Diagnosis of Metastatic Neoplasms

An Immunohistochemical Approach
Murli Krishna, MD

NofContext.—It is important to determine the type and/or site
origin of metastatic tumors for optimal clinical manage-
Conclusions.—Immunohistochemistry is an important
ancillary technique for evaluation of metastatic tumors and
ment. should be used in the context of routine morphology and
Objective.—To summarize the use of currently available clinical information. While a single marker may be used to
immunohistochemical markers in the evaluation of meta- support a known or suspected site of origin, a carefully
static tumors. constructed panel is strongly recommended, particularly
Data Sources.—Review of relevant literature on immu- for tumors of morphologically uncertain lineage or origin.
nohistochemical evaluation of tumors and the author’s (Arch Pathol Lab Med. 2010;134:207–215)
personal experience.

D etermination of the type and origin of metastatic
tumors is an important and potentially challenging
area in pathology. The site of origin is best determined by
clinical information and careful gross and routine histo-
logic evaluation.

correlating clinical and pathologic findings; however, in the SCREENING MARKERS FOR LINEAGE DETERMINATION
absence of a clinically known or suspected primary site, The first step in the evaluation of a metastatic tumor is
morphologic and immunohistochemical evaluations are the determination of tumor lineage (eg, epithelial, mesen-
key to determining the tumor lineage and origin.1 While chymal, melanocytic). Markers for lineage determination
routine microscopy may reveal characteristics that are should include a panel with expected positive and
diagnostic or suggestive of the lineage and/or origin (eg, negative staining in the different lineages under consid-
mucin, melanin, keratin, clear cell change, bile production), eration. For example, to confirm the diagnosis of
absence of morphologically distinctive features often metastatic carcinoma, a reasonable panel may consist of
necessitates the use of immunohistochemistry, particularly epithelial markers such as keratins (expected positive) and
in poorly differentiated malignancies. Even if a basic tumor melanocytic markers such as S100 and HMB-45 (expected
lineage is apparent on routine hematoxylin-eosin stain, negative).
confirmation of a site of origin (eg, lung, colon) may be
clinically important. Tumor characterization is often Epithelial Markers
performed on limited tissue samples obtained by cytologic Markers useful in confirming epithelial differentiation
specimens or core biopsies, underscoring the need for a include low-molecular-weight cytokeratins recognized by
strategic approach to use of immunohistochemistry.2 CAM 5.2 and 35BH11 and broad spectrum cytokeratins
This review outlines the use of immunohistochemistry (pankeratin) recognized by AE1/AE3 antibody. Cytoker-
in the diagnosis of metastatic tumors, both in the context atin (CK) expression may sometimes be seen in none-
of confirming a clinically suspected site of origin as well as pithelial tumors such as melanomas and sarcomas, and
a tumor of unknown origin. It includes review of relevant CK alone does not distinguish a carcinoma from meso-
current markers that may be used and of differential thelioma.3,4 This underscores the utility of a panel of
diagnostic considerations based on presence or absence of immunostains. Conversely, absence of CK does not
staining. It must be emphasized that no marker is entirely always exclude a carcinoma; for example, adrenal cortical
specific; thus, use of a carefully constructed panel of carcinomas are often negative for CK, and hepatocellular
markers is important. Immunohistochemistry and other carcinomas (HCCs) are often negative for pankeratin.
ancillary techniques should not diminish the role of Epithelial membrane antigen (EMA) may be used in
conjunction with keratins; however, it is not specific to
Accepted for publication September 3, 2009. epithelial differentiation and may be expressed in normal
From the Department of Pathology, Mayo Clinic Florida, Jacksonville, and neoplastic hematolymphoid cells including plasma
Florida. cells and anaplastic large cell lymphomas.5 Epithelial
The author has no relevant financial interest in the products or membrane antigen is usually absent in medullary thyroid
companies described in this article.
