Intraductal vs. infiltrating ductal carcinoma: Using basal/myoepithelial cell markers p63, SMA, calponin-1.
Prognostic/treatment biomarkers: ER, PR, HER-2/neu, Ki-67.
Ductal vs. lobular adenocarcinoma: E-cadherin, p120.
Metastatic carcinoma of unknown primary (CUP) as beast: Mammaglobin, GCDFP-15, GATA3, ER.>
Basal cell carcinoma: Positive for CK5/6, CK14, p63.
Melanoma: Positive for S-100 protein, SOX-10, melan-A, melanosome, MiTF, tyrosinase.
Sentinel lymph node: Positive for S-100, melan-A or HMB-45.
Sebaceous tumor: Positive for EMA and EP-CAM (Ber-EP4). Subset positive for GCDFP-15 and AR.
Eccrine gland tumor: Tumors express both luminal (CK7) and myoepithelial (CK5, CK14) markers.
Mammary Paget Disease: Positive for CK7, HER-2/neu, MUC-1, ER.
Vulvar and perianal Paget disease:
Adnexal tumor related: Positive for CK7, MUC-1, GCDFP-15, ER, negative for CK20, CDX-2.
Rectal adenocarcinoma related: Positive for CK20, CDX-2, negative for CK7, GCDFP-15.
Anal gland adenocarcinoma related: Positive for C7, CK20, CDX-2, negative for GCDFP-15.
Adenocarcinoma: Positive for CK7, with variable expression of CK20 and CDX-2, The CDX-2 staining is always weak and focal.
Barrett’s esophagus: Positive for HepPar-1, CDX-2, MUC-2, IMP3.
Squamous cell carcinoma: Positive for p63, CK14, CK5/6, p16 (40%).
Intestinal metaplasia: Positive for HepPar-1, MUC-2, CDX-2.
intestinal type: Positive for CK7, with a variable expression of CK20, CDX-2, MUC1, and MUC5AC. A CK7+/CK20- gastroesophageal adenocarcinoma favors a BE-related adenocarcinoma (90%) over gastric adenocarcinoma (21%). Poorly differentiated gastric adenocarcinoma with lymphoplasmacytic stroma may be positive for EBV-LMP or EBER. HER-2/neu gene amplification is detected in over 15% of cases of gastric adenocarcinomas and up to 33% of gastroesophageal junction adenocarcinomas.
Diffuse type: Over 70% of cases are positive for CDX-2 and CK7 with a variable expression of CK20, MUC2, and MUC5AC and MUC1. Positive for HepPar-1 (60%), and negative for E-cadherin (40%) (CDH1 gene mutation).
Neuroendocrine tumor: Positive for synaptophysin, chromogranin, CD56, Ki-67 (G1 less than 2%, G2 2-10%)
Gastrointestinal stromal tumor (GIST): Positive for CD117 (~95%) and DOG-1 (~95). The CD117 negative GISTs may be positive for DOG-1. Positive for CD34 (80%) and SMA (20%).
adenocarcinoma: Positive for CK7, CK20, CDX-2, villin. AMACR is frequently expressed in colorectal adenocarcinoma, but is rarely positive in small intestinal adenocarcinoma.COLON:
Adenocarcinoma: Positive for CK20, CDX-2, villin, MUC-2, and cadherin 17, and negative for CK7.
Signet ring cell carcinoma: Positive for CDX-2, CK20, and MUC2.
DNA mismatch repair proteins: Lynch syndrome (LS) is an autosomal dominant cancer predisposition syndrome owing to deleterious germline mutations in various DNA mismatch repair (MMR) genes (MLH-1, MSH-2, MSH-6, PMS-2). MSH-2 and MLH-1 are the dominant constituents of their respective pairs. Therefore, MSH-2 and MLH-1 loss is usually simultaneously associated with MSH-6 and PMS-2 loss, respectively. The results of MMR IHC and MSI testing are largely concordant, with MLH-1 and MSH-2 IHC achieving a sensitivity of 92% and a specificity of 100% for identifying MSI tumors. The addition of MSH-6 and PMS-2 to the panel leads to a further increase in sensitivity.
Mucinous adenocarcinoma: Positive for CK7, Ck20, CDX-2, MUC-2.
