Manual of Clinical Oncology (Lippincott Manual), 7 Ed.

Appendix C

Tumor Identifiers

Russell K. Brynes, Nancy Klipfel, and Dennis A. Casciato

Appendix C1 Microscopic Clues of Tumor Origin

Appendix C2 Selected Immunohistochemical Tumor Markers

Appendix C3 Immunohistochemistry Diagnostic Algorithms

I.

Immunohistochemistry Diagnostic Algorithm Based On General Histology

II.

Immunohistochemistry Diagnostic Algorithm for Carcinoma of Unknown Origin

Appendix C4 Expected Immunophenotypes of Tumors

I.

Expected Immunophenotypes for Specific Malignant Cell Types

II.

Small Blue Cell Tumors

III.

Mesenchymal Tumors

IV.

Liver, Pancreas, and Biliary Tract

V.

Neural Tumors

VI.

Germ-Cell and Sex Cord Stromal Tumors

VII.

Skin Tumors

VIII.

Tumors of Unknown Origin

Appendix C5 Discriminatory Immunophenotypes for Lymphocytic Neoplasms

Appendix C6 World Health Organization Classification of Neoplastic Diseases of Lymphoid Tissues, 2008

Appendix C7 Acute Leukemias: Cytology, Immunophenotype, and the 2008

World Health Organization (WHO) Classification

Appendix C1 Microscopic Clues of Tumor Origin

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PAS, periodic acid-Schiff; PNET, primitive neuroectodermal tumor.

Appendix C2 Selected Immunohistochemical Tumor Markers

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DFSP, dermatofibrosarcoma protuberans; GIST, gastrointestinal stromal tumor; NET, neuroendocrine tumors (small cell carcinoma, Merkel cell carcinoma, and carcinoid tumors; paragangliomas; pheochromocytoma; neuroblastic tumors); PEComas, perivascular epithelioid cell tumors; PNET, primitive neuroectodermal tumor; SFT/HPC, solitary fibrous tumor/hemangiopericytoma

Appendix C3 Immunohistochemistry Diagnostic Algorithms

I. Immunohistochemistry Diagnostic Algorithm based on General Histology

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II. Immunohistochemistry Diagnostic Algorithm for Carcinoma of Unknown Origin

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+, positive; 0 or –, negative; CD, clusters of differentiation; CK, cytokeratin; ER, estrogen receptor; HepPar-1, hepatocyte paraffin-1; GCDFP-15, gross cystic disease fluid protein-15; PR, progesterone receptor; PSA, prostate-specific antigen; RCC, renal cell carcinoma; TTF, thyroid transcription factor See Appendix C4.IX for expanded evaluations of carcinoma of unknown origin.

aGlandular, squamoid, epithelioid, small cell, large cell, spindle cell

Modified from Voigt JJ, Mathieu MC, Bibeau F. The advent of immunohistochemistry in carcinoma of unknown primary site: a major progress. In: Fizazi K, ed. Carcinoma of an Unknown Primary Site. New York: Taylor & Francis; 2006:25–35.

Appendix C4 Expected Immunophenotypes of Tumors

I. Expected Immunophenotypes for Specific Malignant Cell Types

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II. Small Blue Cell Tumors

A. Small blue cell tumors in adults

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aPunctate pattern

B. Small blue cell tumors in children

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aMuscle markers: Desmin, MSA, MyoD1, myogenin.

III. Mesenchymal Tumors

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aPleomorphic high-grade sarcoma was previously designated malignant fibrous histiocytoma.

IV. Liver, Pancreas, and Biliary Tract

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aCanalicular pattern; same pattern seen with polyclonal CEA.

V. Neural Tumors

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aSustentacular cells surrounding the zellballen are S100+.

VI. Germ-Cell and Sex Cord Stromal Tumors

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aPositive in syncytiocytotrophoblasts.

bnegative for EMA.

VII. Skin Tumors

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aHigh-molecular-weight keratin.

VIII. Tumors of Unknown Origin

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Key to all parts of Appendix C4: +, Positive; − or 0, negative; AFP, α-fetoprotein; AMACR, P504S α-methylacyl-CoA racemase; CA, cancer antigen; Calc, calcitonin; CD, clusters of differentiation; CD45, leukocyte common antigen (LCA); CEA, carcinoembryonic antigen; CK,cytokeratins; Des, desmin; EMA, epithelial membrane antigen; GCDFP-15, gross cystic disease fluid protein-15; GFAP, glial fibrillary acid protein; GYN, gynecologic cancers; hCG, human chorionic gonadotropin; HepPar-1, hepatocyte paraffin-1; Inh, inhibin; LCA, leukocyte common antigen (CD45); mCEA, monoclonal CEA; MEL, melanocyte markers, HMB-45 and Mart-1 (Melan-A); Musc, muscle markers (Des, MSA, MyoD1); MyoD1, striated muscle specific; MSA, muscle-specific actin; NET, neuroendocrine tumor markers: neuron-specific enolase (NSE), chromogranin, and synaptophysin (Syn), CD56, and CD57; Oct4, octamer transcription factor 4; PAP, prostatic acid phosphatase; PLAP, placental alkaline phosphatase; PNET, primitive neuroectodermal tumor; PSA, prostate-specific antigen; RCC, renal cell carcinoma; S100,S100 protein; SMA, smooth muscle actin; Thyg, thyroglobulin; TTF-1, thyroid transcription factor-1; TFE3, transcription factor-E3; TLE1, transducin-like enhancer of split 1; Vim, vimentin; vWF, von Willebrand factor (factor VIII–related antigen)

