Cytological features of signet‐ring cell carcinoma of the lung: Comparison with the goblet‐cell‐type adenocarcinoma of the lung

Signet‐ring cell carcinoma (SRCC) and goblet‐cell‐type adenocarcinoma (GCA) are mucin‐producing lung adenocarcinomas. Primary SRCC shows an aggressive clinical course, whereas GCA shows infrequent distant metastasis, but more frequent intrapulmonary metastases resembling lobar pneumonia. To distinguish SRCC from GCA, this study investigated the respective cytological features of these lesions. We selected 10 cases each of SRCC and GCA from the archival imprint smears. We assessed them for the following 10 cytological features. Necrosis/debris was observed in 60% of the SRCC and 90% of the GCA. A mucinous background was observed in 10% of the SRCC and 90% of the GCA. Significant inflammation was observed in none of the SRCC and 80% of the GCA. Stromal cluster was observed in 30% of the SRCC and 70% of the GCA. Nuclear overlapping was observed in 50% of the SRCC and in all of the GCA. Single tumor cells were observed in 80% of the SRCC and 10% of the GCA. Honeycomb‐like cluster was observed in none of the SRCC and 80% of the GCA. Prominent nucleolus was observed in 50% of the SRCC and 40% of the GCA. Nuclear membrane irregularity was observed in 70% of SRCC and 60% of the GCA. Nuclear pleomorphism was observed in all of the SRCC and none of the GCA. The cytological features of SRCC were the presence of single tumor cells and nuclear pleomorphism, whereas that of GCA were the presence of abundant mucin and significant inflammation in the background, and a honeycomb‐like cluster. Diagn. Cytopathol. 2009. © 2009 Wiley‐Liss, Inc.     

Primary signet-ring cell carcinoma of the lung: a case report with an immunohistochemical study

Primary signet-ring cell adenocarcinoma (SRCA) of the lung is very rare. A 78-year-old man consulted to our hospital because of loss of appetite. Physical examination showed lymphadenopathy of the cervical lymph nodes. Chest X-ray showed a tumor of the right upper lobe. Blood laboratory test showed an increase of LDH and CRP. Tumor markers (CYFRA, SCC, CEA, ProGRP) were within normal range. Clinical diagnosis was suspected malignant lymphoma of the lung. Transbronchial lung biopsies showed SRCA (70%) mixed with poorly differentiated adenocarcinoma (30%). The SRCA cells were positive for mucins. Immunohistochemically, the SRCA cells were positive for cytokeratin (CK) AE1/3, CK CAM5.2, CK7, CK18, EMA, p53, Ki-67 (labeling=60%), CEA, CA19-9, TTF-1, and MUC1. They were negative for CK34BE12, CK5/6, CK8, CK14, CK19, CK20, vimentin, chromogranin, synaptophysin, CD45, CD20, CD3, surfactant Apoprotein-A, CDX-2, MUC2, MUC5AC and MUC6. A pathological diagnosis of SRCA of the lung was made. The patient showed downhill course, and died of carcinomatosis 3 months after the first manifestation. In conclusion, a vary rare case of primary pulmonary SRCA was reported with an immunohistochemical study.     

Proportion of goblet cell is associated with malignant potential in invasive mucinous adenocarcinoma of the lung

Invasive mucinous adenocarcinoma (IMA) is a newly classified variant of lung adenocarcinoma. The aim of this study was to examine the correlation between the proportion of goblet cells and the clinicopathological characteristics of IMA. Ninety‐nine patients with stage I IMA were included in this study. We estimated prognostic impact of goblet cell proportion. We classified them into two groups: the cases with a high goblet cell proportion (HGP, goblet cell proportion ≥80%) and the cases with a low goblet cell proportion (LGP, goblet cell proportion ≤30%), and compared the expression levels of five cancer progression markers and the number of tumor‐promoting stromal cells between the two groups. Univariate and multivariate analysis revealed that the goblet cell proportion was a prognostic factor for recurrence free survival (P < 0.01) and overall survival (P = 0.01). The expression levels of the cancer stem cell‐related marker, ALDH‐1, and proliferation‐related marker, geminin were significantly higher in the LGP group than in the HGP group. CD204+ tumor‐associated macrophages were significantly more in the LGP stroma than the HGP stroma. Our current study indicated that the proportion of goblet cells was correlated with the malignant potential in surgically resected IMA.     