Goblet cell carcinoid: Positive for CDX-2, CK20, MUC2, and CEA, focally positive for chromogranin (37%) or synaptophysin (40%).
Squamous cell carcinomas: Positive for CK5/6, CK14, p63, p16/HPV (80%).
Ductal adenocarcinoma: Positive for CK7 with variable expression of CK17+ (50%), CK20+ (40%), CDX-2+ (20%), DPC4/SMAD4- (52% ), IMP3+ (90%).
Intestinal type: Positive for CK7, CK20, MUC2, CDX-2, negative for CK17.
IPMN: Positive for CK7, CK 19, MUC-1, MUC-6 (60%), negative for MUC-2 and MUC-5AC.
Solid pseudopapillary neoplasm (SPN): Positive for CK8/18, CD56, CD10, synaptophysin, beta-catenin (nuclear), cyclin D1 (70%), pancytokeratin (70%), negative for E-cadherin.
Serous cystic neoplasms: Positive for CK7, CAM5.2, CK19, EMA, inhibin, MUC-1, MUC-6, negative for CEA, synaptophysin, ER, beta-catenin.
Acinar cell carcinoma (ACC): Positive for pancytokeratin, CK8 and CK18, and CK19. ACC typically express the zymogen enzymes tryptase, chymotrypsin, and lipase. ACC is typically negative for CK7 and CK20.
Neuroendocrine tumor: Positive for PAX-6, Chromogranin, synaptophysin, CD56, Islet 1, insulin, glucagon, somatostatin RT2, Ki-67 (G1 <2%, G2 2-10%).
Hepatic adenoma: Beta-catenin, glutamine synthetase.
Hepatocellular carcinoma: Positive for glypican-3, SALL4, glutamine synthetase, Beta-catenin
Hepatic vs. nonhepatic adenocarcinoma: Positive arginase-1, HepPar-1, CEA (p) (canalicular), CD10 (canalicular). Cholangiocarcinoma: Positive for CK7, CK17, CK20, CDX-2, negative for IDH-1 (30%).
squamous cell carcinoma: Positive for p63, HPV, p16, high Ki-67 index.
Adenocarcinoma: Positive for CEA, MUC-1, MUC-2, p16, negative for vimentin, ER, CD10 (stroma), vimentin.
Endometrial intraepithelial neoplasia (EIN) and endometrial intraepithelial carcinoma (EIC): EIN is positive for PTEN and negative for p53. EIC is negative for PTEN and positive for p53, high Ki-67 index.
Endometrioid adenocarcinoma: Positive for PAX-8, ER, CD10 (stroma), WT-1, p53, vimentin. May be positive for MSI protein (MLH-1, MSH-2, MSH-6 and PMS-2).
Serous adenocarcinoma: Positive for p16, p53, IMP3, PAX-8, ER, WT-1, may be negative for BRCA1/2 (mutation).
Clear cell carcinoma: Positive for PAX-8, napsin A, IMP3, negative for ER, WT-1.
Mucinous adenocarcinoma: Positive for CK7, CK20, PAX-8.
Endometrial stromal tumor: Positive for CD10, h-caldesmon.
Germ cell tumor:
Dysgerminoma: Positive for SALL4, OCT3/4, D2-40.
Embryonal carcinoma: Positive for SALL4, OCT3/4, CD30, pancytokeratin.
Yolk sac tumor: Positive for SALL4, pancytokeratin, AFP, glypican-3.
Teratoma: Positive for SALL4, pancytokeratin
Choriocarcinoma: Positive for pancytokeratin, HCG, p63 (cytotrophoblasts).
Complete hydatidiform moles (CHM): Positive for HCG, negative for p57.
Partial hydatidiform moles (PHM): Positive for HCG, p57.
Ovarian endometrioid, serous, clear cell adenocarcinomas have similar staining pattern as that of endometrial counterparts.
Mucinous tumors: Positive for CK7 with a variable expression of CK20 (~60%) and PAX-8 (25%).
Small cell carcinoma: There are two types of ovarian small cell carcinoma: hypercalcemic type and pulmonary type (neuroendocrine type). Both are positive for pancytokeratin, CK18 EMA, p53, chromogranin and synaptophysin. Unlike small cell carcinomas of other sites, ovarian small cell carcinomas are positive for WT1, PAX-8, calretinin, and CD10 (>90%), and p16. The hypercalcemic type is negative for TTF-1, CD99, and inhibin, whereas pulmonary type is positive for TTF-1 (80%).
