Markeri IHC in diagnosticul tumorilor epiteliale si conjunctive

BCL-2 Reacts with the BCL2 oncoprotein encoded by a gene involved in the t(14;18) chromosomal translocation; Bcl-2 ("B-cell lymphoma/leukaemia-2"), which acts as an inhibitor of apoptosis, was originally discovered as a proto-oncogene in low-grade B-cell lymphomas. In the adult organism Bcl-2 expression is generally confined to cells that are rapidly dividing and differentiating. In lymphocytes, Bcl-2 is highly expressed in T-cells, pro-B cells and mature B-cells (where lifespan is extended) while downregulated in germinal center B-cells (where apoptosis forms part of the developmental pathway in order to select only cells producing antibodies with high avidity) Overexpression of Bcl-2 is common in many types of cancer, including non-Hodgkin's lymphoma and leukaemias, adenocarcinomas (e.g., prostate, colorectum, stomach, and lung), squamous cell carcinoma, small cell carcinoma, neuroblastoma and various sarcomas. Among the latter, strong Bcl-2 positivity has particularly been demonstrated in gastrointestinal stromal tumor, solitary fibrous tumor, and synovial sarcoma, while fibromatosis and "malignant fibrous histiocytoma" are usually negative. Among malignant lymphomas, Bcl-2 protein overexpression is often caused by chromosomal translocation (14;18) with Bcl-2 gene rearrangement. This is especially seen in follicular lymphoma. bcl-2 is expressed in almost 100% of the grade I lymphomas, in >80% of the grade II and in 75% of the grade III lymphomas. Follicular lymphoma of the skin is often bcl-2 negative

Bcl-2 in ggl limfatic

Bcl-2 in SLL

Bcl-2 in GIST

 BCL-6:
encodes a 706 amino acid nuclear protein (repressor of p53), is rearranged in about 30% of diffuse large Bcell lymphomas, and is expressed predominantly in normal germinal center B cells and related lymphomas; The antibody gives a strong nuclear labeling of BCL6 protein in follicular lymphomas, diffuse large B-cell lymphomas, Burkitt's lymphomas, and nodular, lymphocyte-predominance Hodgkin's disease.

Bcl-6 in ggl limf

Bcl-6 in limfom folicular

 ALK (anaplastic large cell lymphoma kinase)

is a protein, 200 kDa, a transmembrane receptor tyrosin kinase, presumably receptor for the growth factor pleiotrophin. In normal tissues, ALK protein is expressed by only few cells within the developing and mature nervous system (glial cells, neurons, endothelial cells and pericytes); ALK gene is translocated in ALCL, but also in inflammatory myofibroblastic tumor and in diffuse large B cell lymphoma (DLBCL).

 ALCL

ALK in ALCL

CD5The CD5 antigen is a 67 kDa transmembrane glycoprotein expressed on the surface of practically all mature human T-cells (about 10% of CD4+ T-cells being CD5 negative). In immature (CD34+) Tcells, CD5 is weakly expressed, the intensity of expression increasing with maturation. CD5 is also expressed in a small subset of normal human B-cells (20% of B-cells in the peripheral blood, scattered cells in the lymph node mantle zone). The CD5+ cells are probably involved in B-T interaction and their ligand is CD72 which is expressed on all B cells. It appears that CD5+ B-cells on activation primarily produce IgM. They also produce more autoantibodies than normal CD5 negative B-cells. Thus, the CD5+ B-cell population is expanded in rheumatoid arthritis and systemic lupus erythematosus. Neoplasms CD5 is detected in most T-cell lymphomas and leukaemias, including 75% of peripheral T-cell lymphomas and 85% of T-ALL cases. Lack of CD5 in the latter signifies a worse prognosis. Among B-cell lymphomas, more explicit CD20+ small-cell lymphomas, small lymphocytic lymphoma and mantle cell lymphoma are CD5+, whereas follicular lymphoma, marginal zone lymphoma and lymphoplasmacytoid lymphoma are CD5 negative. CD5 is detected in 5% of acute myeloid leukaemias. CD5 has been detected in some cases of thymic carcinoma and atypical thymoma. Other carcinomas are CD5 negative.

CD5 in normal T cells

CD5 in MZL

 CD10
CD10 is a single-chain cell surface glycoprotein, 90-110 kDa, also designated common acute lymhoblastic leukaemia antigen (CALLA) CD10 is present on the cell surface of bone marrow stem cells and myelopoietic cells (including neutrophils), follicular centre cells, few mature Blymphocytes; CD10 is also found in enterocytes in the upper part of the intestinal tract (brush border,in liver (bile canaliculi), kidney (glomerular and proximal tubular cells), pulmonary alveolar cells, myoepithelial cells of breast. CD10 is expressed in most cases of precursor B lymphoblastic leukaemia/lymphoma, follicular lymphoma, and Burkitt lymphoma. CD10 is found in some cases of diffuse large B-cell lymphoma, and mantle cell lymphoma; small lymphocytic lymphoma, marginal zone lymphoma, and lymphoplasmacytoid lymphoma are negative. CD10 is found in almost all cases of endometrial stromal sarcoma, in most cases of hepatocellular carcinoma (distinct canalicular pattern), renal cell carcinoma (clear cell and papillary types, but not chromophobic type)

 Limfom folicular

Carcinom renal

 CD15
a haematopoietic differentiation antigen expressed on most terminally differentiated myeloid cells including granulocytes, eosinophils, mast cells, monocytes/macrophages, and Langerhans' cells. The positivity for CD15 is characteristic of Hodgkins cells in classical Hodgkins disease (HD); It is expressed in great majority of nodular sclerosis (NS), mixed cellularity (MC), lymphocyte depletion (LD) and lymphocyte rich-classical HD cases, but not in malignant cells of lymphocyte predominance (LP) HD (L&H cells, popcorn cells)

 CD15 in HD

 CD20
CD20 functions as a Ca2+-permeable cation channel, involved in the regulation of B-cell activation, proliferation and differentiation. CD20 appears on the surface of the pre-B lymphocyte between the time of light chain rearrangement and expression of intact surface immunoglobulin and is lost just before terminal B-cell differentiation into plasma cells. CD20 is expressed in the large majority of cases of B-cell leukaemia/lymphoma. Early stage precursor B lymphoblastic leukaemia/lymphoma may be negative, and chronic lymphocytic leukaemia/small cell lymphoma may show a weak staining. Plasma cell neoplasms are as a rule CD20 negative. However, a special type of CD20 positive myelomas account for 10-20% of the cases.

 CD20 normal

CD20 in CLL

 CD23
- low affinity IgE receptor, Leu-20, FceRII; - In humans, main cellular expression of CD23 is found in B-lymphocytes (strong expression in activated germinal center B-cells, weaker staining of resting mantle zone B-cells), monocytes, follicular dendritic cells (FDCs) predominately in the apical light zone of the germinal center; - CD23 is typically expressed in chronic lymphocytic leukemia (CLL) - the strongest expression is characteristically present in proliferation centers. - sometimes in follicular lymphoma, - rarely in marginal zone and lymphoplasmacytic lymphoma, - not in mantle cell lymphoma. - !! CD23 is also frequently used to demonstrate benign follicular dendritic cells in the background of follicular lymphoma

 CD23 in CLL

 CD30
CD30 is a member of the tumor necrosis factor receptor (TNF-R) superfamily; CD30 is found in activated B lymphocytes, plasma cells, T lymphocytes, NK cells, monocytes; CD30 is expressed in classical Hodgkins disease (cHD), anaplastic large cell lymphoma (ALCL), anaplastic variant of diffuse large B-cell lymphoma (av-DLBCL), and CD30 positive cutaneous lymphoproliferative disorder. Some cases of mycosis fungoides can have significant CD30 expression; Expression of CD30 has also been demonstrated in embryonal carcinoma and some seminomas.

