarian.

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26
Q

Which organs are CK7-, CK20-?

A

Simple visceral epithelia (liver, kidney, prostate), adrenal gland.

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27
Q

Which tumors are CK+, EMA-?

A

HCC (CK18)

Adrenocortical neoplasms (often CK- though)

Most neuroendocrine neoplasms

Embryonal carcinoma, yolk sac tumor

Thyroid

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28
Q

Which tumors are CK-, EMA+?

A

Meningioma

Perineurioma

Plasma cell neoplasms, HL, ALCL

RCC (sometimes)

29
Q

What carcinomas are usually CEA+?

A

HCC (canalicular pattern with pCEA)

Pancreaticobiliary

Stomach

Colorectum

Lung adenocarcinoma

30
Q

Recall some vimentin-positive carcinomas.

A

RCC (clear cell)

Endometrium

Mesothelioma

Thyroid

Salivary gland

Sweat gland

Spindle cell carcinomas in general

31
Q

What is the application of vimentin IHC?

A

A mesencymal marker that is unfortunately too nonspecific for differentiating tumors. Mostly used to confirm tissue immunoviability when all other markers are negative.

32
Q
  1. Name two pan-muscle markers.
  2. Name three skeletal muscle markers.
  3. Name four smooth muscle & myoepithelial markers.
  4. Which of the above in #3 are absent in myofibroblasts?
A
  1. Desmin, muscle-specific actin (MSA)
  2. MyoD, Myogenin, alpha-sarcomeric actin
  3. SMA (alpha-actin), calponin, h-Caldesmon, SMMHC.
  4. Myofibroblasts lack caldesmon and SMMHC. They may variably express calponin.
33
Q

How do desmin and actins complement one another?

A

Usually, desmin staining pairs with actins. Actins are actually slightly more sensitive (may be positive in leiomyosarcomas).

However, some tumors can unexpectedly be desmin+/actin- (desmoplastic small round cell tumor, Wilms tumor, mesothelial cells).

34
Q

Summarize the main 5 neuroendocrine markers.

A

Synaptophysin: More sensitive (order with CHR)

Chromogranin: More specific (order with SYN)

NSE: Not actually specific (stains glial cells), so rarely used.

CD56: Most sensitive, but usually not needed.

CD57: Leu-7, sometimes a second-line marker.

35
Q

What non-neuroendocrine tumors can stain SYN/CHR?

Which are generally SYN+/CHR-?

A

Neoplasms of neuronal origin (eg Gangliocytoma) and PNETs.

Adrenocortical neoplasms and pancreatic solid pseudopapillary tumor.

36
Q

What role do peptide hormone stains serve in identification of neuroendocrine neoplasms?

A

They may help establish identity, but many cases can be nonfunctional or have ectopic hormone expression. Be cautious with occult neuroendocrine tumors.

37
Q

What roles do cytokeratins play in neuroendocrine tumors?

A

Epithelial neuroendocrine tumors (carcinoid, pancreatic tumors, SCLC) are often CK-positive. Usually Cam5.2, but also get AE1/AE3.

High grade NE carcinomas have punctate perinuclear CK staining.

38
Q

Summarize the main four markers of melanocytic differentiation.

A

MelanA/Mart1: Stains almost all epithelioid melanomas, and few/no spindled or desmoplastic. Also stains steroid hormone producers.

HMB45: Like Melan-A, but more specific (does not stain steroid hormon producers). Also does not stain mature melanocytes.

S100: Stains nearly all melanomas. Very nonspecific.

MITF: Nuclear, somewhat specific. Kind of meh.

39
Q

Besides melanomas, what other tumors will stain melanosomal markers?

A

Clear cell sarcoma/melanoma of soft parts, melanotic neurofibroma, melanotic schwannoma, and PEComas (AML, LAM, pulmonary sugar tumor).

40
Q

What role do the markers SOX10, PNL2, and MUM1 play?

A

They are newer melanocytic makers that identify epithelioid but not spindle cell melanoma.

41
Q

In addition to typical neuroendocrine markers, what markers will stain neurons?

A

Neurofilament (axonal)

NeuN (nuclear)

42
Q

What utility is offered by GFAP?

A

Stains glial cells (astrocytes, oligodendrocytes, ependymal cells, and some schwann cells) to distinguish gliomas from non-glial tumors and inflammatory conditions.

43
Q

What markers can identify schwann cells?

A

S-100 (first line)

CD57, GFAP (second line)

44
Q

Summarize 5-6 vascular markers.

A

CD34: Lots of cross-reactivity (see other card)

CD31: More sensitive and specific?

Factor VIII: Actually vWF.

Ulex europaeus I

FLI-1, ERG: Nuclear?

45
Q

Recall some CD34+ non-vascular tumors.

A

Solitary fibrous tumor

Dermatofibrosarcoma protuberans

Gastrointestinal stromal tumor

Epithelioid sarcoma

Nerve sheath tumors

Granulocytic sarcoma

46
Q

What markers can be useful in the assessment of invasion in prostate and breast cancers?

