Histopathological work-up and interpretation of sentinel lymph nodes removed for vulvar squamous cell carcinoma

Aims:  To evaluate the work-up of sentinel lymph nodes (SLNs) removed for vulvar pT1–pT2 squamous cell carcinoma (SCC). Inguinal lymphadenectomy yields metastases in only 30% of cases. Patients with missed inguinal disease, however, have a risk of dying from systemic disease. SLN dissections reduce morbidity, but work-up should reliably identify metastatic disease.
Methods and results:  All SLNs removed from 38 patients with pT1–pT2 SCC and clinically negative inguinal lymph nodes were submitted for frozen section analysis. When negative, SLN were formalin-fixed, sectioned entirely at 330-μm intervals to produce three slides per millimetre [two haematoxylin and eosin (H&E) stained slides; one slide for immunohistochemistry]. If screening of H&E-stained sections was negative, all remaining slides were subjected to immunohistochemistry with an antibody to cytokeratin. Twenty-five of 38 patients (66%) were pN0, 7/38 (18%) had metastases on frozen sections/H&E stains. Immunohistochemistry detected micrometastases in two patients and single tumour cells and anucleate cell structures in four patients. In 12/13 patients the SLN metastases, including all single-cell deposits, were from lichen sclerosus (LS)-associated SCC. Twelve of 13 patients with metastases had a pT2 SCC.
Conclusions:  Micrometastases and single tumour cell deposits in SLNs are typical of LS-associated vulvar SCC. Single tumour cell deposits in SNLs should be regarded as 'positive'. Identification requires serial sectioning and immunohistochemical analysis of all removed SLNs.     

Epstein-Barr Viral Genomes in Carcinoma Metastatic to Lymph Nodes Association with Nasopharyngeal Carcinoma

Lymphoepithelioma of the nasopharynx is a neoplasm known to have a strong association with Epstein-Barr virus (EBV). Using the Southern blot method, polymerase chain reaction (PCR), and/or in situ hybridization, we examined lymph nodes containing metastatic carcinoma, including metastatic lymphoepithelioma, for the presence of EBV genomes in order to determine whether EBV was associated exclusively with lymphoepithelioma. All of six lymph nodes from patients with lymphoepithelioma in the neck were found to have EBV genomes using the above methods. In four of the six cases, the primary site was the nasopharynx, and in the other two no primary site was found. Four of 12 squamous cell carcinomas and one of 18 adenocarcinomas expressed the EBV genome only by PCR, but not by Southern blotting or in situ hybridization, probably due to the presence of latent EBV in lymphocytes. These results indicate that metastatic carcinoma in lymph nodes showing EBV genomes revealed by Southern blotting or in situ hybridization is lymphoepithelioma, and that the nasopharynx is very likely the primary site. Acta Pathol Jpn 41: 437–443, 1991.     

Mediastinoscopy in bronchogenic carcinoma

Mediastinoscopy was performed in 470 patients with bronchogenic carcinoma in the ENT Department, Aalborg. The histological diagnoses were 195 squamous cell carcinomas, 149 adenocarcinomas, and 126 anaplastic carcinomas. Metastases in the mediastinal lymph nodes were found in 177 of the 470 patients (38%). Metastatic lymph nodes were found in approximately one fifth of the squamous cell carcinomas, in almost half of the adenocarcinomas, and in about half of the anaplastic carcinomas. The need is emphasized for lymph node biopsy from both right and left tracheobronchial angles and inferior to the bifurcation irrespective of the site of the carcinoma. Contralateral metastasis was found in approximately one third of the cases, and a positive biopsy from the nodes inferior to the bifurcation was found in about 40% of the patients in whom metastasis in the mediastinum were detected. In 10% of the patients, cytological and histological examinations of specimens obtained by bronchoscopy were negative, and the diagnosis of lung cancer was made by mediastinoscopy exclusively. The value of mediastinoscopy was particularly high in the diagnosis of adenocarcinomas.     