CD30 in normal activated B cells

CD 30 in HD

CD30 in carcinom embrionar

 CD45
CD45 is a family of single chain transmembrane glycoproteins; CD45 is expressed on cells of the human haematopoietic lineage with the exception of mature red cells. CD45 is lost in megakaryocytes and plasma cells. It is not detected on differentiated cells of other tissues. CD45 has intrinsic tyrosine phosphatase activity and is essential for development and effector functions, playing an important role in signal transduction, inhibition or upregulation of various immunological functions. CD45 is detected in the large majority of haematolymphoid neoplasms, i.e., leukaemias and malignant lymphomas. Overall, about 90% of malignant lymphomas are CD45 positive. The proportion is lower among precursor B-cell neoplasms (80% of B-ALL) and large cell anaplastic lymphomas, and only about 10% of plasmacytic neoplasms are positive. In Hodgkin lymphoma, the L&H cells in the LP-type are always positive, while Reed-Sternberg cells in classic Hodgkin lymphoma are negative or only show a faint cytoplasmic staining.

 CD68:
antibodies detect a glycoprotein with a molecular weight of approximately 110 kD, localized in the cytoplasm, often with relation to lysosomes. Positive staining is seen in different types of macrophages of monocyte lineage and antibodies also reacts with myeloid precursor cells in the bone marrow. Expressed in fibrous-histiocytic tumours and Langerhans cell histiocytosis, subtypes of myeloid leukaemia (depending on the Ab used), some epithelial neoplasms, epithelioid cells of some malignant melanomas

 CD68 in celule Kupffer

 CD31
transmembrane glycoprotein, 130-140 kDa, also designated platelet-endothelium cell adhesion molecule (PECAM-1), belonging to the immunoglobulin super family. CD31 is strongly expressed in endothelial cells and weakly expressed in megakaryocytes, platelets, occasional plasma cells, lymphocytes (especially marginal zone B-cells, peripheral T-cells) and neutrophils. CD31 is expressed in the vast majority of all types of vascular neoplasms, such as hemangioendothelioma, angiofibroma, hemangioma, and angiosarcoma. CD 31 is also expressed in most cases of Kaposi sarcoma

 CD31 in hemangioendoteliom infiltrativ in intestin

 CD34
CD34 (also named myeloid progenitor cell antigen) is a heavily glycosylated type I transmembrane protein, 110 kDa; role in adhesion; CD34 is found in most endothelia, expressed on the luminal surface and membrane processes interdigitating between endothelial cells, but is absent from large veins and arteries. CD34 is detected in myeloid blasts in myelodysplastic syndrome and acute myeloid leukaemia; Also expressed in lymphoblasts in most cases of B-acute lymphoblastic leukaemia. The majority of vascular tumours, including haemangiosarcoma and Kaposi sarcoma are CD34 positive ; However, only about 30% of the lymphangiomas are CD34 positive. CD34 positivity is seen in most cases of dermatofibrosarcoma protuberans, solitary fibrous tumor, lipoma (particularly spindle cell lipoma) and liposarcoma, gastrointestinal stromal tumor (strong positivity in about 80% of the cases, which are also CD117 positive), and a varying proportion of meningioma.

CD34 in endothelial cells and precursor cells in BM

CD34 in endothelial cells in placenta

 FVIII related antigen

Factor VIII-related antigen (FVIII) is the von Willebrand factor, a large protein, built up by more than 2000 aminoacids. This is tissue-specific and present only in endothelial cells, megakaryocytes and thrombocytes FVIII is expressed in most tumours with endothelial differentiation. In angiosarcoma, Kaposi sarcoma and Dabska tumour, the antigen can be demonstrated in a majority of, but not not all, cases Due to the specificity of the antigen, rather than the sensitivity, FVIII is often a part of the panel for the identification of benign and malignant vascular neoplasms, along with CD31 and CD34.

FVIII in hemangioendoteliom

 CD99
a 32kDa transmembrane glycoprotein, also known as MIC2 (M = monoclonal; IC = Imperial Cancer Research Fund; 2 = order of discovery)- cell adhesion role CD99 has been detected in almost all cases of Ewing's sarcoma/pPNET, solitary fibrous tumour, meningioma and T-cell acute lymphoblastic lymphoma/leukaemia. Most sex cord-stromal tumours are CD99+ .

 CD99 in sarcom Ewing

CD99 in tumora de granuloasa ovariana

 CD117
CD117 is a 145-160 kDa cell membrane protein encoded by the c-kit protooncogene (chromosome 4q11-12). The protein is a tyrosine kinase growth factor receptor for stem cell factor (SCF); CD117 is expressed in mast cells, melanocytes and interstitial cells of Cajal; The cells (particularly the mast cells) show a strong membrane as well as cytoplasmic staining. CD117 moreover is expressed in various epithelia: breast, sweat glands and salivary glands, renal tubular cells, thyroid follicular cells

The following neoplasms express CD117 in more than 90% of the cases:
Gastrointestinal stromal tumour (GIST) , mast cell neoplasms, malignant melanoma (however, the expression of CD117 is lost during progression and metastasising), seminoma/dysgerminoma and intratubular germ cell neoplasia, endometrial carcinoma, follicular and papillary thyroid carcinoma, Merkel cell carcinoma, cylindroma, malignant glioma, and angiomyolipoma.

 CD117 in GIST

CD117 in seminom

 Cytokeratins
Cytokeratins (CKs) are intermediate filaments. The CK family is a highly complex multigene family of polypeptides, the molecular weight of which ranges from 40 to 68 kDa. Until now, 20 distinct CKs have been revealed (excluding the so-called trichocytic keratins present in hair and nail-forming epithelia only). The classification and numbering (CK1-CK20) is based on the catalogue of Moll et al. Clone AE1/AE3 (AE1 directed to acidic types 9, 10, 13, 14, 15, 16 and 19; AE3 directed to neutral-basic types CK1-8), clone MNF116 (directed to CK5, 6, 8, 17, 19) and clone KL1 (directed to CK2, 5, 6, 8, 10, 18, 19) are broad spectrum cytokeratin antibodies useful for screening and visualisation of epithelial structures Clone 34BE12 (directed to CK1, 5, 10, 14 and an unknown CK subtype) is useful for detection of HMW CKs. Clone CAM 5.2 , directed to LMWCK CK8 and CK7

 P63
p63 protein (p63) is a nuclear protein, a transcription factor. The p63 gene is located at chromosome 3q27-29 and belongs to the p53 gene family. p63 plays a critical role in the growth and development of many epithelial organs. p63 is confined to basal cells of squamous epithelia (including epidermis and hair follicles) and urothelium, as well as basal cells/myoepithelial cells in breast, sweat glands, salivary glands, and prostate p63 is found in the large majority of cases of squamous cell carcinoma (even among low differentiated squamous carcinomas, more than 70% of the cases are positive) as well as adenosquamous carcinoma, urothelial carcinoma, myoepithelial carcinoma, adenoid cystic carcinoma and skin adnexal tumours

 In carcinomas p63 is a very useful marker for squamous, urothelial and myoepithelial differentiation. The same tumours are usually expressing cytokeratin 5. However, p63 often shows a more extended reaction. An important criterion for the diagnosis of prostate adenocarcinoma is the absence of basal cells. As these can be difficult to identify in routine sections, immunohistochemical identification of p63 and cytokeratin 5 may increase the sensitivity and specificity. Since negative staining for high molecular weight cytokeratin (HMW-CK) in atypical prostate glands may not be sufficient for a definitive diagnosis of malignancy, p63 may enhance the ability to diagnose limited prostate cancer. However, p63 should be used in conjunction with HMW-CK and AMACR. A cocktail staining is applicable. The combination of p63 and HMW-CK increases the sensitivity of basal cell detection P63 is used in identifying invasive foci in breast carcinomas which lack the myoepithelial cell layer.