Sex cord-stromal tunor (SCST): Positive for SF-1 with variable expression of WT1, calretinin, melan-A and inhibin-alpha.
Ovarian stromal tumors: Ovarian fibroma, fibrothecoma and leiomyoma are positive for CD56, WT1, ER-β and PR.
Serous tubal intraepithelial carcinoma (STIC): Strong positive for p53 (>75% of cells) with a high Ki-67 index (>10%). Negative for BRCA1/2 (mutation).
B-lymphoblastic neoplasms: Positive for TdT, CD19, PAX-5, and CD79a, CD34 and HLA-DR. CD10 (in pediatric cases), CD20 (30%). Expression of the myeloid markers CD13 and CD33 is frequently seen, especially in adult cases and in association with cytogenetic abnormalities such as BCR-ABL t(9;22) and TEL-AML t(12;21) rearrangements.
Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): Positive CD20, PAX-5, CD79a, CD23, bcl-2, aberrantly express CD43 (90%), CD5 (95%), ZAP70 (40%), cyclin D1/SOX-11 (10%). Diffuse high Ki-67 labeling suggests Richter transformation.
Follicular lymphomas: Positive for CD20, PAX-5, and CD79a, also express bcl-2 in 87% grade 1, 81% grade 2 and 73% grade 3. CD10 and bcl-6 can be used to provide evidence of a follicle center B-cell phenotype, but the more recent markers LMO2 also helpful when CD10 and bcl-6 are negative or indeterminate.
Marginal zone B-cell lymphoma: Three marginal zone B-cell lymphomas (extranodal, nodal and splenic). Positive for CD20, CD79a and PAX-5, and they do not typically express CD5, CD23, CD10, bcl-6 and Cyclin D1. Approximately 80% of MZBCLs express bcl-2 and IgM. Aberrant CD43 coexpression is seen in about 25-30% of cases.
Mantle cell lymphoma: Positive for CD20, PAX-5, CD79a, CD43 (60%), CD5 (90%), negative for CD10 and CD23. Typically positive for cyclin D1 (>95%) and SOX11 (in cyclin D1 negative cases).
Diffuse large B-cell lymphoma (DLBCL): Positive for CD20, CD79a, PAX-5, with the exception of the plasmablastic variant, which occurs frequently in the oral cavity of HIV+ subjects, and is usually negative for CD45 and/or CD20, and is positive for CD138. Approximately two-thirds of DLBCL express surface immunoglobulins, while one-third show aberrant loss. Approximately 30% of cases express CD10, approximately 5% of cases express CD5 (a poor prognostic marker), and approximately 10% of cases show expression of CD23 and CD43. DLBCL may also be divided into germinal center B-cell (GCB) type (CD10 and bcl-6) and activation type (CD138 and MUM1).
T-cell/histiocyte-rich large B-cell lymphoma: Large tumor cells are positive for CD45, CD20, and PAX-5 and are often also positive for bcl-6. Unlike classical Hodgkin lymphoma, they are typically negative for CD15, CD30 and EBV. Bcl-2 is positive in approximately 50% of cases. >br> Primary mediastinal B-cell lymphoma: Positive for CD20, CD79a, PAX-5, BOB.1, Oct-2; sometimes express CD10, bcl-2 and bcl-6; and is typically negative for CD5, CD15, CD21, CD45/RB and surface/cytoplasmic immunoglobulin. 70-80% of cases positive for p63 positive.
Intravascular diffuse large B-cell lymphoma: Positive for CD20, CD45, CD79a, and PAX-5, as well as bcl-2 and CD43. Using CD10, bcl-6, and MUM1 immunohistochemistry, intravascular DLBCL can be divided into GC types (10%) and ABC types (90%).
EBV-positive diffuse large B-cell lymphoma of the elderly: Positive for CD20, CD79a, PAX-5 with EBV infection occurring in patients over 50.
DLBCL-associated with chronic inflammation: Also known as pyothorax-associated lymphoma (PAL). Positive for CD20, PAX-5 and CD79a, EBV. it is also positive for bcl-2, and cytoplasmic Ig.