Reprints: Murli Krishna, MD, Department of Pathology, Mayo Clinic carcinoma and adrenal cortical carcinoma. MOC-31 stains
Florida, 4500 San Pablo Road, Jacksonville, FL 32224 (e-mail: krishna. most adenocarcinomas, and CK5/6 stains most squamous
murli@mayo.edu). cell carcinomas and mesotheliomas.
Arch Pathol Lab Med—Vol 134, February 2010 Metastatic Neoplasms, Immunohistochemistry—Krishna 207

CD43. MOC-31. CD30. CK5/6. CD3.25–27 Among germ cell tumors. embryonal carci- Mesothelioma Markers nomas. Melan.22 of CK7. thrombomodu. Ber-EP4.30 CD30 stains most using a panel of markers for both tumor types. although staining may be patchy. and specific for melanomas and can also be seen in some variably in choriocarcinomas. DETERMINATION OF ORGAN OR TISSUE OF ORIGIN frequently expressed (. February 2010 Metastatic Neoplasms. or microphthalmia transcription carcinomas. thyroid transcription factor 1 Table 1 summarizes the key markers for commonly (TTF-1). adrenal cortical tumors. tures. such as HMB-45. cytoplasmic staining should be present for the staining including serous carcinomas.11–15 Compared to S100.95%) seminomas and and metastatic melanomas (. site (Table 1). Placental alkaline phospha- mesenchymal and epithelial tumors.or organ-specific markers can be used in an than 75% of epithelial mesotheliomas but are frequently attempt to determine or suggest the origin. D2-40.8. Other positive markers that can encouraged.21. the latter produced by stain perivascular epithelioid cell tumors (PEComas). also stains adrenal cortical neoplasms and other steroid.18 cytiotrophoblastic cells in seminomas.3. to determine whether an be used for mesothelioma include HBME-1. For example.80%) in epithelial and sarcomatoid FOR METASTATIC CARCINOMAS subtypes. and desmoplas. it is important to exclude other lineages by incorporating Markers for Germ Cell Tumors appropriate markers in the panel together with vimentin. B72. Rare examples of part of a panel to distinguish between HCC and a 208 Arch Pathol Lab Med—Vol 134. and is therefore not specific result to be interpreted as positive. hepatocellular carcino- marker for hematolymphoid neoplasms. and it is also expressed in melano.16 Melan-A germ cell tumors identifies yolk sac differentiation. Calretinin is a sensitive marker. CD30. tyrosinase. While vimentin could be used include terminal deoxynucleotidyl trans- has been used to support a mesenchymal lineage in ferase. hence.28 of melanoma. There are no embryonal carcinomas and can be used as part of a panel consensus-based guidelines on the choice of markers. CD21.27. These encountered carcinomas and mesothelioma. and CD15 (Leu-M1). and AE1/AE3 may be used as and specificity greater than 95%. a combination lin. most yolk sac tumors. markers have a high specificity for adenocarcinomas relative to mesotheliomas but may also variably stain Cytokeratin Profile squamous cell carcinomas. of markers to distinguish metastatic embryonal carcinoma Positive markers that are useful for mesothelioma but not from somatic carcinoma. Other Determination of site of origin of carcinomas is often tumor types may also be immunoreactive for calretinin. for metastatic tumors of ovarian serous carcinomas. adenocarcinoma is of lung or colonic origin. of patients. useful marker for yolk sac tumors and hepatocellular A/MART-1.17 Melan-A and HMB-45 commonly composed of a and b subunits. to confirm mesenchymal differentiation.24 