Gastric-type mucinous adenocarcinoma of the uterine cervix with neoadjuvant therapy mimicking clear cell carcinoma

Gastric-type mucinous adenocarcinoma, an uncommon subtype of cervical carcinoma, is characterized by a distinct morphology and immunophenotype. Herein, we report a case of a 71-year-old woman who received neoadjuvant radiotherapy and chemotherapy after cervical biopsy revealed moderately differentiated invasive endocervical adenocarcinoma. Subsequently, the outside patient underwent radical hysterectomy with bilateral salpingo-oophorectomy. The post-neoadjuvant therapy hysterectomy specimen showed tumor cells with clear cytoplasm, hyperchromatic nuclei with irregular contours, which mimicked clear cell carcinoma. However, immunohistochemical staining showed that these tumor cells were positive for carcinoembryonic antigen, cytokeratin 7 (diffuse), and cytokeratin 20 (patchy), After review of the pretreatment cervical biopsy specimen, the tumor was favored to represent a gastric-type mucinous adenocarcinoma of the cervix. Pathologists should be aware of this rare tumor and its post-neoadjuvant therapy morphologic changes, which can make diagnosis more challenging.     

Ciliated carcinoma of the endometrium associated with mucinous and neuroendocrine differentiation: A case report with immunohistochemical and ultrastructural study

A case of endometrial ciliated carcinoma mixed with foci of mucinous adenocarcinoma and argyrophil cells is described. The patient suffered from diabetes mellitus, hypertension and obesity, but had no history of estrogen use. Although the tumor presented well differentiated histologic features, it showed complete diffuse, endophytic extension. Approximately half of the cilia had abnormal inner structures, with 8 + 2 microtubular pattern. Some ciliated cells contained intracytoplasmic mucin, while others contained neurosecretory granules. These findings suggest that malignant ciliated cells have the capacity of further transformation into mucinous or endocrine cells.     

Expression of mucins (MUC1, MUC2, MUC5AC and MUC6) in mucinous carcinoma of the breast: comparison with invasive ductal carcinoma

AIMS: Mucinous carcinoma of the breast usually shows less frequent lymph node metastasis and more favourable outcome compared with invasive ductal carcinoma. The aim of this study is to compare the expression profiles of several mucins in mucinous carcinomas and invasive ductal carcinomas to gain insight into the relationship between the less aggressive biological nature of mucinous carcinoma and the role of mucins. METHODS AND RESULTS: We examined the expression profiles of MUC1 (membrane-bound mucin) of different glycoforms (from non-glycosylated form to fully glycosylated form), MUC2 (intestinal type secretory mucin), MUC5AC (gastric surface type secretory mucin) and MUC6 (gastric pyloric gland type secretory mucin) in 17 mucinous carcinomas and 46 invasive ductal carcinomas using immunohistochemistry. Various glycoforms of MUC1 were expressed frequently in both mucinous carcinomas (65-100%) and invasive ductal carcinomas (92-100%), although non-glycosylated MUC1 (MUC1/CORE) and fully glycosylated MUC1 (MUC1/HMFG-1) showed significantly lower expression rates in mucinous carcinomas compared with those in invasive ductal carcinomas. The expression rates of MUC2 (94%) and MUC6 (71%) in mucinous carcinomas were significantly higher than those of MUC2 (15%) and MUC6 (15%) in invasive ductal carcinomas. There was no significant difference in the expression rate of MUC5AC in mucinous carcinomas (12%) and that in invasive ductal carcinomas (4%). CONCLUSIONS: The expression rate of MUC1/CORE and MUC1/HMFG-1, which is related to poor prognosis in the gastric and colorectal cancers, is low in mucinous carcinomas. The high expression rate of gel-forming secretory mucins (MUC2 and MUC6) in mucinous carcinoma suggests that high production of these types of mucins may act as a barrier to cancerous extension resulting in their less aggressive biological behaviour.     