Appendix C5 Discriminatory Immunophenotypes for Lymphocytic Neoplasms

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[X], occasionally positive

ALK-1, anaplastic lymphoma kinase [upregulated by t(2;5) in ALCL]; BCL, breakpoint cluster location (BCL-2 is positive in MCL, most FL, CLL/SLL, and some DLBCL; BCL-6 is positive in FL and some DLBCL); BOB.1 positive in Reed-Sternberg cells of lymphocyte-predominant Hodgkin lymphoma; CD, clusters of differentiation; CD45, leukocyte common antigen (LCA); CNS, central nervous system; Cyclin D1 (BCL-1) is positive in MCL, some HCL, and plasma cell malignancies; CXCL13, C-X-C motif chemokine 13; EBER, EBV-encoded RNA; EBV, Epstein-Barr virus; EMA, epithelial membrane antigen; FMC7, B-cell surface antigen found on mantle cell lymphoma, follicular lymphoma, and HCL; HHV8, human herpes virus type 8; HLA-DR, human leukocyte antigen-DR; HTLV-1, human T-cell lymphotropic virus type I; Igs, immunoglobulins; L & H, lymphocytic and histiocytic; MGUS, monoclonal gammopathy of undermined significance; MUM-1, multiple myeloma oncogene-1; NK, natural killer; OCT2 positive in Reed-Sternberg cells of lymphocyte-predominant Hodgkin lymphoma; Pax-5, pan-B antigen positive in B-cell lymphomas and in lymphocyte-predominant and classical Hodgkin lymphomas; PD-1, programmed death-1; TCL1, T-cell leukemia lymphoma protein 1; TCR, T-cell receptor protein (TCRαβ recognizes αβ chains of the TCR; TCRγδ recognizes the γδ chains of the TCR); Tdt, terminal deoxytransferase (positive in cortical thymic lymphoid cells and lymphoblastic neoplasms); TIA-1, T-cell intracellular antigen (found in cytotoxic T-cell and NK-cell cytoplasmic granules); TRAP, tartrate-resistant acid phosphatase

Appendix C6 World Health Organization Classification of Neoplastic Diseases of Lymphoid Tissues, 2008a

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ALK-1, anaplastic lymphoma kinase; ALL, acute lymphoblastic leukemia; AIDS, acquired immunodeficiency syndrome; CLL / SLL, chronic lymphocytic leukemia / small lymphocytic lymphoma; HTLV-1, human T-cell lymphotropic virus type I; L & H, lymphocytic and histiocytic; NHL, non-Hodgkin lymphoma; NK, natural killer; NOS, not otherwise specified; PCL, primary cutaneous lymphomas; POEMS, polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes

aLymphoma grades: L, low; M, intermediate/high; H, high; V, variable

Extracted from Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW. World Health Organization classification of tumours of haematopoietic and lymphoid tissues. Lyon, France: IARC Press; 2008.

Appendix C7 Acute Leukemias

Acute Leukemias: Cytology, Immunophenotype, and the 2008 World Health Organization (WHO) Classification

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Adapted from Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW. World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2008.

Legend to Appendix C7

++, strongly positive; +, usually positive or present; ±, variable; —, usually negative, absent, or weak; N, nuclei; G, cytoplasmic granules; AR, Auer rods

ALL, acute lymphoblastic leukemia; DIC, disseminated intravascular coagulation; Gp, platelet glycoprotein; LYS, lysozyme (muramidase); MPO, myeloperoxidase and Sudan black B; M0 - M7, categories of AML defined by the older French-American-British system; MS, myeloid sarcoma; NPM, nucleophosmin; NOS, not otherwise specified; NSE, nonspecific esterase; PPH, pseudo-Pelger-Huet anomaly; TdT, terminal deoxytransferase

Note:

Panmyeloid antigens: CD13, CD33, and CD117

Hematopoietic progenitor cell antigens: CD34, HLA-DR

Monocytic antigens: CD11b, CD14 (also CD4, CD11c, CD56, CD64)

Increased lysozyme levels are measured in the serum and characterize mixed (AMML) or pure (AMoL) monocytic leukemias.



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