Subclassification of metastatic hematolymphoid mas.31 entirely specific include calretinin. and CDX-2 markers is likely to Markers for adenocarcinoma include carcinoembryonic establish a higher degree of certainty than TTF-1 alone. S100 is the most sensitive screening marker for primary it is expressed in nearly all (.95%). S100 should be combined with 1 or more a-Fetoprotein is an oncofetal glycoprotein that is a markers with higher specificity. with syncytiotrophoblasts. To confirm the presence for germ cell tumors. TTF-1. Mesenchymal Markers undifferentiated or neuroendocrine tumors have been There is no reliable positive screening marker for reported to be positive for CD45. antigen (CEA). S100 is not embryonal carcinomas. Placental alkaline phosphatase is a membrane-bound Melanoma Markers isoenzyme that is produced by placental syncytiotropho- blasts and many neoplasms. Other markers that are useful include OCT3/4 and Distinguishing mesothelioma from metastatic adenocar. possible and necessary for adequate clinical management including sex cord–stromal tumors. CK20. Most yolk sac tumors are positive with this factor protein. depending on the morphologic fea- and mesothelioma. the use of a panel of markers is strongly tic small round cell tumors. with a sensitivity ma is commonly negative. Immunohistochemistry—Krishna . OCT3/4 is a sensitive and specific marker for cinoma is important and can be successfully achieved by seminoma and embryonal carcinoma. unknown origin.19 Staining is both nuclear and cytoplasmic.20 Cytokeratin 5/6 also or organ-specific’’ markers may variably react with other stains most squamous cell carcinomas. Human chorionic gonadotropin is a glycoprotein producing tumors. however. and positivity in mixed 10% of desmoplastic/spindle cell melanomas. and yolk sac tumors.19 Cytokeratin 5/6 and WT1 both stain more of tissue.10 Both nuclear and tase is also expressed in some nongerm cell carcinomas. Additional markers that confirming mesenchymal differentiation. it is coexpressed with keratins in some carcinomas myeloperoxidase. and WT1 stains most tumor types also. Wilms tumors. Most ‘‘tumor absent in sarcomatoid mesotheliomas. After a metastasis is determined to be a and a minority of adenocarcinomas and squamous cell carcinoma on the basis of screening immunostains. or CD23 and tumors. these markers are less marker. a panel carcinomas. and both CD15 and TTF-1 have and is often used as part of a panel to establish a primary lower sensitivity compared to the other markers.23. and podoplanin.6. mesothelin. malignancies is beyond the scope of this review.7 Therefore.27 Pure semino- sensitive for the diagnosis of melanomas and stain less than mas are negative for a-fetoprotein. AE1/AE3 Leukocyte common antigen (CD45) is a useful screening stains most carcinomas. and Wilms tumor gene product (WT1). Cytokeratins 7 and 19 may be used to distinguish between cholangiocarcinoma (CK7+/CK19+) Hematolymphoid Markers and hepatocellular carcinoma (CK72/CK192).19 Thyroid transcription factor 1 A combination of CK7 and CK20 has been shown to is highly specific for adenocarcinoma of lung if thyroid provide discrimination between subsets of carcinomas carcinoma is excluded. CD20.29 It is therefore a useful marker for less frequent staining for tyrosinase and microphthalmia choriocarcinoma and also identifies multinucleated syn- transcription factor protein.9 However.