Invasive ductal carcinoma of the breast with signet-ring cell and mucinous carcinoma components: diagnostic utility of immunocytochemistry of signet-ring cells in aspiration cytology materials

Breast cancer with signet-ring cells is very rare. In this article, we present a case of invasive ductal carcinoma with signet-ring cells and mucinous carcinoma components, which could be diagnosed as a primary cancer by immunocytochemical study of fine-needle aspiration cytology material. A 73-yr-old Japanese woman noticed a palpable mass in the left breast. The aspiration cytology disclosed the monotonous proliferation of signet-ring cell with cytological atypia. The immunocytochemical examination of neoplastic cells showed a positive reaction for estrogen receptor. The extensive examination of body before the operation did not disclose any tumors in other anatomic sites. The histological examination of surgically resected breast tumor showed invasive ductal carcinoma with foci of signet-ring cell and mucinous carcinomas. Finally, our preliminary report suggests that immunocytochemical examination of aspiration cytology materials may provide useful information in searching the primary site of breast carcinoma with signet-ring cells.     

Immunohistopathological re-evaluation of adenocarcinoma of the lung with mixed subtypes using a tissue microarray technique and hierarchical clustering analysis

To re-evaluate adenocarcinoma, mixed subtypes (ADMIX) of the lung, a total of 201 cases were classified into three main subgroups according to the most differentiated histological growth pattern; namely bronchioloalveolar carcinoma (BAC)-mixed, which was the most predominant (73.1%), papillary (PAP)-mixed (21.9%), and acinar-mixed (5%). The PAP-mixed was significantly male predominant and had more progressed clinicopathological features. A significant cytological difference was observed among the three subgroups. A tissue microarray was constructed and immunohistochemistry was undertaken using 15 biomarkers. Hierarchical clustering analysis was separately applied to the immunohistochemical results of ADMIX and ADMIX subgroups, and it was found that most acinar-mixed cases were placed in a separate cluster, while the BAC-mixed and PAP-mixed failed to form significant independent clusters. The antibody clustering profile for the acinar-mixed was clearly different from that for the BAC-mixed or PAP-mixed, but the PAP-mixed shared a dendrogram profile with the other two subgroups. Statistically, approximately half of the 15 biomarkers were significant for differentiating between ADMIX subgroups and between different histological growth patterns. In conclusion, ADMIX can be classified into three histopathological subgroups according to the most differentiated growth pattern, of which a PAP growth pattern might indicate more aggressive behavior than that of a BAC growth pattern.     

Combined signet ring cell and glassy cell carcinoma of the uterine cervix arising in a young Japanese woman: a case report with immunohistochemical and histochemical analyses

Signet ring cell carcinoma and glassy cell carcinoma are both rare histological subtypes of uterine cervical cancer. This report is of a case of uterine cervical carcinoma arising in a 29-year-old woman who had major components of signet ring cell carcinoma and glassy cell carcinoma within the same tumor. Histochemical and immunohistochemical analyses, including high and low molecular weight cytokeratins, p63 and MUC5AC, additionally demonstrated the squamous and adenocarcinomatous differentiation in the neoplastic cells, which showed otherwise unclassifiable morphology on the haematoxylin-eosin sections. A wide range of differentiation described above supports the speculation that glassy cell carcinoma may arise from the multipotential immature cells that can differentiate into both squamous and glandular cells. It would be precise to classify this tumor as adenosquamous carcinoma. Although adenosquamous carcinoma is not a rare histological subtype in the uterine cervix, it should be necessary to report the presence of glassy cells and signet ring cells when present because the presence of both components is associated with an unfavorable clinical behavior.     