P63 in prostata normala

 CEA
A glycoprotein comp of Ig superfamily (adhesion molecule); In normal adult tissue, CEA is expressed in the apical border and, to a lesser extent in the cytoplasm, of the columnar cells of colon, small intestine, and stomach (surface epithelium, mucous neck cells and weakly in pyloric mucous cells), pancreatic ducts, secretory epithelia of sweat glands, squamous epithelial cells of the tongue, esophagus and uterine cervix, and urothelium. The prostate is negative (apart from urothelium lined secretory ducts). CEA is expressed in epithelial cell membranes and in the cytoplasm of the cells in almost all cases of colorectal adenocarcinoma as well as a high proportion of adenocarcinomas of the salivary glands, esophagus, stomach, biliary tract, pancreas, small intestine, lung, uterine cervix and ovary (mucinous type).

 CEA in colon normal

 Cadherins
Cadherins are a family of calcium-dependent transmembrane cell adhesion glycoproteins. In connecting cells they comprise a part of the zonula adherens and desmosomes. The following tumours are almost always positive: adenocarcinoma of colorectum, stomach, pancreas, prostate, endometrium, uterine cervix, and thyroid. Among ovarian carcinomas, the mucinous type is almost always positive, while varying positivity is seen in the other types. Among breast carcinomas the ductal type (including the tubulolobular subtype) is almost always positive (at least in part of the tumour) while the lobular type is negative in 85 90 %.

E caderina in CDI

 EMA (epithelial membrane antigen)

Epithelial membrane antigen (EMA; MUC1) is a group transmembrane proteins, 40-425 kDa, related to the high molecular weight glycoproteins of human milk fat globule (HMFG). EMA is present in a variety of glandular (secretory) epithelia such as breast, eccrine and apocrine glands, and pancreas, whereas little or no EMA is expressed in the gastrointestinal epithelium, endocervical epithelium, and prostate glands. The immunoreactivity is usually limited to apical cell membranes, but a staining of the Golgi zone may also be seen EMA can be demonstrated in most types of adenocarcinomas derived from secretory epithelia In malignant mesothelioma, EMA is demonstrated mainly in the long microvillous surfaces of the tumour cells with little cytoplasmic labelling Among malignant lymphomas, EMA may be seen in anaplastic large cell lymphoma (50-95%), diffuse large B-cell lymphoma, plasma cell neoplasms (most cases),

EMA in mezoteliom

 Calretinin 32 kDa member of the superfamily of calcium-binding proteins. It is abundantly expressed in central and peripheral neural tissues, particularly in the retina and in the neurons of the sensory pathways it is also expressed in steroid producing cells (adrenal cortical cells, testicular Leydig cells, ovarian theca interna cells), testicular Sertoli cells, rete testis, ovarian surface epithelium, some neuroendocrine cells, breast glands, eccrine sweat glands, hair follicular cells, thymic epithelial cells, endometrial stromal cells, and fat cells Calretinin is also expressed by both normal and neoplastic mesothelial cells; it is an useful marker for the identification of malignant mesotheliomas of the epithelial type and for the differentiation of these malignancies of lung adenocarcinoma In calretinin positive cells, the protein is generally found in both the cytoplasm and nuclei.

 Mezoteliom

 CDX2
Cdx2, a human homeobox gene, encodes a transcription factor, which is involved in proliferation and differentiation of intestinal epithelial cells. The CDX2 protein is widely expressed in intestinal epithelium from the duodenum to the rectum. The majority of colorectal adenocarcinomas, a large part of gastric adenocarcinomas, carcinoids of the GI tract as well as adenocarcinomas of the ovary, urinary bladder and pancreas show CDX2 expression. Antibodies to CDX2 may be useful for identification of both primary and metastatic tumors of the gastrointestinal tract, including carcinoids

 Cromogranin
chromogranins comprise a family of acid calciumbinding glycoproteins closely associated with the matrix of dense-core neurosecretory granules in virtually all neuroendocrine (NE) cells and neurons. Probably, these proteins are involved in packaging and processing of neuropeptides and peptide hormones. Chromogranin A (CGA), 48-75 kDa, 439 amino acids, is the diagnostically most important of these glycoproteins, and probably the major target of the argyrophilic Grimelius staining reaction; Pan- endocrine tumor marker

 Sinaptofizina
SYP is a calcium binding integral-membrane glycoprotein, 38 kDa of presynaptic vesicles in all neurons and corresponding vesicles in all neuroendocrine (NE) cells SYP is detected in virtually all neuronal tumours: Neuroblastoma, ganglioneuroblastoma, ganglioneuroma, ganglioglioma, central neurocytoma, and phaeochromocytoma/paraganglioma. SYP may also be detected in other neural crest derived tumours like oligodendroglioma, astrocytoma and ependymoma. Moreover synaptophysin is detected in NE tumours like pancreatic islet tumours, carcinoid and neuroendocrine carcinoma, small cell carcinoma, medullary thyroid carcinoma, and pituitary and parathyroid adenomas. Also adrenal cortical tumours stain for synaptophysin.

 Syn in carcinoid intestinal

 Actina- clona HHF35

Labels myocardial, skeletal and smooth muscle cells as well as myoepithelial cells. The antibody recognizes rhabdomyosarcomas, leiomyomas and leiomyosarcomas, and also reacts with 'myofibroblasts' in the stroma of certain tumors including many carcinomas Actina - clona 1A4 This antibody labels smooth muscle cells, myofibroblasts and myoepithelial cells, and is useful for the identification of leiomyomas, leiomyosarcomas and pleomorphic adenomas

 Actina- LMS

 Caldesmon
a smooth muscle-specific protein involved in the regulation of smooth muscle contraction.

Calponin
a developmentally regulated protein thought to play a role in the regulation of the thin filamentassociated system of smooth muscle contraction.

 Caldesmon in leiomiom

 Desmin
Desmin is an intermediate filament protein (53 kDa) expressed in all striated muscle cells and most smooth muscle cells; Desmin play no role in contractility but serves to maintain the orientation of actin and myosin filaments and may also play a role in nuclear transcription Desmin is detected in most tumours of myogenic origin, e.g., leiomyosarcoma and rhabdomyosarcoma

 Desmin in normal colon

Desmin in LMS

Desmin in carcinosarcoma

 S100
S100 is a 21kDa highly acidic and water soluble protein first isolated from brain but later shown to be produced by a wide variety of normal and neoplastic cells of mesodermal, neuroectodermal, and epithelial origin. S-100 protein may be found in the cell membranes, cytoplasm and nuclei; S100 (beta protein) is present in glial cells, Schwann cells and satellite cells, melanocytes, myoepithelial cells, some glandular epithelia (breast, kidney), skeletal and heart muscle cells, fat cells and chondrocytes, and follicular dendritic cells. The immunohistochemical evaluation of S-100 (beta) protein expression is important in the diagnosis of undifferentiated malignant tumours of unknown primary origin and should be included in the so-called primary panel. S100 is a very sensitive marker for malignant melanoma of all types, a negative staining is exceedingly rare. Because of its low specificity, other markers should be included in a panel for malignant melanoma, such as vimentin and Melan- A.