Large B-cell lymphomas of terminally differentiated B cells: Weakly positive for CD45 and/or CD20, CD38 and CD138, HHV-8, and EBV, negative for CD20, CD79a, and PAX-5.
B-cell lymphomas with features intermediate between DLBCL Burkitt lymphoma (BL): Positive for CD20, CD79a, bcl-2
B-cell lymphomas with features of intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma (formerly known as grey zone lymphoma): Positive for CD20, CD45, CD30 and CD15 in atypical cells.
Burkitt lymphoma: Positive for CD20, PAX-5 and CD79a, homogenously express CD10 and bcl-6; and often aberrently express CD43. Bcl-2 and TdT are usually negative. The proliferation marker Ki-67 is usually positive in greater than 95% of the neoplastic cells.
Plasma cell neoplasms: Positive for CD38, CD56, CD138, MUM1, cytoplasmic immunoglobulin and lack surface immunoglobulin. The immunoglobulin is usually IgG, occasionally IgA, and rarely IgD, IgE or IgM, negative for CD45, CD20, PAX-5, and bcl-6.
Hairy cell leukemia: Positive for CD20, CD79a, DBA.44, TRAP, CD25.
CLASSICAL HODGKIN LYMPHOMA
Hodgkin cells: Positive for CD15, CD30, PAX-5 (weak to moderate in intensity), MUM1, and EBV-LAP, and are negative for CD138 and CD45/45RB. CD20 and CD79a are positive in approximately 15-25% of cases of classical HL.
T-lymphoblastic neoplasm: Positive for CD2, CD4, CD5, CD8, TdT, CD43.
Peripheral T-cell lymphoma: Positive for CD3 CD43, CD45RO. The T-cell receptor-associated protein βF1 is expressed in approximately 75% of cases. Approximately 75% of cases show aberrant loss of one or more pan T-cell or T-cell-associated markers such as CD2, CD3, CD5, or CD7. Bcl-2 expression may be aberrantly lost.
Angioimmunoblastic T-cell lymphoma: Positive for CD2, CD3, CD4. A unique feature of this malignancy is the aberrant expression of PD-1, CD10 and/or bcl-6 in nearly 90% of cases.
Anaplastic large cell lymphoma: Positive for CD3, CD30, CD43, CD45RO, ALK (12% to 85%). ALK positivity is much more common in ALCL cases in children than in adults and in systemic cases than in cutaneous cases. The ALK staining may be cytoplasmic and nuclear (most common) or it may be restricted either to the nucleus or to the cytoplasm, depending on the specific gene translocation present. ALK-positivity shows a strong correlation with EMA positivity.
Adult T-cell leukemia/lymphoma: Positive for CD2, CD3, CD4 and CD5, and CD25, negative for but CD7, associated with human T lymphotropic virus infection.
Enteropathy-associated T-cell lymphoma: Classical type is CD3+, CD4-, CD8- and CD56- phenotype. Small cell type is CD3+, CD4-, CD5-, CD8+, CD56+, TIA+, CD30-.
Hepatosplenic T-cell lymphoma: Positive for CD3, CD2, TIA-1, less often positive for CD7, and negative for CD4, CD5, CD8, and EBV, with a γδ T-cell receptor phenotype.
Mycosis fungoides and Sézary syndrome: Tumor is CD4+, CD7-. Loss of pan-T-cell markers, including CD2, CD3, and CD5, is rarely observed in early disease stages but may be seen as the disease progresses. CD30 may be positive in a subset of early stage MF tumor cells.
Primary cutaneous CD30-positive T-cell lymphoproliferative disorders: Positive for CD30, ALK, CD15 and negative for PAX-5 and EBER.
Subcutaneous panniculitis-like T-cell lymphoma: Positive for CD3, β−F1, and CD8, granzyme B, perforin, and TIA-1. Approximately one-half of cases express CD2, CD5 and CD7 in the majority of cells. They do not express CD56.
Natural Killer (NK)/T cell neoplasms: Positive for CD56, CD2, and cytoplasmic CD3ε (epsilon), T-bet, TIA-1, granzyme B, and TIA-1. Approximately 50-75% of cases may express CD7 or CD30. Ki-67 stains approximately 50% of the tumor cells. In situ hybridization shows the presence of EBV in virtually all cases of extranodal NK/T cell lymphoma, and EBV-LMP is positive in 50% of cases.