Protein expression profiles in adenocarcinomas and squamous cell carcinomas of the lung generated using tissue microarrays

With the appearance of defect-targeted therapies, the definition of tumour protein expression profiles has gained increasing importance. Two lung carcinoma tissue microarrays, one including 75 primary adenocarcinomas (ACs) and the other comprising 67 primary squamous cell carcinomas (SQCCs), were generated in the present study. On both arrays, each tumour was represented by an average of five cores. In addition, one punch of normal lung parenchyma adjacent to each tumour was included in the array. Immunohistochemical expression of 86 proteins was evaluated and the results were analysed by non-parametric tests, hierarchical clustering, and principal component analysis. In both tumour entities, parenchyma and tumours were clearly separated by hierarchical clustering. By the same statistical approach, it was possible to distinguish ACs from SQCCs with 98% accuracy and to distinguish parenchyma adjacent to ACs from that adjacent to SQCCs with 96% accuracy. It was also possible to separate ACs into three groups that significantly differed in survival. Cathepsin E and hsp105 were identified as previously unknown predictors of survival in lung AC. In summary, this study has shown that protein profiles are feasible tools for anticipating biological behaviour.     

Chromogranin A expression correlates with tumour cell type and prognosis in signet ring cell carcinoma of the stomach

Aims:  To investigate neuroendocrine (NE) differentiation in gastric signet ring cell carcinoma (SRCC) using chromogranin A (CgA) as an indicator of a well-differentiated NE phenotype and to determine its relationship to cell type, stage and prognosis.
Methods and results:  102 SRCCs were categorized into five subtypes according to the predominant cell type in the World Health Organization classification. 38 cases (37.3%) showed focal or diffuse CgA positivity. The positive cells were mostly histiocytoid and eosinophilic SRCC cells and some were classical SRCC cells. Small cell and anaplastic-type SRCC cells were only rarely immunopositive. There was no significant relationship between CgA expression and the extent of invasion or presence of metastasis. However, a significant positive correlation existed between CgA positivity and favourable prognosis, with a tendency for greater positivity to be associated with better overall survival. Multivariate analysis showed expression of CgA to be an independent prognostic factor.
Conclusion:  CgA expression is restricted to certain tumour cell types and may help to predict prognosis in gastric SRCCs.     

Mucin-producing adenocarcinoma of the lung, with special reference to goblet cell type adenocarcinoma: Immunohistochemical observation and Ki-ras gene mutation

To clarify its biological nature, 10 samples of goblet cell-type adenocarcinoma of the lung were collected and compared with 10 other pulmonary much-producing adene carcinomas with respect to Immunohistochemical features and the presence of Ki- ras gene mutation in codons 12 and 13. Goblet cell-type adenocarcinomas lacked lmmunoreactlvlty for surfactant apoprotein and S-100 protein-positive Langerhans cells, which was in marked contrast to other mucin-producing adenocarcinomas. In addition, the mucin gene products, MUC-1 and MUC-2 glycoproteins were immunohistochemically stained. The msuh showed that MUC-1 giycoprotein is frequently expressed by mucin-producing adenocarcinomas except the goblet cell-type. Ki- ras gene mutation was detected in 12 of 20 (60%) mucin-producing adenocarcinomas. These mutations were exclusively found in codon 12 and G to A transitions were the most frequent type of alteration in the KI- ras gene. In goblet cell-type adenocarcinomas, the frequency of KI- ras gene mutation was 80% consisting of G to A transitions and G to T transversions in six and two tumors, respectively. Therefore, goblet cell-type adenocarcinomas differed from other mucin-producing adeno-carcinomas in terms of immunohistochemical and molecular biological features, suggesting that goblet cell-type adenocarclnomas are distinctly different from other subtypes of adenocarcinomas.     