Ovarian serous carcinoma WT1+. calretinin+. follicular cell–derived tumors and medullary carcino- papillary) mas. Thyr. Anaplastic thyroid carcinomas are usually negative for both markers CK72/CK20+ but commonly coexpress keratin and vimentin. It is expressed by CK7 /CK20 most adenocarcinomas (72%). RCC. large cell neuroendocrine Urothelial carcinoma Uroplakin+. CK5/6+ bryonic antigen. GCDFP. CEA2 ity is also maintained in these tumors at metastatic sites. A reasonable panel to confirm (subset) metastatic MTC would be chromogranin. or when CEA2. they CEA2. p63+. synaptophysin. and thus are less helpful in the Gastric adenocarcinoma setting of metastases. thyroglobulin. + + and diencephalon during embryogenesis. Thyr2. carcinoembryonic antigen. mesothelin+. ring cell carcinomas. Chr. which stains most pulmonary adenocarcinomas. EMA2 are not specific to MTC and may also stain other neuroendocrine tumors. Hep Par 1 is not metastatic carcinoma. Thyroid transcription factor 1 is also a useful marker for CDX-2+/2. carcinomas (75%). CD10+. CA19-9+. chromogranin. respectively. MOC-31+. Syn+ (medullary) lung origin. Cytokeratin 5/6 is a useful marker entirely specific for hepatocyte differentiation and may for squamous cell carcinomas. being expressed in more than 90% of Thyroid carcinoma TTF-1+. renal carcinoma marker. cytokeratin. and calcitonin (Figure 2. CD10+ calcitonin and calcitonin gene–related peptide mRNA can (canalicular). carcinomas from other sites. calcitonin staining may be patchy in medullary carcinomas CEA2. WT1. GCDFP+.33 (subset) Other markers for lung primary tumors include napsin Cholangiocarcinoma (subset) A. Expression is particularly strong and diffuse in well-differentiated HCC but de- creases in higher-grade tumors. stain small cell carcinomas from other sites. CK202 Markers for Thyroid Carcinomas Breast carcinoma ER/PR+.36 Although highly specific. (canalicular). synapto. Syn+. CK7/20 Profile and Other Relevant Markers Markers for Lung Carcinoma for Select Carcinomas and Mesothelioma Thyroid transcription factor 1 is a nuclear transcription CK7/20 Profile and Tumors Markers and Immunoreactivity factor that regulates gene expression in the thyroid. CK. Chr+.34 Cholangiocarcinoma CEA+. associated with familial MTC.38 Carcinoem- CK192 Squamous cell carcinoma p63+. However. while follicular and papillary Melan-A+. vimentin+. A through D). and a CK7+/CK202 novel marker. Abbreviations: CC. CEA2 staining more than 95% of these tumors. Calcitonin+. Ber. Hepatocyte paraffin 1 (Hep Par 1) stains a cytoplasmic prostate-specific antigen. urinary bladder. It CK72/CK202 can also be used to evaluate for C-cell hyperplasia Prostate adenocarcinoma PSA+. mesothelin+. Thyroglobulin is a marker that is highly sensitive and Mammaglobin+. ES1. and rarely. widely used. thyroid transcription factor 1. pCEA. epithelioid mesotheliomas. A and B). therefore a reliable marker for thyroid differentiation 40+. be demonstrated by in situ hybridization. expressed by most MTCs. pCEA+ In tumors with no staining and still suspected to be MTC. CEA+. CEA+ specific for follicular and papillary thyroid carcinomas.32 While most pulmonary small Ovarian mucinous carcinoma CDX-2+/2 cell carcinomas are positive for this marker. ation. PSA. Immunoreactiv- Endometrial adenocarcinoma Vimentin+. Chr+. CK5/6+ (. Hep Par 1. TTF-1 may also Adenocarcinoma of bladder Thrombomodulin+. also be seen in other carcinomas. carcinomas are negative for these markers. RCC+. epithelial membrane antigen. such as gastric signet and urothelial carcinomas. TTF-1 also stains carcinomas of TTF-1+.32 These markers are currently not Lung adenocarcinoma TTF-1+. MOC-312. ER/ PR. CEA2. CK5/62 Lung small cell carcinoma TTF-1+. D2. Syn. cytokeratin