HISTIOCYTIC AND DENDRITIC NEOPLASMS:
Histiocytic sarcoma: Positive for CD163 (sensitive and specific), CD68 (highly sensitive but not highly specific), CD43 (highly sensitive but not at all specific), and lysozyme. May be positive for CD45 (78%), CD4 (50%) or S-100 (33%). Histiocytic sarcomas do not stain for CD1a, langerin (with rare exceptions), CD21/CD35, or myeloperoxidase.
Langerhans cell histiocytosis: Positive for for CD1a, Langerin, S100, CD43. CD68 and CD4.
Rosai-Dorfman disease: Positive for S-100, CD68 and CD163. CD1a and Langerin are consistently negative.
Follicular dendritic cell tumor: Positive for CD21, CD23 and/or CD35.
Blastoid plasmacytoid dendritic cell neoplasm: This is a rare dendritic cell tumor (previously considered as blastic NK-cell lymphoma) that probably arises from plasmacytoid dendritic cells. Tumor is positive for CD4, CD33, CD56, CD43, CD123, CD68 (punctate Golgi pattern), and HLA-DR. The tumor cells are also positive for CD45/RB (weak). TdT is expressed in a subset of cases (60%). There is variable expression of granzyme B. The neoplastic cells do not express most T-cell markers (CD2, CD3, CD5, CD7), B-cell markers (CD20, PAX-5, CD79a, CD138), CD57, CD34, perforin, or markers of myelomonocytic lineage.
MAST CELL NEOPLASMS
Positive for CD117, CD43, CD68, tryptase and lack B-cell and T-cell markers.
Lung and Mediastinum Pathology
Adenocarcinoma: Positive for TTF-1, napsin A, surfactant, EGFR (E746-A750del)+EGFR (L858R) (10-45%), ALK (3-7%). Enteric type: Positive for CK7, CK20, CDX-2, negative for TTF-1.
Squamous cell carcinoma: Positive for p40, desmoglein 3, CK5/6, p63 (less specific than p40).
Typical carcinoid: Positive for synaptophysin, chromogranin, TTF-1 (20%), CD56, Ki-67 (<2%)
Atypical carcinoid: Positive for synaptophysin, chromogranin, TTF-1 (30-40%), CD56, Ki-67 (2-10%).
Small cell carcinoma: Positive for synaptophysin, chromogranin (50%), TTF-1 (80%), Ki-67 (>80%)
Large cell neuroendocrine carcinoma: Positive for synaptophysin, CD56, chromogranin (20-30%), TTF-1 (50%)
Sclerosing hemangioma: Lining cells positive for TTF-1, napsin A, pancytokeratin; polygonal cells positive for TTF-1, EMA and negative for pancytokeratin and napsin A.
Thymoma: Tumor cells positive for p63, CK5/6, CK14, CD205. Negative for CD5, CD117 and only rare cases positive for MUC-1 and GLUT1. Lymphocyte positive for CD1a, TdT.
Thymic carcinoma: Positive for p63, CK5/6, CK14, CD5, GLUT1, MUC1, CD117 without TdT positive immature lymphocytes.