Vimentina Vimentin (57 kDa) is the most ubiquituos intermediate filament protein and the first to be expressed during cell differentiation. All primitive cell types express vimentin but in most non-mesenchymal cells it is replaced by other intermediate filament proteins during differentiation. Vimentin is expressed in a wide variety of mesenchymal cell types fibroblasts, endothelial cells etc., and in a number of other cell types derived from mesoderm, e.g., mesothelium and ovarian granulosa cells. However, in non-vascular smooth muscle cells, vimentin is often replaced by desmin. In striated muscle, vimetin is also replaced by desmin. However, during regeneration, vimentin is reexpressed. Cells of the lymfo-haemopoietic system (lymphocytes, macrophages etc.) also express vimentin, sometimes in scarce amounts. Vimentin is also found in mesoderm derived epithelia, e.g. kidney (Bowman capsule), endometrium and ovary (surface epithelium), in myoepithelial cells (breast, salivary and sweat glands), an in thyroid gland epithelium Vimentin is present in many different neoplasms but is particulary expressed in those originated from mesenchymal cells. Sarcomas e.g., fibrosarcoma, malignt fibrous histiocytoma, angiosarcoma, and leio- and rhabdomyosarcoma, as well as lymphomas, malignant melanoma and schwannoma, are virtually always vimentin positive . Mesoderm derived carcinomas like renal cell carcinoma, adrenal cortical carcinoma and adenocarcinomas from endometrium and ovary usually express vimentin. Also thyroid carcinomas are vimentin positive. Any low differentiated or sarcomatoid carcinoma may express some vimentin.

Vimentina in limfocite din amigdala

Vimentina in glanda mamara

 Neurofilamente
NFP is a class 4 intermediate filament protein comprising three heteropolymeric polypeptide units, 70 kda, 160 kda and 200 kDa. NFP is represented in virtually all neurons. NFP can be demonstrated in the large majority of differentiated neuronal tumours: ganglioneuroma, ganglioneuroblastoma, etc., in some cases of primitive neuroectodermal tumour (neuroblastoma etc.,), phaeochromocytoma/paraganglioma, and neuroendocrine tumours like medullary thyroid carcinoma, carcinoid, Merkel cell carcinoma, and small cell carcinoma.

NF in meningiom

NF in neurofibrom (cel Schwann si fibroblaste neg)

 Myo D1
The MyoD1 protein is a 45 kDa nuclear phosphoprotein which induces myogenesis through transcriptional activation of muscle-specific genes; Nuclear expression of MyoD1 is restricted to skeletal muscle tissue and has been demonstrated to be a sensitive marker of myogenic differentiation; The antibody strongly labels the nuclei of myoblasts in developing skeletal muscle tissue, whereas the majority of adult skeletal muscle is negative; MyoD1 immunostaining has been demonstrated in the majority of rhabdomyosarcomas of various histological subtypes.

 Myogenin
Myogenin belongs to a family of regulatory proteins essential for muscle development. Expression of myogenin is restricted to cells of skeletal muscle origin, and appears to be inversely related to the degree of cellular differentiation. The antibody recognizes an epitope located in the amino acid region 138-158 of the myogenin protein. It labels nuclei in the majority of human rhabdomyosarcomas and Wilms' tumors

 Myogenin in rabdomiosarcom

 Cancer antigen 125 (CA125)

is a membrane mucin-like glycoprotein greater than 200 kDa. The specific function is unknown. In foetal tissue, CA125 is expressed in the amnion, coelomic and mullerian epithelium. In adult tissue CA125 is primarily expressed in mesothelial cells and in the luminal surface of epithelial cells of the fallopian tube, endometrium and endocervix. CA125 is expressed in almost all cases of (epithelial) malignant mesothelioma and ovarian serous adenocarcinoma CA125 is also expressed in the majority of primary peritoneal carcinoma and ovarian clear cell and endometrioid adenocarcinomas.

 CA-125 in mezoteliu Ca125 in mezoteliom

CA125 in carcinom ovarian

 AFP (alfa feto protein) a 70 kDa glycoprotein, synthesized by the cells of the embryonic yolk sac, fetal liver and fetal intestinal tract. Expression of AFP has been demonstrated in many hepatocellular carcinomas and in gonadal and extragonadal germ cells tumors, including yolk sac tumors. The antibody may be useful for the identification of non-neoplastic and neoplastic liver diseases, yolk sac tumors and mixed germ cell tumors

 AFP in tumora sac yolk

 Estrogen receptor
Estrogen receptor (ER) belongs to the steroid receptor superfamily of nuclear receptors; ER is mainly expressed in tumours of female sex steroid hormone responsive tissues such as :
the mammary gland, endometrium, and ovary. ER protein is expressed in 60-70% of female breast cancers Other tumours expressing ER are meningiomas, salivary gland tumours, some neuroendocrine tumours, and some colorectal and hepatocellular carcinomas.

 ER in adenoc uterin

ER in sarcom stromal uterin

ER in tumora pancreatica

 Her 2
HER-2 (also called HER-2/neu, c-erbB2, ERBB2 or neu) is a transmembrane receptor tyrosine kinase, which was originally discovered from a rat neuroblastoma cell line (named neu) more than 20 years ago. HER-2 is a proto-oncogene, i.e. its activation causes malignant transformation and increases the malignant potential (cell proliferation, invasiveness etc.) of the cells. In human cancers HER-2 is activated via gene amplification, which is a genomic mutation where a small fragment at chromosome band 17q12-q21 is multiplied in a cell up to 50-100 folds. In tumours, HER-2 is over-expressed in 15-25% of primary breast cancers. Metastases usually have the same amplification status as the primary tumours. HER-2 amplification and over-expression are typical features of hormone receptor negative, rapidly growing histologic grade 2-3 tumours. Of the histologic types, Pagets disease is almost invariably HER-2 positive, whereas only a small minority of lobular and tubular carcinomas shows HER-2 amplification. HER-2 amplification and over-expression can also be found in intestinal type gastric and gastroesophageal carcinomas, ovarian carcinomas, high grade endometrial carcinomas and some salivary duct tumours

AMACR (P504S): - is an enzyme that is involved in bile acid biosynthesis and -oxidation of branched-chain fatty acids. - it is expressed in cells of premalignant highgrade prostatic intraepithelial neoplasia (HGPIN) and prostate adenocarcinoma (1). - In glandular epithelial cells of normal and benign hyperplastic prostates AMACR is present at low or undetectable levels.

AMACR in carcinom prostatic

 Prostate-specific antigen (PSA)

is a 33 kDa protein belonging to the kallikrein family of proteases. It is primarily produced by the prostatic epithelium and the epithelial lining of the periurethal glands. PSA is strongly expressed in both normal and neoplastic prostatic tissue

 PSA in carcinomul de prostata

WT-1
The WT1 gene located at chromosome 11p13 codes for a transcription factor, a DNA-binding nucleoprotein, 52-62 kDa, that plays a role primarily in the development of genitourinary organs. In normal epithelia, nuclear WT1 expression is largely restricted to ovary (surface epithelium and inclusion cysts) and fallopian tube, while WT1 is not found in endometrial or cervical epithelium. As regards nonepithelial cells, nuclear WT1 is found in mesothelium and some submesothelial stromal cell Among epithelial tumours, nuclear WT1 is strongly expressed in ovarian serous carcinoma (97% of the tumours, usually a widespread reaction), peritoneal serous carcinoma, ovarian transitional carcinoma, and about half of ovarian endometrioid carcinoma (grade 2 and 3 but not grade 1). Also metanephric adenoma is positive Among nonepithelial tumours, nuclear WT1 is strongly expressed in the large majority of malignant mesothelioma and sex cord-stromal tumours. Nuclear WT1 has moreover been demonstrated in Wilms' tumour (about 50% of the cases, involving epithelial, stromal and blastemal elements), malignant rhabdoid tumour, adenomatoid tumour, endometrial stromal sarcoma, uterine leiomyosarcoma, mixed mullerian tumour, as well as in some malignant lymphomas (lymphoblastic and Burkitt's lymphoma), and most cases of acute leukaemia.

