Protein expression profile of primary human squamous cell lung carcinomas indicative of the incidence of metastases

The purpose of this investigation was to evaluate firstly whether different protein expression patterns exist in primary squamous cell lung carcinomas of patients with and without lymph node involvement and secondly, whether or not different patterns exist in tumours with positive lymph nodes. For this reason, formalin-fixed, paraffin-embedded specimens from 130 patients with squamous cell lung carcinomas were analyzed by immunohistochemistry. In a first step, proteins were selected which showed a relationship to lymph node involvement. The expression of JUN, ERBB2, MYC, cyclin D, PCNA, bFGF, VEGF and Hsp70 proteins revealed a positive correlation to lymph node involvement. In contrast, caspase-3, Fas ligand, Fas/CD95, and PAI showed an inverse correlation to lymph node involvement. In a second step, these parameters were further analyzed by hierarchical cluster analyses. The resulting clusters were correlated to patients with or without lymph node involvement. The data show that different protein expression patterns exist between primary squamous cell lung carcinomas with and without lymph node involvement and within carcinomas with lymph node involvement. The data suggest that various metastasis profiles exist. This revised version was published online in July 2006 with corrections to the Cover Date.     

Aktuelle TNM/FIGO-Stadieneinteilung f��r das Zervix- und Endometriumkarzinom sowie maligne M��ller-Mischtumoren

Numerous recent studies of endometrial and cervical carcinomas as well as malignant mixed Müllerian tumors (MMMT) of the uterus have made a revision of the FIGO/TNM classification necessary, effective as of January 1st, 2010. There will be a new subclassification of carcinoma of the uterine cervix with proximal vaginal infiltration, using the same cut-off for the tumor extension as used for stage FIGOIB/T1b (??/>4?cm), resulting in stage FIGO IIA1/T2a1 and FIGO IIA2/T2a2. In endometrial carcinoma, the previous FIGO IA/pT1a and FIGO IB/pT1b will be merged to FIGO IA/pT1a. The former category FIGO IC/T1c will be changed into FIGO IB/T1b. The category FIGO IC/pT1c will not longer been used. Additionally, there will be no separate classification for the involvement of the endocervical glands by endometrial carcinoma. This feature will be incorporated in stage FIGO I/T1 disease. The new category FIGO II/T2 will be defined as endocervical stromal involvement. There will be a new category, termed T3c/IIIC, which includes regional lymph node involvement. Stage T3c1/IIIC1 will be defined as pelvic lymph node involvement and stage T3c2/IIIC2 para-aortal lymph node involvement with or without pelvic lymph node disease. In the TNM system, regional lymph node involvement can alternatively be classified as N1. The MMMT will be staged like endometrial carcinoma.     

EGFR gene copy number increase in vulvar carcinomas is linked with poor clinical outcome

EGFR copy number increases have been frequently reported in cancer including vulvar carcinomas. Co-amplification of cancer genes plays an important role in the development of many tumour types. To better understand the effect of EGFR aberrations on vulvar cancer phenotype and patient prognosis, the authors analysed EGFR copy number changes using fluorescence in situ hybridisation and EGFR expression by immunohistochemistry in a tissue microarray containing 183 squamous cell carcinomas of vulva. Furthermore, the authors analysed the co-amplification frequency of EGFR with HER2, CCND1, MYC and PIK3CA, respectively. EGFR copy number increase was found in 39.3% of the tumours. Seventeen per cent of vulvar carcinomas showed EGFR high polysomy including 9% with amplification of the EGFR gene. Copy number gain of the EGFR locus was associated with non-basaloid phenotype (p=0.03), high-tumour stage (p<0.001), human papillomaviruse negativity of tumours (p=0.04) and the number of lymph node metastases (p=0.02). EGFR protein expression was statistically correlated to EGFR copy number increase (p<0.05). The observed co-amplification rate of EGFR with all four additionally examined oncogenes was much higher than statistically expected. There was a highly significant association between EGFR copy number increase and CCND1 amplifications (p<0.001) as well as the total number of gene amplifications (p=0.04). EGFR copy number gains were significantly related to unfavourable patient outcome in univariate analysis and multivariate Cox regression analysis. In conclusion, EGFR copy number increases are detectable in a substantial proportion of vulvar carcinomas with relationships to advanced tumour stages and the development of lymph node metastases. EGFR copy number aberrations are connected to other gene amplifications and probably define an human papillomaviruses-independent pathway in the development of vulvar carcinomas. These data support the potential utility of EGFR inhibitors as a therapeutic alternative in a subset of vulvar carcinomas.     

p53 expression in carcinoma of the cervix.