stains should always be combined with Canalicular staining with polyclonal CEA (pCEA) can more specific markers if available. Chr+. carcinoma (Figure 3. Poorly differen- EP42. including those CDX-2+/2 Gastric adenocarcinoma arising from prostate. EMA+ and 5% of these tumors may be negative for this marker. It is Mesothelioma Calretinin+. TTF-1. in 7% and adenocarcinoma CDX-2+/2 20% of cases. PAP+. WT1+ when a lung primary tumor can be excluded. Syn+ useful marker for medullary thyroid carcinomas (MTCs). CK19+. antigen and is highly sensitive for hepatocyte differenti- physin. and synaptophysin are also Adrenal cortical carcinoma Inhibin+. and uterine cervix. lungs.37 Hepatocellular carcinoma Hep Par 1+. Squamous cell and large cell Pancreatic ductal CEA+. gross cystic disease Markers for Hepatic Carcinomas fluid protein–15. Hep Par 12 thyroid tumors. carcinomas are less frequently positive for TTF-1.35 As described above. and small cell carcinomas of the lung thrombomodulin+. However. be used as a specific marker for the diagnosis of Arch Pathol Lab Med—Vol 134. CK5/62 Renal cell carcinoma (CC) Vimentin+. EMA. CA19-9+.39 sion. Thyr+ (follicular. thus is useful in the diagnosis of hepatocellular Wilms tumor gene product. polyclonal carcinoembryonic antigen. Immunohistochemistry—Krishna 209 . chromogranin. ER/PR+. February 2010 Metastatic Neoplasms. PAP. MOC-312. estrogen and progesterone receptors. Colorectal adenocarcinoma CDX-2+ Calcitonin is a protein secreted by thyroid C cells and is a Merkel cell carcinoma TTF-12. CEA.90%) (Figure 1. prostatic acid phosphatase. hepatocyte paraffin 1. ER/PR+. A and B). Because of overlap in expres. clear cell. TTF-12 tiated (insular) carcinomas are focally and/or weakly Pancreatic carcinoma (subset) Gastric carcinoma (subset) positive for both thyroglobulin and TTF-1. used in conjunction with thyroglobulin. CK5/6+. Table 1. TTF-1.

February 2010 Metastatic Neoplasms. Another marker that is cross-reactivity with biliary glycoprotein I and is demon. calcitonin (C). amphicrine variant. A. 210 Arch Pathol Lab Med—Vol 134. Metastatic adenocarcinoma (hematoxylin-eosin). villin and CD10 also show a ical staining for albumin is difficult to interpret because of Figure 2. B. with signet ring cells (hematoxylin-eosin). confirming pulmonary origin (original magnifications 3200). A. and thyroid transcription factor 1 (D) immunostains are positive (original magnifications 3400). hepatocellular carcinomas.40 Similar to pCEA. Chromogranin (B). specific for hepatocyte differentiation is albumin. This pattern results from canalicular pattern of staining.Figure 1. Metastatic medullary thyroid carcinoma. Thyroid transcription factor 1 immunostain is positive. Immunohistochemistry—Krishna . which is strable in 90% of HCCs and is not seen with monoclonal produced exclusively by hepatocytes. Immunohistochem- CEA.

GCDFP- features and the use of markers that exclude carcinomas 15 has a high (. This can be achieved by and anogenital skin apocrine glands. The utility of this marker. extraintestinal adenocarcinomas including those arising in although both have also been reported in extraprostatic lung. BRST- (such as hepatoid gastric adenocarcinomas) may also be 2).44 Like sites.45 hybridization. axillary of HCC and metastatic carcinoma. and seminal fluid. A specific marker for cholangiocarcinoma is currently milk.23. the abundance of this protein in the serum. B. metastatic prostatic carcinomas.50 A combination of PSA and PAP detects most nomas. Arrows indicate bile production. Therefore.46. is a glyco- positive for these markers. Hepatocyte paraffin 1 immunostain is positive (original magnifications 3400). staining may also be seen in a minority of gastrointestinal and extragastrointestinal