WT-1 in mezoteliul normal

WT-1 in mezoteliom

Melan-A
Melan-A is a melanocyte differentiation antigen, recognized by autologous cytotoxic T lymphocytes. Melan-A is also called MART-1 (melanoma antigen recognized by T cells). Using the monoclonal antibody A-103, staining is also seen in steroid hormone producing cells: adrenal cortex , granulosa and theca cells of the ovary and Leydig cells of the testis. This is due to cross reaction (as the Melan-A gene is not detected in these cells). Melan A is expressed in 80-100% of malignant melanomas, including all primary cutaneous malignant melanomas and mucosal melanomas. In metastastic melanomas the staining may be patchy and somewhat less often positive than in the corresponding primary tumours. In desmoplastic melanoma the staining reaction is frequently patchy or negative. Melan-A is also demonstrated in other tumours of melanocytic origin or differentiation (i.e., melanosome producing), such as clear cell sarcoma, melanotic neurofibroma, melanotic schwannoma and other melanotic neural crest derived tumours, as well as in so-called PEComas (perivascular epitheloid cell tumour; derived from modified smooth muscle cells in the so-called tuberous sclerosis complex: angiomyolipoma, lymphangioleiomyoma(-tosis), and pulmonary sugar tumour. Using the antibody A-103, staining is furthermore seen in steroid hormone producing tumours: adrenocortical adenoma and carcinoma , sex cord-stromal tumour of the ovary and Leydig cell tumour of the testis.

Melan A in epiteliul normal

Melan A in melanom

 HMB-45
Melanosoma antigen (MSA) is an incompletely characterized oligosaccharide side chain of a glycoconjugate, 10 kDa, detected by the monoclonal antibody HMB-45 (Human Melanoma, Black). Malignant melanoma are MSA positive in most cases (60-90%). However, spindle cell and desmoplastic malignant melanoma are MSA negative or only focally positive Being a highly specific marker, MSA has been widely used for the identification of melanocytic differentiation. However, MSA is generally a less sensitive marker than Melan-A and microphthalmia transcription factor (Mitf), particularly in the dermal component of benign melanocytic tumours and in spindle cell melanoma. MSA is useful for the identification of PEComa (together with alpha smooth muscle actin), but also here Melan-A may give a stronger staining.

HMB-45 in melanom pattern punctiform

 TTF-1
TTF1 was first identified as a thyroid-specific DNA-binding activity which interacted with the rat thyroglobulin gene Among thyroid neoplasms, TTF1 is seen in virtually all tumours of follicular derivation, i.e. follicular adenoma and follicular and papillary carcinoma. Also the C-cell derived medullary carcinomas are positive for TTF1 immunoreactivity in virtually all cases (lower frequencies in some studies being possibly due to technical causes). Most anaplastic thyroid carcinomas have been reported negative. Among lung neoplasms, TTF1 is widely expressed in pulmonary adenocarcinomas, the frequency of positive tumours being 60-85%, depending on the clone used Small cell lung carcinoma express TTF1 almost consistently, about 90%, while other pulmonary neuroendocrine tumours, i.e., typical and atypical carcinoid and large cell neuroendocrine carcinoma do so variably, according to the literature 0-95% being positive!

 Inhibin is a dimeric glycoprotein hormone comprised of an and a subunit. It is produced by ovarian granulosa cells and inhibits the production or secretion of pituitary gonadotropins, particularly follicle-stimulating hormone. The antibody was raised against the terminal 1-32 amino acid sequence of the inhibin subunit. In abnormal ovarian tissues, inhibin is a sensitive marker for the majority of sex-cordstromal tumors.

TTF-1 in carcinom tiroidian folicular

 Thyroglobulin
is the precursor of thyroid hormones. It is synthesized by thyrocytes and transported to the apical surface where it is secreted into the lumen of thyroid follicles and stored as the major component of colloid. The antibody is useful for the detection of thyroglobulin in thyroid tissue and is a useful tool for the identification of well-differentiated thyroid carcinomas

Tireoglobulina in carcinomul papilar tiroidian

 The Ki-67 antigen is a large nuclear protein (345, 395 kDa) preferentially expressed during all active phases of the cell cycle (G1, S, G2 and M-phases), but absent in resting cells (G0-phase). In diagnostic histopathology and cell biology, antibodies against the Ki-67 antigen have proven valuable by allowing direct monitoring of the growth fraction of normal and neoplastic cells

Ki-67 in mucoasa colonica normala

 Melanomul tipic:
Pozitiv: vimentin, S-100, HMB-45, Melan-A, tirozinaza si MTF (microftalmia transcription factor); Vim cel mai consistent marker (prezent in 100%din cazuri) , dar cel mai putin folositor (nespecific); S-100 , de asemenea nespecific, dar mult mai folositor (negativ in multe tumori cu care se face diagn. diferential); HMB-45 mult mai specific, dar mai putin sensibil decat S-100 (util de ex, in diagn dif cu metast de carc de gl mamara S100 poz); recunoaste o glicoproteina premelanosomica (g100), implicata in sistemul tirozinazic de producere a melaninei) si este, prin urmare, neg in melanoamele nepigmentare si in melanomul desmoplastic. Melan A (MART-1)- antigen de diferentiere melanocitara- poz in aprox 80% din aceste tumori; poz de asemenea in celulele de corticosuprarenala producatore de hormoni steroizi, ovar, testicul sin tumorile care au originea in acestea; Tirozinaza pozitiva in peste 90% din cazuri; alte tumori pozitive: MPNST si tumorile endocrine; MiTF proteina nucleara necesara in viabilitatea melanocitara marker al majoritatii melanoamelor conventionale; neg in melanoamele desmoplazice; pozitiv de asemenea in dermatofibrom si tumori de muschi neted; !! Un nr semnificativ de melanoame este poz la keratine cu greutate moleculara joasa (Cam 5.2); altele sunt pozitive la CEA, EMA, alfa1 antichimotripsin si CD68.

HMB-45

Vimentina

 Melan A (Mart-1)

 Carcinom cu celule Merkel:

Aspect monomorf ; celule cu citoplasma putina ; nuclei rotunzi, vacuolati, nucleolati, cromatina in sare si piper; numerosi nuclei fragmentati, stroma cu numeroase vase cu endoteliu inalt IHC : poz pentru:
citokeratine cu greutate mica (CK 20- aspect punctiform, perinuclear, rar intalnit in alte organe) Neurofilamente; Enolaza neuron specifica Cromogranina, sinaptofizina, VIP Diagn. Diferential cu carc neuroendocrin cu cel mici de plaman (CK7 poz si TTF poz);

 HFB
Pozitiv :
Vimentin FXIIIa - De multe ori poz la markeri de muschi neted (actina, miozina, desmina)- !! Confuzie cu tumori de muschi neted!! Negativ: - CD34 (care este poz in DFSP)

FXIIIA

 DFSP:
Neoplasme cu crestere nodulara, polipoida, care se dezvolta in derm si de unde invadeaza tesutul subcutanat; Arhitectura storiforma, celularitate crescuta, activitate mitotica moderata spre crescuta, lipsa CGM, inglobarea celulelor adipoase IHC pozitiv pentru - CD34!!
- actina, vimentina

IHC negativ pentru : S100, HMB-45, keratine, FXIIIa

Bednar tumor(pigmented DFSP) neg for S100

CD34 in DFSP

 Sarcom Kaposi:
Mi: celule fuziforme ce formeaza fante ce contin hematii ce se intrepatrund cu macrofage, limfocite, etc; IHC celulele fuziforme sunt probabil celule mezenchimale nediferentiate sau care manifesta tendinat de diferentiere spre celula endoteliala, de aceea sunt poz la : FVIII-related antigen, FXIIIA, CD31, CD34, factori de adeziune vasc..