AIM: To assess overexpression of the proposed tumour suppressor gene product p53 using the mouse monoclonal antibody DO-7 in the three main subtypes of carcinoma of the uterine cervix and to evaluate its value as a prognostic indicator. METHODS: Eighty two cases of FIGO Stage IB/IIA uterine cervical carcinoma were studied retrospectively. The tumours had been previously typed into adenocarcinomas, squamous carcinomas and adenosquamous carcinomas after the tissue had been fixed in formalin and embedded in paraffin wax. p53 protein expression was assessed using a standard immunohistochemical technique and the findings were correlated with tumour type, lymph node status and clinical outcome. RESULTS: In total, the p53 gene product was overexpressed in 17.1% (14/82) of all carcinomas and also in areas of cervical intraepithelial neoplasia grade III adjacent to invasive squamous carcinoma. Where present, the normal epithelium was uniformly negative. No association was found between p53 overexpression and tumour subtype, lymph node status or clinical outcome. CONCLUSIONS: It seems unlikely that p53 analysis will be of value in determining prognosis in carcinoma of the uterine cervix.     

Karzinosarkome (maligne Müller-Mischtumoren) des Uterus

Malignant mixed Mullerian tumors (MMMT; carcinosarcomas) are rare epithelial-mesenchymal tumors. With an overall survival rate of 30%–40% the prognosis is much worse compared to high grade endometrioid or serous/clear cell carcinomas. Depending on the histology of the mensenchymal components a distinction is made between homologous and heterologous MMMT. Clinical, morphologic and molecular data suggest that MMMTs are really metaplastic carcinomas in which the mesenchymal part retains epithelial features. The strongest prognostic factor is tumor stage followed by lymph node metastases, deep myometrial infiltration, involvement of the cervix and tumor size. The distinction between homologous and heterologous MMMT is prognostically insignificant. Due to unreliable clinical staging and a high rate of occult lymph node metastases, the pathological-anatomical work-up is of great importance. Clinical and pathologic staging should be performed as in endometrial carcinoma. The main differential diagnoses include uterine sarcomas, adenosarcoma and benign metaplastic change within the endometrium.     

Cervical cancer: what's new in squamous cell neoplasia

Up to 90% of cervical cancers are squamous cell carcinomas. These are divided in the WHO 5^th Edition (2020) classification into HPV associated (HPVA) and HPV independent (HPVI) categories. Immunohistochemistry for p16INK4A is a reliable surrogate for the presence of high risk transforming HPV infection and the distinction should be made where resources permit. Squamous precursor lesions are classified in a single HPV associated category. Recognition of the varied histologic patterns of squamous cell carcinoma is useful in consideration of differential diagnosis. Reporting cervical carcinomas requires a comprehensive and consistent approach to provide information required for staging and management. The most recent FIGO staging update was published in 2018 with notable changes in consideration of tumour size and lymph node involvement.     

The value of ultrasound in the assessment of cervical and abdominal lymph node metastases and selecting surgical strategy in patients with squamous cell carcinoma of the thoracic esophagus treated with neoadjuvant therapy