Mesothelial markers: Calretinin (>90%), CK5/6(75-100%), WT-1 (70-95%), D2-40 (90-100%) Adenocarcinoma markers: MOC31 (95-100%), Ber-EP4 (95-100%), BG8 (90-100%), CEA (m) (80-100%)
Mutations, Translocations and Amplifications
The FDA has approved targeted therapies for the treatment of some patients with the following types of cancer (some targeted therapies have been approved to treat more than one type of cancer):
Brain cancer: VEGF Bevacizumab (Avastin®)
Breast cancer: ER tamoxifen, toremifene (Fareston®), fulvestrant (Faslodex®), letrozole (Femara®), palbociclib (Ibrance®) HER-2 Trastuzumab (Herceptin®), pertuzumab (Perjeta®)
Cervical cancer: VEGF Bevacizumab (Avastin®)
Colorectal cancer: EGFR Cetuximab (Erbitux®), panitumumab (Vectibix®), VEGF bevacizumab (Avastin®), ramucirumab (Cyramza®)
Dermatofibrosarcoma protuberans: CD117 (c-kit) Imatinib mesylate (Gleevec®)
Endocrine/neuroendocrine tumors: Somatostatin receptor type 2 Lanreotide acetate (Somatuline® Depot)
Head and neck cancer: KRAS Cetuximab (Erbitux®)
Gastrointestinal stromal tumor: CD117 (c-kit) Imatinib mesylate (Gleevec®)
Kidney cancer: VEGF Bevacizumab (Avastin®), PD-1 nivolumab (Opdivo®)
Leukemia: CD117(c-kit) imatinib mesylate (Gleevec®), CD20 rituximab (Rituxan®),fatumumab (Arzerra®), CD52 alemtuzumab (Campath®), CD19 blinatumomab (Blincyto®)
Lung cancer: EGFR Bevacizumab (Avastin®),erlotinib (Tarceva®), gefitinib (Iressa®), afatinib dimaleate (Gilotrif®), osimertinib (Tagrisso™) ALK crizotinib (Xalkori®), ceritinib (LDK378/Zykadia), VEGF ramucirumab (Cyramza®), PD-1 nivolumab (Opdivo®), pembrolizumab (Keytruda®)
Lymphoma: CD20 Ibritumomab tiuxetan (Zevalin®), rituximab (Rituxan®), CD30 brentuximab vedotin (Adcetris®), CXCL12 and CXCL13 ibrutinib (Imbruvica®)
Melanoma: BRAF V600E mutation vemurafenib (Zelboraf®), trametinib (Mekinist®), dabrafenib (Tafinlar®), , cobimetinib (Cotellic™) PD-1 pembrolizumab (Keytruda®), nivolumab (Opdivo®)
Multiple myeloma: CD38 daratumumab (Darzalex™)
Myelodysplastic/myeloproliferative disorders: CD117 (c-kit) Imatinib mesylate (Gleevec®), JAK1 & JAK2 ruxolitinib phosphate (Jakafi®)
Ovarian epithelial/fallopian tube/primary peritoneal cancers: EGFR Bevacizumab (Avastin®), BRCA1 and BRCA2 olaparib (Lynparza™)
Pancreatic cancer: EGFR Erlotinib(Tarceva®)
Prostate cancer: AR enzalutamide (Xtandi®)
Stomach or gastroesophageal junction Adenocarcinoma: Her-2 Trastuzumab (Herceptin®), ramucirumab (Cyramza®)
Systemic mastocytosis: CD117 (c-kit) Imatinib mesylate (Gleevec®)
Thyroid cancer: VEGFR2 Cabozantinib (Cometriq®), lenvatinib mesylate (Lenvima®)RET vandetanib (Caprelsa®)
DIAGNOSIS AND PROGNOSIS
BRAF: Melanoma and thyroid papillary carcinoma
IDH1 and ATRX: Oligodendroglioma, astrocytoma and glioblastoma multiforme
ALK: Anaplastic large cell lymphoma, inflammatory myofibroblastic tumor, subset of long adenocarcinoma
TFE3: Subset of renal cell carcinoma, alveolar soft part sarcoma.
MDM2 and CDK4: Atypical lipomatous tumor/well differentiated liposarcoma/dedifferentiated liposarcoma, low grade periosteal osteosarcoma
HER-2/neu: Breast adenocarcinoma (25-30%), gastric/GE junction adenocarcinoma (30%).
Glial tumor: Positive for GFAP, SOX-2, SOX-10, IDH1, ATRX, EFGFR, p53, Ki-67 (WHO I <1%, WHO II 4%, WHO III 4-6%, WHO IV >6%)
Oligodendroglial: Positive for Olig 2, CD57.
Ependymal tumor: Positive for GFAP, SOX-10, EMA, pancytokeratin (95%).
Chordoid plexus: Positive for S-100, SOX-10, GFAP, CK7 (80%), transthyrerin (specific).
Neuronal: Positive for NeuN, neurofilament, chromogranin, synaptophysin.
Meningioma: Positive for EMA, claudin 1, S-100 (50%).
Medulloblastoma: Positive for GFAP, S-100, synaptophysin, neurofilament, NeuN (focal).
Atypical lipomatous tumor/well-differentiated liposarcoma/dedifferentiated (ALT/WDLPS/DDLPS): Positive for MDM2, CDK4.