Plaman si pleura
Mezoteliom
AA pozitiv/ PAS negativ IHC poz pt. : calretinin, CK 5/6 si WT1, EMA
neg: CEA, B72.3 si MOC-31 (poz in adenoc)

 Calretinin

EMA pattern membranar

 Carcinom scuamos pulmonar:

CK de greutate mica si mare Vimentin,EMA, CEA P63, p53 ( mutatia apare in stadii timpurii); Adenocarcinom pulmonar - TTF-1 - LMW keratins (CK 7 +/ CK 20 neg) - EMA, CEA ! Cateodata vimentin +CK - S100 prez in celulele Langerhans din stroma

TTF in adenoc pulmonar

 Carcinom cu dezvoltare lepidica (fostul carcinom bronhiolo-alveolar) !! Subtipul mucinos este CK 20 poz si TTF-1poz MUC3 si MUC6 poz ( diagn. diferential cu ADK); Carcinomul cu cel mica: - caracteristic: nuclei mulati, hipercromatici, cromatina fina, nucleoli absenti, citoplasma putina, mitoze numeroase ( posibil ca aceasta celula apare din celule epiteliale si in cursul tranformarii maligne sufera diferentiere endocrina). IHC: - pozitivitate variabila pentru : neurofilamente, Leu-7, cromogranina, sinaptofizina, enolaza neuron specifica (marker seric de asemenea!), keratine. CD99 - neg (dgn dif cu PNET/ sarcom Ewing) TTF poz in aprox. 85% de cazuri;

 Carcinom pulmonar cu celula mica

Markeri neuroendocrini : crg, syn, NSE, Neurofilam Leu-7 LMW CK (Ck 7+/ CK 20 -) TTF-1 (poz in 85% din cazuri).

 Carcinoid - apare din celule Kulchitsky - celule mici, monomorfe, nuclei centrali, citoplasma putina, fin granulara; arhitectura cordonala sau insulara, rar papilara. IHC markeri identici cu carc cu cel mica + diferiti hormoni (VIP, ACTH) - CK 7+/ CK 20 neg - TTF poz ! Carcinoid atipic hipercromazie, necroza, activit mitotica (2-10/10HPF)

Sinaptofizina

 Tumora cu celule clare (sugar cell tumor)

HMB-45, enolaza, sinaptofizina, focal S-100.
Metastaze!

Tiroida
Carcinom papilar tiroidian
CK 7+/CK 20 CK19 + HMW CK 34betaE12 + Tireoglobulina, TTF-1 + (intensitate mai scazuta de obicei decat in carc folicular); Alti markeri poz: S100, EMA, CEA, galectin, ER, HBME-1;

 Carcinom folicular tiroidian:

TTF-1, tiroglobulina + LMW keratins, EMA, laminina
Tumori cu celule oncocitare:
TTF-1, tiroglobulina + CEA, S100, HMB45+ !! CK14 - specific

TTF in carc folicular tiroidian metastatic

 Carcinom medular
TTF-1+ Markeri pan-endocrini + Calcitonina!! Keratine, CEA ACTH, somatostatina..

Calcitonina in carcinom medular tiroidian

Tract digestiv
Gastric carcinoma
MUC-1+: tip intestinal; MUC5AC+: tip difuz; (cardia) MUC2+ : tip mucinos CEA, EMA, LMW CK + ( dar cateodata CK13, 16); CK7 + (70% din cazuri); CK20 + (20%); Hepatoid ADK: Hep- Par-1+ si AFP +

CK7 CEA

 Tumori stromale gastrice:

Origine: celule Cajal, celule de origine mezodermica, cu rol in coordonarea activitatatii contractile a muschiului neted; IHC :
CD117 + CD34 + Ki-67

CD117

 Tumori cu celule endocrine

WDNET (tumora endocrina bine diferentiata su carcinoid) :
arhitectura microglandulara, trabeculara, mai rar insulara Nuclei regulati si normocromatici, rare mitoze, necroza absenta, vascularizatie bogata. IHC : - NSE, CRG, SYN, keratine

 Carcinom neuroendocrin bine diferentiat

Aceleasi caracteristici microscopice + trasaturi de atipie: necroza, mitoze (>2%), caracter invaziv Aceiasi markeri neuroendocrini Carcinom cu celule mici ( carcinom endocrin slab diferentiat) analog carc cu celule mici pulmonar - comportament agresiv (Ki-67 >30%), - de obici cromogranina este absenta sau prezenta focal, NSE si sinaptofizina intens poz

Intestin subtire
Tumori endocrine:
Origine in celulele endocrine ale glandelor Lieberkuhn; Pozitivitate: CEA, CK7(10%), CK20 (20%); Markeri neuroendocrini: Syn, NSE, CRG, PGP9.5, Leu7;

 Boala celiaca (sprue)

Atrofia vilozitatilor, infiltrat inflamator cu limfocite Tc (CD3 si CD8 pozitive) in corion si intraepitelial; !sprue refractar se caracterizeaza prin prezenta LT gamma delta Boala Whipple - Generata de Tropheryma whipelii; - Mi: plaje de macrofage in lamina propria ce determina distorsiuni arhitecturale ale vilozitatilor intestinale si care contin in citoplasma material PAS pozitiv datorita bacililor; - IHC : CD4/ CD8 LT scazut;

 GIST ADK Limfoame

 Intestin gros
Adenocarcinom clasic :
MUC1 si MUC3 poz CK20 poz/ CK 7 neg CEA poz CDX2 poz (poz de asemenea in carcinomul mucinos ovarian si de vezica urinara); Tag-72 (mAb 72.3) poz (de asemenea si in polipii hiperplazici si adenomatosi si chiar si in mucoasa normala).

CDX2 nuclear marker

 Carcinom mucinos:
MUC-2 poz Carcinom cu celule in inel cu pecete - CK7-/CK20+ (origine in colon) versus CK7+/CK20(stomac). - Carcinoame endocrine si mixt

 GIST Limfoame

 Canal anal
Carcinom scuamos
IHC- HPV Boala Paget: CK7 poz, CK20+/-, GCDFP+/- ( pattern diferit de adenocarcinomul clasic care este CK7-). Melanom

 Ficat:
Carcinom hepatocelular:
Pozitivitate pentru : AFP, keratine: CK8 (CAM 5.2) si CK7 (intr-un nr mic de cazuri), EMA, Hep-Par-1 (mAb ce interactioneaza cu o proteina citoplasmatica inca necunoscuta prezenta in hepatocite normale si neoplazice). MOC31 negativ (pozitiv in colangiocarcinom si metastaze hepatice); CEA negativ sau focal pozitiv (ajuta in diagnosticul diferential pentru ca este pozitiv in carcinomul de cai biliare si in carcinoame metastatice) ! Pozitivitate de tip canalicular! Pozitivitate de asemenea la ER si AR. Tumorile bine diferentiate: laminina, fibonectina Vasele sunt pozitive la CD34, ceea ce nu se intampla pentru sinusoidele hepatice.

CK-7 CK-8

 Colangiocarcinom
Coloratie pentru mucina pozitiva (!) IHC- pozitivitate pentru CEA (pozitivitate citoplasmatica si luminala !), EMA, Cam 5.2 (LMW CK), AE1/AE3 (HMW CK). Profilul CK in colangiocarcinomul intrahepatic (CK7+/CK20+) este diferit fata de colangiocarcinomul extrahepatic (CK7+/CK20-)

 Tumori mezenchimale
Angiosarcom
Pozitivitate: FVIII related antigen, alti markeri endoteliali; Angiomiolipom - Pozitivitate la : actina, desmina, S100, HMB-45.