PurposeTo establish the role of ultrasound (US) in the assessment of cervical and abdominal lymph node metastases and its impact on making decision about surgical strategy in patients with squamous cell carcinoma of the thoracic esophagus.Material/MethodsThe results of US lymph node assessment before and after a neoadjuvant treatment in 83 patients were compared with the results of histopathological evaluation of lymph nodes harvested during surgery (transthoracic esophagectomy and 2-field extended or 3-field lymph node dissection). A diagnostic value of cervical and abdominal US in terms of sensitivity, specificity, positive and negative predictive value after a neoadjuvant treatment were determined.ResultsThe sensitivity, specificity, positive and negative predictive value of the US assessment of cervical lymph node metastases were 100%, 96%, 81% and 100%, respectively. The sensitivity, specificity, positive and negative predictive value of the US assessment of abdominal lymph node metastases were 82%, 94%, 91.5% and 87%, respectively.ConclusionsThe high sensitivity and specificity of cervical US make this investigational method sufficient in the assessment of cervical nodal involvement. In esophageal cancer patients with negative cervical lymph nodes on US, three-field lymph node dissection could be avoided. In patients with positive cervical lymph nodes on US one should consider to extend lymph node dissection about lymph nodes of the neck to achieve a curative resection. In patients with negative abdominal US this investigation should be supplemented by more detailed diagnostic methods.     

Neuroendocrine differentiation in cervical carcinoma.

AIMS: To examine neuroendocrine differentiation, as shown by chromogranin A (CGA) expression, in cervical carcinomas. METHODS: Sixty seven cervical carcinomas were studied and were classified as adenocarcinomas, adenosquamous carcinomas or squamous cell carcinomas based on the assessment of haematoxylin and eosin staining and stains for mucin. Where features of glandular differentiation were identified, sections were also stained for evidence of intestinal type mucin. CGA immunostaining was done and the results were graded on a three point scale: 0, + (1-5% of cells positive) and ++ (> 5% of cells positive). These findings were then analysed with respect to lymph node status, tumour differentiation and clinical outcome. RESULTS: There were 32 adenocarcinomas, 18 adenosquamous carcinomas and 17 squamous cell carcinomas. Positive staining was seen in 14 (20.9%) cases, of which four were strongly positive. All but one case were either adenocarcinomas or adenosquamous carcinomas. There was a trend for CGA positivity to be related to intestinal differentiation but this failed to reach statistical significance. No correlation could be demonstrated between CGA staining and lymph node status, tumour differentiation and clinical outcome. CONCLUSIONS: Neuroendocrine differentiation is common in cervical carcinomas where there is evidence of glandular differentiation. Whilst the numbers in this study are relatively small, the presence of neuroendocrine cells in otherwise typical carcinomas does not seem to have any association with clinical behaviour.     

Overexpression of carbonic anhydrase IX (CAIX) in vulvar cancer is associated with tumor progression and development of locoregional lymph node metastases

Carbonic anhydrase IX (CAIX) is a strictly membranous expressed metalloenzyme involved in cell adhesion, pH homeostasis, and cancer progression. The protein is specifically overexpressed in a wide variety of malignant tumors. This study was designed to assess the role of CAIX in primary vulvar cancer. One hundred forty-two well-characterized primary vulvar carcinomas were analyzed on a tissue microarray (TMA). Three tissue cores were sampled from each tumor. CAIX expression was determined by immunohistochemistry, using a four-step scoring system. To determine CAIX expression in benign vulvar tissue, we constructed a TMA with 120 samples of normal mucosa and non-neoplastic diseases. CAIX expression was found in 77/135 (57%) of all assessable vulvar cancer specimens and 48 (35.5%) exhibited a moderate or strong expression. CAIX expression in vulvar carcinomas was significantly stronger compared to non-neoplastic vulvar tissue (p?<?0.001). High levels of CAIX expression were related to pT stage (p?<?0.01), tumor size (p?<?0.01), depth of invasion (p?<?0.05), as well as inguinal lymph node metastases (p?<?0.05). There was also a trend towards shorter recurrence-free patient survival in CAIX-positive compared to CAIX-negative vulvar cancers. CAIX staining results in different tissue cores from the same tumor were homogeneous, raising the possibility of a hypoxia-independent expression. In conclusion, CAIX is overexpressed in the majority of vulvar carcinomas with relationships to advanced tumor stages and development of lymph node metastases. Our data support the potential therapeutic benefit of newly developed targeting antibodies in advanced vulvar cancer.     