Myogenic expression in esophageal polypoid tumors

Four cases of esophageal polypoid tumors composed of squamous cell carcinoma and spindle cell sarcomatous components were investigated. Squamous cell carcinoma was consistently present in the base of the polypoid lesions in all four cases and was also intermingled with spindle-shaped sarcomatous cells in two cases. Metastases in the lymph nodes were observed in two cases: one was squamous cell carcinoma with a sarcomatous component and the other consisted of a pure sarcomatous component. All tumors involved at least the muscularis mucosae. In the sarcomatous region, the tumor was composed of highly anaplastic cells with or without forming interlacing fascicles. Pleomorphism was marked and bizarre giant cell forms were frequent. Mitoses were frequently present. Immunohistochemical study revealed that the anaplastic cells in the sarcomatous component in all cases were immunoreactive to desmin, muscle actin, vimentin, and alpha 1-antichymotrypsin, but were negative for cytokeratin, even in the metastatic tumors of the lymph nodes. The immunohistochemical results favor myogenic differentiation of the anaplastic cells, and these tumors were considered to be true carcinosarcomas composed of squamous cell carcinoma and leiomyosarcoma.     

High-risk cutaneous squamous cell carcinoma of the head and neck

Nonmelanoma skin cancers (squamous cell and basal cell carcinomas) occur at an epidemic rate in many countries with the worldwide incidence increasing. The sun-exposed head and neck are the most frequent sites for these cancers to arise and in most patients diagnosed with a cutaneous squamous cell carcinoma, local treatment is usually curative. However, a subset is diagnosed with a high-risk cutaneous squamous cell carcinoma. High-risk factors include size (>2 cm), thickness/depth of invasion (>4 mm), recurrent lesions, the presence of perineural invasion, location near the parotid gland, and immunosuppression. These patients have a higher risk (>10-20%) of developing metastases to regional lymph nodes (often parotid nodes), and in some cases also of experiencing local morbidity (perineural invasion), based on unfavourable primary lesion and patient factors. Despite treatment, many patients developing metastatic cutaneous squamous cell carcinoma experience mortality and morbidity usually as a consequence of uncontrolled metastatic nodal disease. It is therefore important that clinicians treating nonmelanoma skin cancers have an understanding and awareness of these high-risk patients. The aim of this article is to discuss the factors that define a high-risk patient and to present some of the issues pertinent to their management.     

A case report of papillary thyroid carcinoma dedifferentiated to squamous cell carcinoma presenting as a lung metastasis: A potential diagnostic pitfall

Papillary thyroid carcinoma (PTC) tall cell variant (TCV) with squamous dedifferentiation is a rare entity. We present a case of 90‐year‐old woman who initially had a 2.8 cm conventional PTC in right lobe of thyroid who, couple decades later, had metastatic dedifferentiated PTC to right neck lymph nodes level II and IV with tall cell features; to right level IV and V lymph nodes with tall cell and squamous components, which recently presented exclusively as squamous cell carcinoma (SCC) metastasizing to lung. The squamous component in the lymph node and SCC in the lung were both positive for squamous marker p63 and PTC markers TTF1, PAX‐8 and BRAF V600E while negative for thyroglobulin and p16. The papillary component was positive for TTF‐1, BRAF V600E and P63 (majority); negative for thyroglobulin and p16. Final diagnoses were rendered based on combination of cytological features and immunohistochemical profiles. This report highlights the utilization of current biomarkers to distinguish between metastatic dedifferentiated PTC with squamous features and primary lung SCC, as well as the importance of recognizing this rare entity.     

癌干细胞标记物CD44与ESA在舌癌淋巴道转移模型中的表达及其意义

目的:探讨癌干细胞标记物CD44与ESA蛋白在舌癌淋巴道转移模型中表达情况及其表达意义。方法:采用癌细胞足垫注射法建立淋巴道转移模型,4周后,取转移淋巴结进行原代细胞培养,从中分离、纯化舌癌细胞进行连续传代培养,建立舌癌永生化细胞系,命名为Tca8113-Ml。以舌癌永生化细胞系Tca8113-Ml为研究对象,采用足垫注射细胞的方法建立淋巴道转移模型。4周后,收集淋巴结,免疫组织化学染色检测癌干细胞标记物CD44与ESA蛋白的表达情况。结果:采用Tca8113-Ml建立了舌癌淋巴道转移模型,4周后收集淋巴结,检测癌干细胞标记物CD44与ESA蛋白在舌癌转移淋巴结组织中均呈阳性表达。结论:癌干细胞标记物在淋巴结转移性癌组织中呈阳性表达,表明淋巴结转移灶中有癌干细胞存在,提示癌转移的"种子"细胞极有可能是癌干细胞。     

Epstein-Barr viral genomes in carcinoma metastatic to lymph nodes. Association with nasopharyngeal carcinoma.