 FVIII related antigen

 Pancreas
Adenocarcinom ductal- pozitivitate pentru:
EMA, keratine (CK 7,8, 18, 19, 15, 17, 20, 5/6, 10, 13) CEA, CA19-9, B72.3 MUC1 (dgn. diferential cu carcinomul papilar intraductal, carcinomul ampular si cel mucinos)

Glanda suprarenala
Tumori de corticosuprarenala (adenom/carcinom de corticosuprarenala):
Pozitivitate pentru : vimentina, syn, inhibina si Melan A Negativitate pentru: cromogranina Pozitivitate de asemenea pentru calretinin (focal), bcl2, keratine ( in special adenoamele, focal si sporadic) !!Adenoamele au expresie mai scazuta pentru vimentina si mai crescuta pentru LMW CK. Negative pentru :EMA, CEA, B72.3

 Adenom de corticosuprarenala versus carcinom renal:

C. renal: pozitivitate pentru vimentina, RCC, CK, EMA, CD10

 Tumori de medulosuprarenala ale adultului

Hiperplazie de medulosuprarenala Feocromocitom IHC: - pozitivitate pentru catecolamine, cromogranina, NSE, neurofilamente, sinaptofizina, serotonina, gastrina, alte peptide vasoactive - celule sustentaculare: pozitive la S100

Cervix CIN

Tract genital feminin

P16- inhibitor de CDK inactivat de HPV-E7, ceea ce implica ca supraexpresia P16 indica prezenta HPV de risc inalt- in leziunile CIN II si CIN III mai mult de jumatate din grosimea epiteliului prezinta pozitivitate (2/3 -1/1);

exista leziuni de grad inalt p16 negative !!! KI-67 in mod normal prezent numai la nivelul stratului parabazal; in CIN II indica rata de proliferare inalta; in CIN III prezent in toata grosimea epiteliului.

 Carcinom scuamos invaziv

Pozitivitate pentru :
Keratine P63 CEA Adenocarcinom endocervical: -! Coloratii histochimice si marcaje IHC pentru mucina poz (prez difuz intracelular) - pozitivitate pentru CEA - negativitate pentru vimentina - negativitate sau prez slaba pentru ER, PR -HPV prezent (col IHC pentru HPV sau p16) Toate acestea ajuta la diagnosticul diferential cu adenoc. endometrioid de endometru! (atentie la carcinomul seros de endometru care este pozitiv la p16)

 (Adeno)carcinom mezonefric:
CD10+ Calretinin +
Carcinom neuroendocrin - NSE + - Cromog + (cazurile bine diferentiate) - Syn + - Serotonin - CEA - keratine

 Uter
Adenocarcinom endometrioid:
Keratine 7, 8, 18, 19 + Vimentina + (65-80%) CEA + in ariile de metaplazie scuamoasa (! Diagn diferential cu adenoc endocervical) CA125 + ER, PR (pozitivitatea cea mai mare in adenoc endometrioid , urmat de carcinomul papilar seros si carcinomul cu celule clare); ! Carc adenoscuamos de grad inalt este neg la ER, PR; !WT-1 pozitiv in carc papilar seros ovarian si neg in carc papilar seros de endometru si alte carcinoame primare de endometru

 Tumori stromale uterine

Mi
Constit din celule mici uniforme, asem celor din stroma endom, invelite de fibre de reticulina; Arhitectura multinodulara Arteriole spiralate, unele cu pereti hialinizati; Focare de hialinizare si izolate celule spumoase; Absenta vaselor mari cu perete gros Przenta spatiilor de clivare - IHC: - CD10 + - vimentina + - actin + (de obicei) - ER, PR + - Desmin, -/ + (uneori prez. focal); - h-Caldesmon - S100 -

 Tumori combinate musculare si stromale (stromomioma):

MI aspect caract de starbust a componentei musculare netede IHC : CD10+ Desmin, h-Caldesmon poztive pe ariile starbust

 Tumori uterine similare tumorilor ovariene cu origine in cordoanele sexuale:

IHC:
CD99 + Inhibin +

 Tumori mixte mulleriene maligne:

Aspect mixt constituit din elemente carcinomatoase (de tip glandular : endometrioid, celula clara sau papilar seros) si elemente sarcoma-like homologe (de tip fibro sau leiomiosarcom) sau heterologe ( condro sau osteosarcom); Pot fi intalnite elemente scuamoase, slab diferentiate;

 IHC :
Keratine + (in ariile epiteliale, dar si - in aprox jumatate din cazuri- in componenta sarcomatoasa); CD10 + in componenta sarcomatoasa Her2 neu +

 Tumori de muschi neted (leiomiom/leiomiosarcom)

Actina, desmin, calponin, h-caldesmon + Vimentin+ LMW keratins (CAM 5.2)+ (de obicei) ER, PR + ( cu intensitate mai mare in leiomioame decat in leiomiosarcoame);

 Ovar
Tumori epiteliale seroase
IHC
CK7+ CK20CK , 18, 19, EMA, B72.3 + S100 + in special in t. borderline WT-1+ difuz in carcinoamele seroase (la fel in mezotelioame peritoneale, mai putin carcinoamele endometrioide si de obicei negativ in carcinoamele mucinoase); Ca125 + CEA -

 Tumori epiteliale mucinoase

IHC:
CEA + (in special t. maligne si de tip intestinal) Keratine + EMA (in special cele maligne)+ CK 7+ in toate cazurile CK20+ aprox 50% din cazuri

 Carcinom endometrioid
IHC:
Keratin + EMA + Vimentin + CEA sau slab +

 Tumori cu celule germinale:

Tumora de sac yolk
IHC:
AFP+ Pankeratin + CK 7 WTCEA pattern canalicular cu Ac policlonal

 Carcinom embrionar :
IHC :
hCG + CK 7 + (pentru un subset de celule trofoblastice) Teratom matur/imatur IHC: - GFAP + in structurile nervoase mature si imature (!poate fi pozitiv si in condrocite)

 Tumori de cordoane sexuale:

T. de granuloasa: IHC: - vimentin + - desmoplakin + - inhibin + - CD99 + - CK8, 18 + ( in aprox 1/3 din cazuri , cu pattern punctat) - ! Pozitivitate intensa si difuza citoplasmatica pentru keratine indica carcinom!! - SMA + - EMA - S100 + in aprox 50% din cazuri

IHC utila uneori in diagnosticul diferential tumora primara/ tumora secundara ovariana

ex. Met. de ADK de colon CK7-/ CK20+ CEA + CA125 MUC 2 + T. primara mucinoasa ovariana - CK 7+ - CK20 + focal, uneori - CEA - CA 125 + - MUC 5AC+ !Atentie la carc. gastrice , pancreatice, etc

GGL limfatic
NLPHL
Celula popcorn Pozitivitate pentru CD19, CD20, CD22, CD45RA, CD45; Uneori pozitivitate pentru CD30 si EMA CD15 negativ

GGl Limfatic
HL clasic celula RS
CD 15 + (pattern golgian, difuz citoplasmatic sau membranar) in peste 80% din cazuri CD30 + in aprox 90% din cazuri; CD45+ in mai putin de 10% din cazuri; CD20+ in 10-20% din cazuri; CD45RO si CD43 +in mai putin de 10% din cazuri

 NHL

 SLL
Arhitectura stearsa de o proliferare de limfocite mici cu citoplasma putina, cromatina grunjoasa, nucleoli absenti si activitate mitotica redusa IHC:
CD20, CD22, CD19, CD79a + CD5+ CD23+ CD43+ Ciclina D

 Limfom limfoplasmocitic
Proliferare de limfocite mici, plasmocite si limfocite plasmacitoide cu localizare im maduva osoasa si maduva hematopoietica Prezenta de corpi Dutcher (pseudoincluzii nucleare PAS+) IHC
IgM in citoplasma + CD5-, CD10-, CD23CD19, CD20, CD22, CD79a+ CD138+

 Mielom plasmocitar
Maduva osoasa 30% din volum ocupat de plasmocite; corpi Russell; IHC:
CD79a, VS38c, CD138+ K, monoclonale CD19 CD20, CD117, CD10 -/+

 Plasmocitom extraosos
Localizare extramedulara; diagnosticul se pune prin excluderea unui limfom MALT cu diferentiere plasmacitoida