Myxoid/round cell liposarcoma: Negative for MDM2, CDK4. Need morphology or cytogenetics for t(12;16)(q13;p11) or a t(12;22)(q13;q12) translocations.
Pleomorphic liposarcoma: Negative for MDM2, CDK4, and t(12;16)(q13;p11) or t(12;22)(q13;q12). May positive for S-100.
Desmoid-type fibromatosis: Positive for MSA, SMA, calponin, β-catenin (nuclear).
Solitary fibrous tumor: Positive for STAT6, CD34, CD99, and bcl-2.
Inflammatory myofibroblastic tumor: Positive for MSA, SMA, ALK (30-40%).
IgG4-related disease: The diagnosis of IgG4-related disease requires the combination of clinical (autoimmune disease), serological (elevated serum IgG4 and IgE levels) and pathological findings (triad of histologic appearances plus absolute IgG4 positive plasma cell count (>50/HPF) and percentage of IgG4+/IgG+ cells (>40%).
Low-grade myofibroblastic sarcoma: Positive for MSA, SMA, and desmin.
Myxoinflammatory fibroblastic sarcoma: Positive for vimentin and CD68, with variable expression of CD34 and SMA.
Fibrosarcoma: Positive for vimentin with minimal MSA, SMA expression.
Myxofibrosarcoma: Positive for vimentin with minimal and focal expression of MSA and SMA.
Low-grade fibromyxoid sarcoma: Positive for MUC-4 with focal immunoreactivity for MSA or SMA.
Sclerosing epithelioid fibrosarcoma: Positive for MUC-4 with specific EWSR1 and CREB3L2/L1 translocation.
Dermatofibrosarcoma protuberans: Positive for CD34.
Giant cell tumor of tendon sheath: Positive for CD68, CD163, SMA.
Smooth muscle tumors: Positive for MSA, SMA, h-caldesmon, desmin. H-caldesmon is the most specific for demonstrating a smooth muscle phenotype
Perivascular tumors: Positive for SMA, h-caldesmon
Skeletal muscle tumors: Positive for myogenin, MyoD1, and myoglobin.
VASCULAR TUMORS: Positive for CD31, CD34, ERG, FLI1, and D2-40. Among them, CD31 and ERG are most specific. Kaposi sarcoma is positive for HHV-8.
PERIPHERAL NERVE SHEATH TUMORS
Neurofibroma: Positive for S-100 protein and SOX-10.
Schwannoma: Positive for S-100 protein and SOX-10.
Perineurioma: Positive for EMA, claudin-1 and collagen IV. Among them, claudin-1 is specific. In contrast with other nerve sheath tumors, perineuriomas are typically negative for S-100 protein and SOX-10.
Malignant peripheral nerve sheath tumor: Positive for S-100 protein (50%-70%) and SOX10, but S-100 immunoreactivity is typically focal or patchy in comparison with S-100 staining in neurofibroma and schwannoma.
TUMORS OF UNCERTAIN DIFFERENTIATION
Angiomatoid fibrous histiocytoma: 50% of cases positive for desmin, CD99, EMA and pancytokeratin, Cytogenetically, this tumor typically shows EWS-CREB1 and EWS-ATF1 fusion genes.
Ossifying fibromyxoid tumor: Positive for S-100 protein, and may also express desmin and MSA in a subset of cases. Approximately 75% of cases have deletion of INI1 gene.
Mixed tumor/myoepithelioma/parachordoma: Positive for epithelial (keratin, EMA) and myoepithelial (S-100 protein, SMA, calponin, p63) markers. Parachordoma is positive for S-100 protein, EMA, pan-keratin, keratin 8/18, and type IV collagen.
Synovial sarcoma: Positive for TLE1, pancytokeratin and subset positive for keratin 7 and keratin 19.
Epithelioid sarcoma: Positive for pancytokeratin and EMA, negative for INI-1. CD34 immunoreactivity is present in approximately 70% of cases, a feature which is useful in distinguishing epithelioid sarcoma from carcinoma, which virtually never expresses CD34.
Alveolar soft part sarcoma: Positive for TFE3 and myogenic marker MSA, SMA, desmin.
Clear cell sarcoma of soft part: Positive for S-100 protein, HMB-45, Melan-A, and MiTF. Distinction from melanoma can be problematic may require molecular studies for t(12;22)(q13;q12).