neuroendocrine tumors and is Markers of Prostatic Carcinoma therefore less specific in this setting than it is for Prostate-specific antigen (PSA) and prostatic acid adenocarcinomas. Arch Pathol Lab Med—Vol 134.53 While a- specific marker is not currently available for pancreatic methylacyl coenzyme A racemase is useful for the ductal adenocarcinoma. Both canalicular pCEA and albumin are more specific for HCC than Hep Par 1. Immunohistochemistry—Krishna 211 .40 specificity for prostate carcinoma and better sensitivity for As with primary hepatobiliary adenocarcinomas. villin may also stain HCC with a canalicular marker that is less widely used but demonstrates high pattern. Estrogen and progesterone receptors are not specific to testinal carcinomas that are frequently positive for CDX-2 breast and cannot be used as primary markers to support include urachal adenocarcinomas arising in the urinary evidence of a breast primary tumor. but like the latter. marker for gastrointestinal tract adenocarcinomas and is Mammaglobin is a marker that is overexpressed in 48% expressed in most (. a higher-grade carcinomas than PSA and PAP. endometrium. esophagus. kidney. also known as prolactin-inducing protein. however. February 2010 Metastatic Neoplasms. carcinomas. specific than GCDFP-15 for diagnosis of a breast primary sion is also seen in adenocarcinomas arising in the tumor. It is also commonly negative for CEA. It is more sensitive but less adenocarcinomas.95%) colorectal and duodenal to 84% of breast carcinomas. unlike albumin mRNA can be demonstrated by using in situ ductal adenocarcinomas.49 stomach. and does not appear to be decreased in metasta. with nuclear staining. is somewhat limited by a lower Markers for Gastrointestinal Carcinomas (50%–74%) sensitivity. it is not useful as the pancreas can be confirmed with stains for pancreatic a specific marker for prostatic carcinoma. and a diagnosis is established by exclusion apocrine features including those present in breast. but may be used in bladder and ovarian mucinous carcinomas. Markers for Breast Carcinoma tumors arising at other sites with hepatoid differentiation Gross cystic disease fluid protein 15 (GCDFP-15. salivary glands. and bladder.to intermediate- of the intestine and proximal renal tubular epithelium. as it is expressed enzymes such as trypsin. Extrain.23 The specificity of villin is limited by its expression in is more specific as a marker for prostate than PAP.52 Prostate-specific membrane antigen is another pCEA. Metastatic hepatocellular carcinoma (A. elastase. Prostate-specific antigen ses. Essentially. Variable expres. and in many normal tissues and nonprostatic tumors. all low. however. and the presence of appropriate clinical and radiographic Paget disease of skin.Figure 3.47 It is expressed in cells with not available. It is grade prostatic adenocarcinomas stain for both markers. A.95%) specificity for breast primary tumor if from other sites (eg.43 phosphatase (PAP) are 2 commonly used markers for Villin is a cytoskeletal protein associated with microvilli prostatic carcinoma. absence of staining does CDX-2 is a nuclear transcription factor that is used as a not exclude a breast primary tumor. and biliary tract. The rare acinar cell carcinoma of diagnosis of carcinoma in the prostate.48 For a metastatic carcinoma. pancreas. the other mentioned sites are clinically excluded. stains most with reactivity decreasing by 10% to 20% in high-grade (82%–100%) primary and metastatic colonic adenocarci.42 CDX-2 conjunction with GCDFP-15 and mammaglobin. a marker of gastrointestinal adenocarcinomas.51. ovary. lipase.41 protein present in various body fluids including saliva. chymotrypsin. lung and breast). hematoxylin-eosin).