 Limfom folicular
proliferare constituita din centroblaste/centrocite cu arhitectura foliculara, cel putin partial Foliculii neoplazici sunt slab definiti, cu zona de manta discreta sau absenta Cele 2 tipuri de celule (centroblaste si centrocite) sunt difuz distribuite si nu polarizate, ca in centrii germinali reactivi; Macrofagele cu corpi tingibili sunt de obicei absente IHC: - CD19, CD20, CD22, CD79a +, IgM+/- bcl2, bcl6, CD10+ - CD5- CD21 si CD23 detecteaza FDC - gradul 3B poate fi lipsit de CD10, dar retine expresia bcl6 - bcl2- exprimat in 85-90% din LF gradul 1 si 2, dar in numai 50% din limfoamele grad 3

 Limfom de manta
Proliferare limfoida monomorfa cu arhitectura difuza, vag nodulara a zonei de manta sau, rar, foliculara; Este alcatuita din celule mici sau medii, cu usoare neregularitati ale conturului nuclear (asemanatoare centrocitelor) IHC
CD5, CD7, bcl-2, ciclina D1 + sIgM/IgD+ Restrictie k/ CD10, bcl-6 Fenotipuri aberante: CD5-

 Limfom cu celule mari B difuz:

Neoplasm cu celule B cu nucleu egal sau mai mare decat nucleul macrofagelor sau mai mare de 2 ori decat al unui limfocit normal; Etiologie: de novo sau prin progresia CLL/SLL, FL, MZL, NLPHL Variante : centroblastica, imunoblastica, anaplazica (celule mari, cu nuclei pleomorfi, bizari, asem cel S-R); IHC: - CD19, CD20, CD22, CD79a +/- IgM>IgG>IgA - CD30 + (varianta anaplazica) - CD5 + (10% din cazuri) - CD10 (30-60% din cazuri) - bcl-6 + (60-90% din cazuri) - ki-67>40%!!

 Limfom Burkitt
Proliferare cu rata de dedublare f crescuta (mitoze multe!), compusa din celule monomorfe cu translocatie myc IHC
CD19, CD20, CD22, CD10, bcl-6, CD38 + Translocatie myc la regiunea IGH

 Limfom MALT = limfom de zona marginala extraganglionar Mi: - limfom extraganglionar alcatuit din limfocite mici centrocitlike, celule centroblast like precum si imunoblaste, cu extensie in zonele interfoliculare
In tes epiteliale, celulele infiltreaza epiteliul, generand leziuni limfoepiteliale; IHC: - IgM, CD20, CD79a + - CD5, CD10, CD23, ciclina D1- ! Rareori CD5+ - CD21 si CD35 +, evidentiind retele de celule dendritice foliculare aflate in foliculii colonizati; - restrictie de lanturi usoare / (prin care se face diagnosticul diferential cu infiltrate limfoide benigne) - abs CD5 utila in diagn diferential cu MCL si CLL - abs ciclinei D1- utila in diagn diferential cu MCL - abs CD10 utila in diagn diferential cu FCL

 Limfom cu celule T periferice NOS

IHC:
CD5, CD7, CD4, CD8+ CD30, CD15 + exceptional Rearanjare TCR prezenta Limfom anaplazic cu celule mari ALK pozitiv IHC: - CD30 + (marcaj membranar si golgian) - ALK+ (de preferat mAb)

 Limfom limfoblastic
neoplazie constituita din celule precursoare (limfoblaste) cu citoplasma redusa si cromatina laxa sau condensata IHC
CD19, cCD79a, cCD22, CD10+ Pax+ Tdt +

Tumori tesuturi moi

T fibroase (fibromatoza, fibrosarcom)
Contin fibroblaste, miofibroblaste si matrice extracelulara (colagen si subst fundam) IHC- vimentina, actina, desmin (in masura mai mica), colagen

 T fibrohistiocitare
Derivate probabil din fibroblaste; Datorita lipsei markerilor specifici pentru acest lineaj, diagnosticul se bazeaza pe lipsa markerilor pentru alte lineaje ( DFSP CD34+++; neurofibromas S100); Poate fi identificata imunoreactivitate pentru :
Vimentina, CD68, feritina, antitripsina Focal: Keratine, desmina, NF (HFM angiomatoid exp desmina in 50% din cazuri!) Dgn de HFM este mentinut doar in 50% din cazuri

 T adipoase
Adipocitele normale si lipoblastele exprima S-100; T. slab diferentiate pot sa nu exprime deloc acest marker, desi el este indicat in diagn. dif cu HFM Poate exista expresie focala de actina

 T. de muschi neted
SMA+ (mai sensibila) Desmina+ Vimentina + Caldesmona:
pozitiva in leiomiom, leiomiosarcom, t. glomica Negativa in t. rabdoide, t.desmoide
! Alti markeri (CK cu GM mica, S100, Leu-7 si chiar CD34 )pot fi prezenti inconstant atentie la interpretare

 T. muschi striat:
Desmin Actin sarcomeric Miogenin (MyoD1) Miozin Mioglobin Vimentin Focal exprim: CK, protein S100 (in t. slab diferentiate) i protein asociat neurofilamentelor Ki-67 factor important

 Sarcom Ewing extrascheletal

Pozitiv: Vim, CD99 Negativ: Des, Act, LCA, GFAP, Mio, ChrA

Tumor primitiv neuroectodermic

Pozitiv: CD99, NF, Syn Negativ: markeri musculari

Condrosarcom mezenchimal
Pozitiv: CD99, S100, NSE Negativ: CK, Des, Act, EMA, Syn

 Tumori ale tecii nervului:

Neurofibromul: Proliferare combinat de elemente ale nervului periferic IHC
NSE + axoni S100 + Schwann Vim + fibroblaste EMA + celule perineuriale CD34 + celule ?

 Schwannomul
ncapsulat IHC: S100, colagen IV, laminin, vim, rar CD68 i GFAP Tip A
Celule fusiforme Palisad Corpi Verocay

S100

Tip B
Arii edematoase Spaii chistice

Schwannom celular

 Tumora maligna a tecii nervului periferic:

Pozitiv: S100 (50-70%), CD57 (50%), proteina bazic a mielinei EMA negativ, pan.CK +/-, CK7/19 Diferenial: leiomiosarcom (S100), sarcom sinovial (S100, CK7/19), melanom cu celule duziforme

 T. vasculare
Hemangioendoteliomul :
Keratine, vim, CD31, + CD34+/Angiosarcomul: CD31+ Limfangiom: CD31, CD34, FVIIIrAg Limfangiomiomul: Act, Des, HMB45

 Prostata
AMACR (p504S)
Marker pozitiv al celulelor neoplazice si preneoplazice (PIN) util in diagn P63, CK 34E12 (CK903), CK 5/6 - Markeri ai celulelor bazale, elimina diagn de leziune maligna in leziuni precum atrofia si adenoza ! In prezent se face dublu marcaj p63-AMACR (p504S). PSA are rol in diagnosticul tumorilor slab diferentiate dezvoltate in regiunea cervico-prostatica precum si in diagnosticul tumorilor metastatice (! Poate fi neg dupa hormonoterapie).

T genitale masculine
Tumori cu celule germinale Seminomul:
IHC:
PLAP+ (pozitivitate membranara in 90% din cazuri) C-kit (CD117)+ CD30, AFP, CK-

 Carcinomul embrionar:
IHC:
CD30+ CK AE1/AE3, CK4,17,18,19+ PLAP + focal (membranar si/sau citoplasmatic) AFPCD117-

 T de sac yolk
IHC:
AFP+ CK+ (pozitivitate constanta, puternica) CD117 + in aprox 80% din cazuri CD30 -

 T de cordoane sexuale:
IHC:
Inhibina, CD99, calretinina + vimentina + CK - sau cu pozitivitate variabila