Extraskeletal myxoid chondrosarcoma: S-100 protein expression occurs in approximately 20%-30% of cases and is generally focal and weak. Focal positivity for keratin and EMA may also be present in a minority of cases.
Desmoplastic small round cell tumor: Positive for WT1, keratin, EMA, PLAP, and desmin.
Extrarenal rhabdoid tumor: Absence of INI1 nuclear immunoreactivity. Focally positive for MSA and S-100.
PEComas: Positive for HMB-45, Melan-A, MITF, tyrosinase, MSA, SMA.
Ewing sarcoma/primitive neuroectodermal tumor (ES/PNET): Positive for CD99 (strong membrane), FLI-1, and NKX2.2.
Neuroblastoma: Positive for PHOX2B, chromogranin, synaptophysin, and CD56.
Adenocarcinoma: Positive for AMACR (90%) and ERG (50%).
Basal cell: Positive for CK5/6, p40, p63, HMW CK 34BE12
Prostate vs non-prostate adenocarcinoma: Positive for NKX3.1, prostein, PSA, PSAP, PMSA.
Urothelial carcinoma: Positive for CK7 (89%), CK20 (60%), GATA3 (70%), CK5/6 (60%), HMW CK34BE12 (80%), p63 (92%), uroplakin III (60%), S-100P
Depth of carcinoma invasion: Smoothelin is a novel smooth muscle-specific marker expressed only in terminally differentiated smooth muscle cells as part of its contractile cytoskeletons. Unlike traditional smooth muscle markers (ie, SMA and MSA), smoothelin expression is absent or limited in noncontractile and proliferative smooth muscle cells or cells with smooth muscle-like features (ie, myofibroblasts). Smoothelin expression is detected in the muscularis propria (strong) of the urinary bladder and the gastrointestinal tract, but is weak or absent in the muscularis mucosae. This immunohistochemical staining pattern is very helpful in determining the depth of bladder carcinoma invasion since normal or hyperplastic muscularis mucosae may be easily misdiagnosed as muscularis propria in superficial bladder biopsy or transurethral resection specimens.
Bladder adenocarcinoma: Positive for CK7 (70%), CK20 (70%), CDX-2 (40%), AMACR, (65%), thrombomodulin, and nuclear β-catenin negative
Urachal adenocarcinoma: Positive for CK7 (50%), CD20 (100%), CDX-2 (80%), CEA (100%), HMW CK34BE12 (70%).
Clear cell renal cell carcinoma: Positive for PAX-2, PAX-8, CA IX, CD10, RCC, vimentin
Papillary renal cell carcinoma: Positive for PAX-2, PAX-8, CK7, AMACR
Chromophobe renal cell carcinoma: Positive for PAX-2, PAX-8, CK7, E-cadherin, CD117
Renal oncocytoma: Positive for PAX-8, CD117, E-cadherin
Collecting duct renal cell carcinoma: Positive for PAX-8, CK7, HMW CK34BE12
Mucinous and spindle cell renal cell carcinoma: Positive for PAX-8, CK7, AMACR
Tubulocystic renal cell carcinoma: Positive for PAX-8, AMACR, CD10, E-cadherin
Renal cell carcinoma with translocations: Positive for PAX-2, PAX-8, RCC, TFE3(t(X;1)), melan A and HMB-45 (t(6;11))
Angiomyolipoma: Positive for HMB-45, melan-A, Mitf, tyrosinase, MSA, SMA)
Metanephric adenoma and Wilms tumor: Positive for PAX-2. PAX-8, WT-1 and CD56. Positive p53 stain is consistent with anaplasia.
Intratubular germ cell neoplasia (ITGCN): Positive for SALL4, TCL1, PLAP, OCT3/4.
Seminoma: Positive for SALL4, OCT 3/4, HAHOG, D2-40, TCL1.
Embryonal carcinoma: Positive for SALL4, OCT3/4, CD30, NANAOG, pancytokeratin.
Yolk sac tumor: Positive for SALL4, glypican 3, pancytokeratin, AFP.
Teratoma: Positive for SALL4, SOX2, pancytokeratin.
Choriocarcinoma: Positive for HCG, glypican 3, pancytokeratin, SALL4, p63.
Penile squamous cell carcinoma: Positive for p63, CK5/6, p16 (60%).