Lymphoepithelioma of the nasopharynx is a neoplasm known to have a strong association with Epstein-Barr virus (EBV). Using the Southern blot method, polymerase chain reaction (PCR), and/or in situ hybridization, we examined lymph nodes containing metastatic carcinoma, including metastatic lymphoepithelioma, for the presence of EBV genomes in order to determine whether EBV was associated exclusively with lymphoepithelioma. All of six lymph nodes from patients with lymphoepithelioma in the neck were found to have EBV genomes using the above methods. In four of the six cases, the primary site was the nasopharynx, and in the other two no primary site was found. Four of 12 squamous cell carcinomas and one of 18 adenocarcinomas expressed the EBV genome only by PCR, but not by Southern blotting or in situ hybridization, probably due to the presence of latent EBV in lymphocytes. These results indicate that metastatic carcinoma in lymph nodes showing EBV genomes revealed by Southern blotting or in situ hybridization is lymphoepithelioma, and that the nasopharynx is very likely the primary site.     

Human chorionic gonadotropin in esophageal carcinomas. An immunohistochemical study.

We have examined immunohistochemically the presence of human chorionic gonadotrophin (hCG) in 29 esophageal carcinomas: 24 squamous cell carcinomas, 2 adenocarcinomas, 2 adenoid cystic carcinomas and 1 adenosquamous carcinoma. In hCG-positive tumors, the presence of human placental lactogen (hPL) and pregnancy-specific beta-1 glycoprotein (SP-1) was also assessed. HCG immunoreactive cells were found in 5 squamous cell carcinomas (21%) and in none of 5 non-squamous cell tumors. The hCG positive cells were found in the most infiltrating areas of the tumors where poorly differentiated and pleomorphic cells predominated. The positive tumors were 4 poorly differentiated (31%) and one moderately differentiated carcinoma (12%). Four out of 10 cases (40%) with lymph node metastases had hCG in the primary tumor, whereas only one out of 11 cases (9%) without metastases was hCG positive. HPL and SP-1 were found in two cases. These placental proteins were detected in similar areas than hCG but the number of hPL and SP-1 immunoreactive cells was lower than hCG positive cells. SP-1 was also seen in areas of squamous cell differentiation negative for hCG. None of these two cases showed trophoblastic differentiation.     

Primary and metastatic high-grade carcinomas of the salivary glands: A cytologic-histologic correlation study of twenty cases

We reviewed the clinical and fine-needle aspiration (FNA) findings in 20 patients with poorly differentiated carcinomas presenting initially as parotid or as submandibular masses. There were 11 primary tumors and nine metastatic malignancies in 14 males and six females ranging in age from 39 to 89 yr (median = 66). The tumor types included three primary carcinomas with oncocytic features, three additional cases of high-grade parotid carcinoma, one case of primary neuroendocrine carcinoma, two examples of malignant mixed tumor, one high-grade mucoepidermoid carcinoma, and a single example of malignant lymphoepithelial lesion. Six patients with metastatic carcinoma had previous diagnoses of malignancy. In the three remaining individuals, primary carcinomas of the lung (two cases), and an unknown primary site presented initially as parotid masses. Five examples of metastatic squamous cell carcinoma, one metastatic basal cell carcinoma, and two metastatic renal cell carcinomas were identified. One parotid lymphoepithelioma was interpreted cytologically as an atypical lymphoproliferative process suggestive of Hodgkin's disease. Nineteen cases (95%) were correctly classified as carcinoma at the time of FNA. High-grade carcinomas aspirated from the parotid may be primary, but are frequently metastatic to either the gland, or to an intraparotid lymph node. Our experience indicates that some metastatic carcinomas present at this site, without a previous history of malignancy. Distinguishing primary from metastatic lesions has important therapeutic implications. © 1995 Wiley-Liss, Inc.     