A

Prostate: CK903 (cytoplasmic) and p63 (nuclear) mark basal cells. They are absent in invasion, and the invasive acinar cells should express racemase.

Breast: SMA, SMMHC, Calponin, p63, S100, C10 should all stain myoepithelial cells, which are absent in invasion.

47
Q
  1. Do carcinomas normally express S-100?
  2. Do spindle cell and desmoplastic melanomas stain S-100?

Do pheochromocytoma/paraganglioma stain S-100?

A
  1. No, but 30% of breast cancers do.
  2. Yes, but they may not express MelanA/HMB45.
  3. S-100 reactivity is present in sustentacular (supporting) cells.
48
Q

What hematopoietic neoplasms do not express CD45?

A

Lymphoblastic lymphoma (variable)

Anaplastic large cell lymphoma (variable)

Classical HL

Plasma cell neoplasms

Follicular dendritic cell sarcoma

Myeloid sarcoma (variable)

49
Q

Name some site specific markers of breast.

A

ER/PR (60%)

GCDFP-15 (50%)

Mammaglobin (50%)

(Her2 is not specific!)

50
Q

Name some site specific markers of prostate.

A

PSA, PSAP

Prostein (P501S)

PSMA

51
Q

Name some site specific markers of lung

A

TTF-1 (75% of non-mucinous adenocarcinomas, 90% of SCLCs)

Napsin A

Surfactant (PE10)

52
Q

Name some site specific markers of thyroid (Papillary/follicular vs medullary!).

A

Papillary/follicular: TTF-1, thyroglobulin, PAX8

Medullary: TTF-1, calcitonin

53
Q

Name some site specific markers of liver

A

HepPar-1

Canalicular CD10

54
Q

Name some site specific markers of pancreas

A

Loss of DPC4 expression (55% of adenocarcinomas)

55
Q

Name some site specific markers of kidney.

A

PAX2

PAX8

CAIX

56
Q

Name some site specific markers of adrenal gland.

A

Inhibin

(melan-A is not very specific)

57
Q

Name some site specific markers of Gyne tract.

A

Pax8

ER/PR (100% of endometrioid, 50% of serous, 0% of cervical)

WT1 (serous carcinomas)

58
Q

Name some site specific markers of pituitary, parathyroid, and pancreatic islet.

A

Pituitary: Prolactin, GH, FSH/LH, TSH, ACTH

Parathyroid: PTH

Pancreatic islet: Glucagon, insulin, somatostatin

59
Q

Name some site specific markers of bladder.

A

p63

Uroplakin

GATA3

(thrombomodulin is less specific)

60
Q

Name some site specific markers of intestine, gallbladder, and stomach.

A

Intestine: CDX2, villin

Gallbladder/stomach: (no specific markers available).

61
Q

Name some site specific markers of squamous cell cancers of cervix, anus, and tonsil.

A

HPV (ISH)

p16

62
Q

Recite a differential diagnosis for small round cell blue cell tumors of childhood, and what stains would be useful.

A

Lymphoblastic lymphoma (CD45, CD34, CD99)

Rhabdomyosarcoma (desmin)

Wilms tumor (WT1)

PNET/Ewing (CD99, NE markers)

Neuroblastoma (Phox2B)

Medulloblastoma (NE markers, GFAP variable)

Small cell osteosarcoma (CD99 variable, osteocalcin)

63
Q

Recite a differential diagnosis for small round blue cell tumors of adulthood, and some useful stains.

A

Lymphoma (CD45)

Small cell carcinoma (CK, NE markers, TTF1 variable)

Merkel cell carcinoma (CK7/20, NE markers)

Desmoplastic small round cell tumor (CK, WT1, desmin)

Mesenchymal chondrosarcoma (CD99, Sox9)

64
Q

Recite some categories of tumor differentiation that should be considered in spindle cell tumors, and what markers can define them.

A

Muscle (Desmin)

Nerve sheath (S100, CD34)

Vascular (CD34)

Myofibroblastic (SMA)

Fibrohistiocytic (CD34?)

Adipose (S100)

Spindle carcinomas (CK)

Others: GIST, SFT, synovial sarcoma…

65
Q

In what contexts is ER/PR staining considered uninterpretable?

Negative?

A

Internal control issue fails to stain, or specimen handling did not conform to requirements (6-72hrs fixation in 10% NBF)

Negative only if <1% staining with appropriately staining internal control.

66
Q

How is Her2 Dako HercepTest IHC scored?

A

0 = <30% staining

1+ = >30%, partial membrane staining

2+ = >30%, weak but complete membrane staining

3+ = >30%, strong complete membrane staining.

67
Q

How is Her2 FISH scored?

A

Her2 amplified: >6 HER2 copies per nucleus or ratio of FISH signals to chr17 > 2.2

Her2 non-amplified: <4.0 Her2 gene copies per nucleus or FISH ratio < 1.8

68
Q

How is EGFR PharmDx assay interpreted?

A

0 = no staining

1+ = >1%, weak membranous

2+ = >1%, moderate membranous

3+ = >1%, strong membranous

Quick Reference Handbook for Surgical Pathologists (9 decks)

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