Prostein is a transmembrane protein with a high specific. calponin+. Only a minority of nomas are less frequently positive for this marker. caldesmon+ Melan-A. positive for keratin. CD117 immunostain is positive (original magnifications 3400). MyoD1+.59 Markers for Adrenal Cortical Carcinoma Table 2. Brenner tumors. However.60. is limited protein. staining up to 60% of urothelial carcinomas. Immunohistochemistry—Krishna . however. and calretinin and negative or weakly Pleomorphic Myogenin+. B.1 and prostein. Ib. Gastrointestinal stromal tumor CD117+.56 mesothelioma. cyclin-dependent kinase 4. Melan-A has been desmin+/2. and RCC. FLI1. and 212 Arch Pathol Lab Med—Vol 134.54 Uroplakins (Ia. cytokeratin. testicular germ cells and lobular carcinoma of breast. A monoclonal Markers for Renal Cell Carcinoma antibody for uroplakin III is highly specific for urothelial Renal cell carcinoma (RCC) marker antibody is directed differentiation and expressed in urothelial carcinomas and against a normal proximal tubular brush border glyco. inhibin. II. Inhibin A Malignant peripheral nerve S100+/2 identifies steroid-producing cells. but the sensitivity decreases in high-grade carcinomas at primary sites. Potential future markers for prostatic carcinoma include Renal cell carcinomas are also commonly positive for NKX3. hepatocellular carcinoma. smooth muscle actin. ovarian granulosa cell tumor.Figure 4. desmin+. ER/PR+ with steroid-producing cells of the adrenal cortex. S100+/2 primarily used in the diagnosis of melanoma but also reacts Endometrial stromal sarcoma CD10+. CK+ (epithelial component). and III) are transmembrane proteins that are specific to urothelial cells. endothelial tumors. EMA. markers are used. NKX3. overlapping morphologic and staining characteristics.57 Use of this marker. ACCs show a Sarcoma Markers and Immunoreactivity relatively specific immunoprofile when a combination of Leiomyosarcoma SMA+. A. ER/PR.61 Adrenal cortical carcinomas may be rhabdomyosarcoma myoglobin+. Friend leukemia virus integration 1. TUMORS OF THE FEMALE GENITAL TRACT a Carcinoma and melanoma should be excluded with appropriate Carcinomas arising in the female genital tract have markers. estrogen and progesterone recep- tors. desmin+/2 positive for synaptophysin but are negative for chromogra- Angiosarcoma CD31+. and a marker for papillary RCC. factor VIII+. SMA+/2. February 2010 Metastatic Neoplasms. sarcomatoid renal cell carcinomas are positive for RCC Thrombomodulin is a marker that is expressed by most marker. mesothelioma and ovarian sex cord–stromal tumors. a-methylacyl coenzyme A racemase is by squamous cell carcinomas. however. When included as part of a panel.61 epithelial membrane antigen. SMA. and testicular Malignant fibrous histiocytoma No specific marker Sertoli-Leydig cell tumor. CD34+. it lacks specificity and Staining has also been reported in some breast therefore should not be used alone as confirmatory carcinomas and embryonal carcinoma. Markers for Urothelial Carcinoma ity for benign and malignant prostatic epithelium. It stains most clear cell and papillary renal cell by low sensitivity.1 is a nuclear marker that CD10 and vimentin and negative for CEA. nin. Diagnostically Relevant Markers for A specific marker for adrenal cortical carcinoma (ACC) is Select Sarcomasa not commercially available. and thus is a sensitive sheath tumor Pleomorphic liposarcoma MDM2/CDK4+ marker for ACC.55 Among the evidence for urothelial differentiation. such as pheochromocytoma. these markers are FLI1+ effective in distinguishing ACC from the usual differential Synovial sarcoma EMA+. Calretinin is a calcium-binding Fibrosarcoma No specific marker protein that is also commonly used as a marker for Abbreviations: CDK4. Metastatic urothelial carci- carcinomas and metastatic carcinomas.23 urothelial carcinomas. CK. such as conjunction with other markers. It is also expressed subtypes of RCC. Metastatic gastrointestinal stromal tumor (hematoxylin-eosin). They are commonly positive for vimentin.58. however. CD99+ diagnostic considerations. It markers are not specific and should always be used in may also be expressed in some other tissues. these more frequently stains high-grade carcinoma than PSA.