Expression of Bcl-2 and Survivin in uterine cervical carcinogenesis and correlation between the expression and infection of HPV_(16/18)

Carcinomaofthecervixisthesecondleading causeofdeathamongwomenworldwide.Each year,anestimated500000casesarenewlydiag nosed[1].Manystudiesshowedinfectionofhu manpapillomavirus(HPV)wasoneofthemost importantetiologicfactorsforcervicalcarcinoma[24].Morethan95%ofallcervicalcarcinomas havebeenfoundtobeassociatedwithHPV(ma inlytypes16and18)[5].Thestudiesinmolec ularoncologyrecentlyshowedthatitresultedin occurrenceanddevelopmentofcervicalcarcinomasthatcarcinogenicfactorsmadeproto oncogene activatean…     

Metastasierung von Malignomen des Uterus und therapeutische Konsequenzen

Malignancies of the uterus metastasize by direct invasion of neighboring structures, lymphatically or hematogenously. Endometrial and cervical cancers lymphatically spread to the pelvic and para-aortic lymph nodes. For endometrial cancer the depth of myometrial invasion, lymphosvascular space involvement (LVSI) and a microcystic, elongated and fragmented (MELF) glandular invasion pattern are predictors for lymph node metastases. Metastases to the pelvic lymph nodes occur in approximately 10?% of endometrial cancer patients and in 30?% of these cases the para-aortic lymph nodes are also involved. Sentinel lymph node biopsy is possible for clinical stage I endometrial cancer and early stages of cervical cancer but is not yet routine. The presence of LVSI is considered to be the strongest predictor of distant metastases, particularly if assessed by immunohistochemistry with antibodies against factor VIII-related antigen or CD31. Endometrioid and clear cell carcinomas can hematogenously metastasize to the lungs, bones, liver and brain and can rarely be manifested as a solitary metastasis. In contrast, serous carcinomas can show extensive peritoneal spread. To date molecular biomarkers cannot predict the occurrence of distant metastasis. Overexpression of P53, p16 and L1CAM have been identified as negative prognostic factors and are associated with the prognostically unfavorable serous tumor type. The metastatic spread of squamous cell cervical cancer is strongly associated with tumor volume. Microinvasive carcinomas have a very low rate of parametrial and lymph node involvement and do not require radical hysterectomy. In contrast, lymph node metastases occur in up to 50?% of bulky stages IB and II cervical cancers. Distant metastases can occur in the lungs, liver, bones and brain. Molecular biomarkers have not been shown to predict metastatic spread. In well-differentiated adenocarcinoma of the cervix the pattern of invasion is strongly predictive for the presence of lymph node metastases, irrespective of tumor size and depth of invasion.     

The influence of nodal size on the staging of colorectal carcinomas

AIMS: The reliable identification of node negative colorectal carcinomas (CRCs) has often been linked to the histological examination of a minimum number of lymph nodes. The sizes of the lymph nodes, their metastatic status, and their number were investigated to establish whether these parameters are related, and whether their relation could help in determining the adequacy of staging. METHODS: One thousand three hundred and thirty four negative lymph nodes, 189 metastatic lymph nodes, and 43 pericolonic/perirectal tumour deposits measuring > or = 3 mm from 60 node positive and from 63 node negative patients with CRC were assessed for size. RESULTS: The mean size (SD) of these structures was 4.5 (2.7) mm. The lymph nodes were significantly larger in the CRCs with metastatic nodes (4.7 v 4.3 mm). Involved nodes were significantly larger than negative nodes (6.3 v 4.2 mm), despite the fact that the largest node was < or = 5 mm in one third of node positive CRCs. The examination of the seven largest nodes could have adequately staged 97% of node positive CRCs and 98% of all CRCs. CONCLUSIONS: The nodal staging of CRCs is dependent not only on the number of lymph nodes investigated, but also on qualitative features of the lymph nodes assessed, including their size. Lymph nodes are not equivalent and any study neglecting this fact will give grounds for error in the recommendation of a minimum number of nodes for the reliable determination of node negative CRCs. Although pathologists should aim to recover all nodes, a negative nodal status based on only seven nodes can be reliable.     