The Diagnostic Significance of Intracytoplasmic Lumina in Metastatic Neoplasms

The diagnostic significance of intracytoplasmic lumina (ICL) was evaluated in a series of 61 consecutive and unselected metastatic neoplasms in lymph nodes, soft tissues, and bone studied by light and electron microscopy. Their only common denominator was a light microscopic diagnosis of “metastatic tumor of unknown primary site.”

With only rare exceptions, all previous reports of ICL on neoplastic cells deal with glandular organs or organs in which a glandular “metaplasia” may occur. Since primary or metastatic lesions of poorly differentiated squamous carcinomas, melanomas, and lymphomas may often cause problems in the differential diagnosis of poorly differentiated metastases, we also studied a large series of these neoplasms to see if they exhibited ICL.

Our study shows that when ICL are present in a metastatic carcinoma of undetermined primary site, the breast is the most likely site of the primary tumor, but that the clinical context may, and often does, modify the validity of this criterion. Our demonstration of ICL in two adnexal carcinomas of sweat and meibomian glands should discourage pathologists from jumping to a conclusion of a metastatic breast carcinoma whenever ICL are found in a tumor in the skin.

The presence of ICL seems to rule out the possibility of the neoplasm being a squamous carcinoma, a lymphoma, or a malignant melanoma.

Histochemical techniques were useful in diagnosing cases of mesotheliomas and adenomatoid tumors in which ICL are positive with Alcian blue but become negative after hyaluronidase digestion. The notion that mucicarmine positivity might exclude breast carcinoma was not confirmed in our study.     

The Diagnostic Significance of Intracytoplasmic Lumina in Metastatic Neoplasms

The diagnostic significance of intracytoplasmic lumina (ICL) was evaluated in a series of 61 consecutive and unselected metastatic neoplasms in lymph nodes, soft tissues, and bone studied by light and electron microscopy. Their only common denominator was a light microscopic diagnosis of “metastatic tumor of unknown primary site.”

With only rare exceptions, all previous reports of ICL on neoplastic cells deal with glandular organs or organs in which a glandular “metaplasia” may occur. Since primary or metastatic lesions of poorly differentiated squamous carcinomas, melanomas, and lymphomas may often cause problems in the differential diagnosis of poorly differentiated metastases, we also studied a large series of these neoplasms to see if they exhibited ICL.

Our study shows that when ICL are present in a metastatic carcinoma of undetermined primary site, the breast is the most likely site of the primary tumor, but that the clinical context may, and often does, modify the validity of this criterion. Our demonstration of ICL in two adnexal carcinomas of sweat and meibomian glands should discourage pathologists from jumping to a conclusion of a metastatic breast carcinoma whenever ICL are found in a tumor in the skin.

The presence of ICL seems to rule out the possibility of the neoplasm being a squamous carcinoma, a lymphoma, or a malignant melanoma.

Histochemical techniques were useful in diagnosing cases of mesotheliomas and adenomatoid tumors in which ICL are positive with Alcian blue but become negative after hyaluronidase digestion. The notion that mucicarmine positivity might exclude breast carcinoma was not confirmed in our study.     

Comparison of cytokeratin expression in primary and metastatic carcinomas. Diagnostic application in surgical pathology