February 2010 Metastatic Neoplasms. Small cell carcinoma (A) is positive for TTF-1 (B) and negative for CK20 (C).Figure 5. Merkel cell carcinoma (D) is negative for TTF-1(E) and positive for CK20. A combi. surrogate marker for high-risk human papillomavirus Arch Pathol Lab Med—Vol 134. and differential expression of markers progesterone receptors.62 Use of p16 as a germ cell tumors are discussed separately in this review. in contrast to endometrial adeno- may suggest a site of origin or tumor type. with a paranuclear dotlike accentuation (F) (original magnifications 3400). Endocervical adenocarcinomas are usually positive for nation of markers may be used to suggest origin in the CEA but negative for vimentin and for estrogen and female genital tract. Immunohistochemistry—Krishna 213 . reliable site-specific markers are not available. Metastatic pulmonary small cell carcinoma and Merkel cell carcinoma can be distinguished with a panel including thyroid transcription factor 1 (TTF-1) and CK20 immunostains. Markers for carcinomas of endometrioid type.

CD452. synaptophysin. S1002. J Clin Pathol. WT1. 5. Watanabe S.a Chr+. desmin+. A through F).25(1):51–57. CD452. Clarkson KS. Lancet. Application of immunohistochemistry to diagnosis of malignant mesothelioma. February 2010 Metastatic Neoplasms. HMB-45 and A103 (MART-1. also stain adrenal cortical tumors. 1981. EMA. but usually not breast. Nakajima T. 1. Chr+. Sturdgess IC.66 Inhibin and calretinin are markers Churchill Livingstone Elsevier. tumors: an immunohistochemical analysis on biopsies. novel T311 antibody (anti-tyrosinase) with S100.6(1):12–18. and as mentioned above. Melan-A/MART-1 expression in various melanocytic lesions and non-melanocytic soft tissue tumors. desmoplastic CD99+. terminal deoxynucleotidyl transferase. Positive in most pulmonary and some nonpulmonary small cell carcinomas. Microphthalmia transcription factor expression in cutaneous benign and malignant melanocytic and attempt to define the subtype. and neuroblastoma. pleomorphic. Weilbaecher KN. a new melanocytic differentiation round cell tumor. Immunohistochemistry in the diagnosis of melanocytic ticobiliary carcinomas. Grant JJ.70.15(4):210–207. Table 3.22(1):57–63. Gaynor R.57(4): versial. Wilms tumor gene product. such as therapy with 17. J Cutan Pathol. Histopathology. Am J Surg Pathol. Morton D. Rhabdomyosarcoma CK2. and 6. gonadotropin.1(8441):1302–1305. Hammar SP.54(3):196–200. characteristics of a select group of sarcomas are summa- 20. Sanders DS. followed by an 15. Characterization of type and origin of metastatic tumors plastic small round cell tumor. Undifferentiated infection to prove endocervical origin has been contro. with emphasis on reactivity with key guishing between mesothelioma and renal cell carcinoma: a comparative study. myogenin+. markers. References b Lymphoblastic lymphomas are commonly Tdt+ and may be CD452. Comparison of immunohistochemical currently available markers in all cases.64 embedded tissues. Melanoma marker in high grade. gastrointestinal tract. 1985. 214 Arch Pathol Lab Med—Vol 134. 18. Miettinen M. Subtyping will require a nonmelanocytic tumors. WT1+ tumor. Smoller BR. Diagnostic Immunohistochemistry. Friend markers. TTF-1+. 1993. desmin2. theliomas and therefore should be used as part of a panel 10. Typical immunoprofiles of these tumors are summarized MyoD1+ in Table 3. CD45+. 1982.72 Abbreviations: CK. TdT+/2b the use of a panel of markers (Figure 5. neoplasms. Wick MR. 2001. Gown AM.67 It also commonly stains meso.35(6):697–710. Ordonez NG.1(8225):869–871.2(2):371–383. and include angiomyolipoma of the liver and kidney: a comparative study. and available therapeutic options. clinical and radiographic findings and careful routine a morphologic evaluation. Vege DS. Ishaq KG. Vogel AM. cytokeratin.68. confirmed with positive staining for human chorionic 12. Am J (Figure 4. 1992. Distinction between high-grade endometrioid and serous 4. Orosz Z. 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