Lymph node metastasis in a gynecologic malignancy

A radical hysterectomy was performed on patients with stage IA2 to IIB cervical cancer. For these patients, many histopathological parameters have been reported to be prognostic factors of cervical cancer, such as a pelvic lymph node (PLN) metastasis, the histological subtype, the tumor diameter, the depth of the stromal invasion, a lymph-vascular space invasion (LVSI), a parametrial invasion, a corpus invasion and a vaginal invasion. Ovarian cancer is normally treated with cytoreductive surgery followed by chemotherapy. Although physicians have paid a great deal of attention to intraperitoneal disease, a substantial number of ovarian cancers have reported to involve the retroperitoneal lymph nodes. Therefore, a lymph node metastasis has been introduced into FIGO staging. However, the prognostic significance of a lymph node metastasis is controversial. In order to determine the possibility of individualizing a pelvic lymph node (PLN) dissection in patients with endometrial cancer, the relationship between PLN metastasis and the various prognostic factors was investigated. In this paper, various prognostic variables including a lymph node metastasis were analyzed in cervical cancer, endometrial cancer, and ovarian cancer.     

Medullary carcinoma of the thyroid presenting as tumours of the pharynx and larynx

Two cases of medullary carcinoma of the thyroid presenting as tumours of the pharynx and larynx are described. One patient had a tonsillar mass that resembled a carotid body tumour clinically, radiologically and microscopically. The other had an arytenoid tumour with multiple cervical lymph node metastases but without intrathyroidal carcinoma. The endocrine nature of the neoplasms was indicated by the presence of stromal amyloid, cellular argyrophilia and secretory granules whilst the demonstration of calcitonin and carcinoembryonic antigen provided evidence that they were medullary carcinomas.     

Staging and classification of testicular tumours: pitfalls from macroscopy to diagnosis

The accurate assessment of testicular tumours is vital for appropriate treatment to be instituted. The assessment begins at specimen receipt, as careful macroscopic examination is vital for staging, and this, in part, determines whether adjuvant treatment is given. More challenging specimens may include partial orchidectomies, biopsies and resection of lymph node or visceral metastases. Accurate histological typing is also a potential source of error as two classifications are in use, and this may lead to misunderstanding between clinician and pathologist. A specialist and multidisciplinary approach is advocated. Microscopic staging includes assessment of vascular invasion which may be complicated by artifactual spread at the dissecting bench, local invasion, assessment of the cord and occasionally lymph node deposits. From careful macroscopic examination, to accurate histological typing and reporting of adverse pathological parameters, the pathologist plays a major role in the successful treatment of a group of rare, but largely treatable, tumours.     

Telomerase activation and human papillomavirus infection in invasive uterine cervical carcinoma in a set of Malaysian patients

AIM: Telomerase activity was studied in invasive uterine cervical carcinoma to assess whether it was activated during cervical malignant transformation and to look for a possible association with human papillomavirus (HPV) infection in a set of Malaysian patients. METHODS: Histologically confirmed invasive cervical carcinoma and benign cervices were assayed for telomerase activity using a commercial telomerase polymerase chain reaction (PCR) enzyme linked immunosorbent assay kit. The same cases were subjected to PCR detection of HPV using type specific (HPV types 6b, 11, 16, and 18) followed by L1 open reading frame (ORF) consensus primers. RESULTS: HPV was detected in 18 (13 HPV-16, one HPV-6b, four only L1 ORF) of 20 invasive cervical carcinoma and one (only L1 ORF) of 19 benign cervices. Raised telomerase activity (A(450 nm) > 0.215) was detected in 11 cervical carcinomas, with A(450 nm) ranging between 0.238 and 21.790 (mean, 3.952) in positive squamous carcinomas, whereas A(450 nm) was only 0.222 in the one positive adenosquamous carcinoma. Five of 11 cervical carcinomas in stage I, three of six in stage II, both in stage III, and the only case in stage IV showed telomerase activation. Increased telomerase activity was noted in five of the 12 lymph node negative, five of the seven lymph node status unknown cases, and the one case with presumed lymph node metastasis. Ten of 18 HPV positive and one of two HPV negative cervical carcinomas showed telomerase upregulation. CONCLUSIONS: Telomerase is activated in invasive cervical carcinoma. Although larger studies are needed, there seems to be no clear association between telomerase upregulation and HPV status, although there is a suggestion of increased telomerase activity in squamous carcinomas and late stage disease.     