Metastatic poorly differentiated carcinomas often represent diagnostic difficulties in surgical pathology. Therefore, the expression of cytokeratins of different molecular weights (54, 57, and 66 kd) were compared in paraffin sections of 37 primary carcinomas with their lymph node metastases by an avidin-biotin complex (ABC) method, using monoclonal antibodies. The epithelial tumors consisted of 16 squamous cell carcinomas (SCCs) and 17 adenocarcinomas with different degrees of differentiation (well, moderately, or poorly differentiated), a renal cell carcinoma, a hepatocellular carcinoma, a transitional cell carcinoma of the bladder, and a carcinoid tumor of the stomach. The primary and metastatic tumors showed the same cytokeratin profiles. All SCCs and their metastases were positive for 57-kd cytokeratin and negative for 54-kd cytokeratin. All adenocarcinomas and their metastases were positive for 54-kd cytokeratin and negative for 66-kd cytokeratin. The extent of reactions varied with the differentiation of the carcinomas, with well-differentiated tumors showing more diffuse staining. Cases of lymphoma, sarcoma, and melanoma were negative for the three types of cytokeratins. The results indicate that identification of different molecular weight cytokeratins may be used to distinguish poorly differentiated SCCs from poorly differentiated adenocarcinomas, even in metastatic tumors. In addition, demonstration of these cytokeratins is useful in substantiating presence and identity of small foci of metastases in lymph nodes.     

Intranodal benign thyroid tissue: significance of HBME-1 in differentiation from metastatic papillary thyroid carcinoma

The aim of this study was to determine the significance of HBME-1 immunostaining in the differentiation between intranodal benign thyroid tissue and metastatic papillary thyroid carcinoma in the lymph node. Immunohistochemically we examined normal-appearing intranodal thyroid tissue in four patients who did not show evidence of papillary carcinoma histologically or clinically. We also examined follicular-pattern-predominant papillary carcinoma with metastatic foci in the lymph nodes. Normal-appearing intranodal thyroid tissue and normal thyroid showed no immunopositivity for HBME-1. In contrast, all papillary carcinomas in both the lymph nodes and thyroid demonstrated strong positivity for HBME-1. HBME-1 was predominantly positive for the luminal surface of the tumor cells. The immunopositivity of the cuboidal and low columnar carcinoma cells was more intensive than that of the flat-shaped cells in the lymph nodes and thyroid. The results probably indicate that HBME-1 immunostaining is helpful in distinguishing between intranodal benign thyroid tissue and metastatic papillary carcinoma in lymph nodes. We emphasize that the HBME-1 reactivity should be evaluated in connection with the histological findings, and that positive and negative controls stained in parallel are necessary.     

Sentinel lymph node radiolocalization with 99mTc filtered tin colloid in clinically node-negative squamous cell carcinomas of the oral cavity

The objective of this study was to evaluate the feasibility of sentinel lymph node biopsy by using a radiotracer lymphatic mapping technique in patients with squamous cell carcinoma of the oral cavity, and the diagnostic value of this technique. We studied twenty patients with previously untreated squamous cell carcinomas of the oral cavity and N0 necks. After the peritumoral injection of 99mTc filtered tin colloid preoperatively, lymphoscintigraphy and intraoperative mapping using a gamma detector were performed to localize sentinel nodes. An open biopsy of the sentinel node was followed by complete neck dissection. We identified the sentinel nodes in 19 of 20 patients (95.0%) by lymphoscintigraphy and in all (100%) by intraoperative gamma detector. In all cases, the status of the sentinel node accurately predicted the pathologic status of the neck with the false negative rate being 0%. The negative predictive value for the absence of cervical metastases was 100%. In conclusion, our radiolocalization technique of sentinel nodes using 99mTc filtered tin colloid in N0 squamous cell carcinomas of the oral cavity is technically feasible and appears to accurately predict the presence of the occult metastatic disease.     

Large cell neuroendocrine carcinoma of the urinary bladder with lymphoepithelioma-like features