Schnellschnittdiagnostik bei Erkrankungen des weiblichen Genitaltrakts

Intraoperative frozen sections are particularly important for ovarian tumors because definitive preoperative histology is not possible. The diagnostic accuracy of frozen sections is highest for primary invasive ovarian carcinomas and benign ovarian lesions, followed by borderline tumors and poorest for ovarian metastases and rare neoplasms, such as germ cell tumors. Endometrial carcinoma should be diagnosed preoperatively by curettage or biopsy. For endometrioid endometrial carcinomas the indications for lymphadenectomy are often based on intraoperative assessment of the uterus. The differential diagnosis of low grade stromal neoplasms is based on myometrial invasion and can be supported by assessment of frozen sections as well as the diagnosis of other mesenchymal uterine tumors suspected of being malignant. Frozen sections of pelvic lymph nodes provide the possibility of immediate subsequent para-aortic lymphadenectomy in endometrial and cervical carcinomas but have recently lost importance. Sentinel node biopsy with intraoperative frozen section analysis is routinely performed only for vulval carcinoma. The German Association of Gynecological Oncology (AGO) recommends deferred diagnosis and a two stage surgical procedure for any doubtful intraoperative ovarian histology. Intraoperative frozen sections for endometrial carcinoma and lymphadenectomy specimens as well as for sentinel node biopsies are currently not recommended but are also not completely rejected.     

The value of cytokeratin immunohistochemistry in the evaluation of axillary sentinel lymph nodes in patients with lobular breast carcinoma

BACKGROUND: Cytokeratin immunohistochemistry (IHC) reveals a higher rate of occult lymph node metastases among lobular carcinomas than among ductal breast cancers. IHC is widely used but is seldom recommended for the evaluation of sentinel lymph nodes in breast cancer patients. Objective: To assess the value of cytokeratin IHC for the detection of metastases in sentinel lymph nodes of patients with invasive lobular carcinoma. METHODS: The value of IHC, the types of metastasis found by this method, and the involvement of non-sentinel lymph nodes were analysed in a multi-institutional cohort of 449 patients with lobular breast carcinoma, staged by sentinel lymph node biopsy and routine assessment of the sentinel lymph nodes by IHC when multilevel haematoxylin and eosin staining revealed no metastasis. RESULTS: 189 patients (42%) had some type of sentinel node involvement, the frequency of this increasing with increasing tumour size. IHC was needed for identification of 65 of these cases: 17 of 19 isolated tumour cells, 40 of 64 micrometastases, and 8 of 106 larger metastases were detected by this means. Non-sentinel-node involvement was noted in 66 of 161 cases undergoing axillary dissection. Although isolated tumour cells were not associated with further lymph node involvement, sentinel node positivity detected by IHC was associated with further nodal metastases in 12 of 50 cases (0.24), a proportion that is higher than previously reported for breast cancer in general. CONCLUSIONS: IHC is recommended for the evaluation of sentinel nodes from patients with lobular breast carcinoma, as the micrometastases or larger metastases demonstrated by this method are often associated with a further metastatic nodal load.     

宫颈癌组织中survivin和CD44v6的表达及其与HPV16/18感染的相关性

目的研究survivin、CD44v6在宫颈癌组织中的表达及其与HPV16/18感染的相关性,以探讨宫颈癌的发生机制。方法用免疫组化方法进行survivin和CD44v6的检测,用PCR检测HPV16/18感染情况。结果survivin和CD44v6的阳性率在宫颈癌组织中远高于CIN和正常宫颈组织,差异显著(均P<0.01),其表达率与淋巴结转移有关(均P<0.05)。CD44v6随着临床分期、病例分级的升高阳性率升高(P<0.05),survivin的阳性率则随着病例分级的升高而增加(P<0.05)。HPV16/18在正常宫颈组织、CIN和宫颈癌中的阳性率逐渐升高(P<0.01),但与临床分期、病理分级、淋巴转移无关。survivin与HPV16/18感染有相关性(P<0.05)。结论宫颈癌组织中survivin的异常表达与HPV16/18感染有关。survivin和CD44v6与宫颈癌的恶变程度有关,可作为宫颈癌筛查预后判断的有利指标。