The group of undifferentiated carcinomas of the urinary bladder encompasses small cell undifferentiated carcinoma, giant cell carcinoma, lymphoepithelioma-like carcinoma (LELC), and large cell neuroendocrine carcinoma (LCNEC). These tumors are either pure or can be associated with other components, such as transitional cell carcinoma, squamous cell carcinoma, and adenocarcinoma. We report a case of LCNEC of the urinary bladder in a 54-year-old woman. Histologically, the tumor showed features of LELC; immunohistochemically, the tumor cells reacted to chromogranin A, NSE, and synaptophysin. In addition to these neuroendocrine markers, tumor cells were positive for cytokeratin CAM 5.2 and AE1/AE3, and there was focal positivity for vimentin. In situ hybridization for the detection of Epstein-Barr virus was negative. Despite radical cystourethrectomy and six courses of chemotherapy, the patient developed metastases invading the left inguinal lymph nodes 11 months postoperatively. Currently, 16 months postoperatively, the patient has developed metastases spreading into the lymph nodes of the right ischiorectal fossa; therefore, she is receiving a new cyclus of chemotherapy. There are only three previously reported cases of LCNEC of the urinary bladder, and the significance of neuroendocrine differentiation in non-small cell carcinomas at this location remains to be established. However, LELC appears to be a separate clinicopathological entity with sensitivity to chemotherapy and a relatively favorable prognosis. The differentiation between LELC and LCNEC with prominent inflammatory reaction could be of therapeutic relevance. However, in our case, this was possible using immunohistochemistry only.     

Necrobiotic palisading granulomas associated with breast carcinoma

AIMS: The presence of granulomas within the stroma of carcinomas and in the lymph nodes draining carcinomas has been well described. To date, however, there have been few studies examining the occurrence and relevance of necrobiotic granulomas occurring in association with breast carcinoma.METHODS/RESULTS: Four cases of breast carcinoma with necrobiotic granulomas were examined using periodic acid Schiff and Ziehl Neelsen stains for fungi and tubercle bacilli and with immunohistochemistry using CAM 5.2, cytokeratin 7, and cytokeratin AE1/3 for tumour cells. In one case the stroma was involved, in the other three cases the lymph nodes contained necrobiotic granulomas. In two of the cases, one with stromal and one with lymph node involvement, the necrobiotic granulomas contained necrotic tumour cells.CONCLUSION: In this study the features of four cases of breast carcinomas with necrobiotic granulomas are examined and their relevance explored. Close scrutiny of such granulomas is necessary to avoid underdiagnosis of metastatic disease.     

Breast carcinoma with predominant neuroendocrine differentiation

Neuroendocrine differentiation can be identified in a subset of human breast carcinomas, either as scattered cells or as a predominant neuroendocrine component. We report a case of an invasive breast carcinoma largely composed of neuroendocrine cells. Eight years after a left mammary lumpectomy for a pT2N1MO SBR III invasive ductal carcinoma, a 67-years-old woman presented with a metastastic neuroendocrine sternal mass. To establish a relationship between mammary carcinoma and bone metastasis, histological slides of both the breast tumor and axillary lymph nodes were reviewed, and an immunohistochemical study was performed. They showed that: a) the mammary carcinoma was composed of a majority of small and large neuroendocrine cells synaptophysin +, NCAM+, chromogranin - (80%), associated with 2 other differentiated non endocrine components, one of metaplastic squamous carcinoma (10%) and the other of ductal carcinoma (10%); b) 4 axillary lymph nodes were involved by the ductal component which contained few NCAM + but synaptophysin - cells; c) Estrogen and progesterone receptors and HER2 were negative in the breast tumor and the metastatic nodes. We discuss the histogenesis of composite mammary carcinomas with neuroendocrine differentiation, the outcome of each component and the prognostic relevance of such a diagnosis.     

VEGF和D2-40在食管鳞癌中的表达及其临床意义

目的观察血管内皮生长因子(VEGF)和D2-40在人食管鳞癌组织内的表达,探讨VEGF的表达与食管鳞癌组织淋巴管密度(LVD)及淋巴结转移之间的关系。方法将67例食管鳞状细胞癌分为有淋巴结转移和无淋巴结转移两组,免疫组化法检测食管鳞癌组织中VEGF和D2-40的表达,并与正常组进行对照。结果 VEGF蛋白主要表达于癌细胞胞浆内,D2-40表达于癌组织内淋巴管内皮细胞,在食管鳞癌的癌组织中VEGF的阳性表达率和D2-40阳性淋巴管密度均高于正常食管组织(P0.05),且有淋巴结转移组的阳性表达率高于无淋巴结转移组(P0.05)。结论 VEGF的高表达可能与食管鳞癌的淋巴管生成和淋巴道转移密切相关。