Colorectal adenocarcinoma with mucinous component: relation of MMP‐13, EGFR,and E‐cadherin expressions to clinicopathological features and prognosis

The aim of this study was to compare colorectal adenocarcinoma with mucinous component, ordinary adenocarcinoma (OA) and mucinous adenocarcinoma (MA) regarding clinicopathological parameters, survival, EGFR, MMP‐13, and E‐cadherin. We studied tumor tissue specimens from 28 patients with adenocarcinoma with mucinous component, 47 with OA, and 56 with MA, who underwent radical surgery from January 2007 to January 2012 at the Gastroenterology Centre, Mansoura University, Egypt. High density manual tissue microarrays were constructed and immunohistochemistry for EGFR, MMP‐13, and E‐cadherin was done. Colorectal adenocarcinoma with mucinous component (AWMC) was significantly associated with more perineural invasion, lower EGFR, and MMP‐13 expressions than OA, with no difference in E‐cadherin expression. Conversely, only microscopic abscess formation was significantly more with colorectal AWMC than MC with no difference in EGFR, MMP‐13 and E‐cadherin expression between both groups. Colorectal AWMC showed a better survival than MA with no difference with OA. In a univariate analysis, EGFR, MMP‐13, and E‐cadherin expressions did not show a significant impact on disease‐free or overall survival in patients with colorectal AWMC. Colorectal AWMC remains a vague entity that resembles OA in some clinicopathological and molecular respects as well as MA.     

Extremely high Langerhans cell infiltration contributes to the favourable prognosis of HPV-infected squamous cell carcinoma and adenocarcinoma of the lung

AIMS: The infiltration of Langerhans cells in adenocarcinomas and squamous cell carcinomas of the lung was examined in relation to prognostic implications and human papillomavirus (HPV) infection. METHODS AND RESULTS: Samples from 62 adenocarcinoma and 59 squamous cell carcinoma patients in 1995-97, the prognosis of which had been followed up, were used. The Langerhans cells were demonstrated immunohistochemically using anti S100a and CD1 antibodies. Human papillomavirus (HPV) infection was examined by polymerase chain reaction (PCR) and nonisotopic in-situ hybridization (NISH) methods. Statistical analysis was carried out using the Kaplan-Meier method (Wilcoxon analysis) and multiple regression analysis. HPV infection was demonstrated in 12 cases (19.4%) of adenocarcinoma. The HPV-infected adenocarcinomas had abundant faintly eosinophilic cytoplasm, and were immunohistochemically positive for the surfactant apoprotein A. In the 59 cases of squamous cell carcinomas 19 were of the well differentiated form, and 29 and 11 were moderately and poorly differentiated cases, respectively. HPV was detected in 29 cases (49.2%) (13 well and 16 moderately differentiated cases). In all HPV-infected adenocarcinoma and squamous cell carcinoma cases, extremely large numbers of Langerhans cells (more than 100 per high-power field) were demonstrated in the tumour nests. In contrast, in the non-HPV-infected adenocarcinomas and squamous cell carcinomas, only a few (less than about 10 per high-power field) Langerhans cells were observed. The squamous cell carcinoma cases with high Langerhans cell infiltration, which were also infected with HPV, showed a significantly good prognosis (P = 0.007). The adenocarcinoma cases with high Langerhans cell infiltration tended to have a better prognosis than the cases with low Langerhans cell infiltration, but the difference was not statistically significant. The low number of highly infiltrated cases was insufficient for an adequate statistical analysis. Furthermore, there was no significant correlation between either Langerhans cell infiltration and smoking, or HPV infection and smoking, in either squamous cell carcinoma or adenocarcinoma cases. CONCLUSIONS: It was considered that the extremely high Langerhans cell infiltration in the tumours was caused by HPV infection. The extremely large number of Langerhans cells in the tumours contributes to the favourable prognosis for HPV-infected lung cancer.     

Loss of alveolar basement membrane type IV collagen alpha3, alpha4, and alpha5 chains in bronchioloalveolar carcinoma of the lung

Type IV collagen, the major component of basement membrane (BM), is composed of six genetically distinct alpha(IV) chains. This study investigated for the first time the expression of these six alpha(IV) chains immunohistochemically, using alpha(IV) chain-specific monoclonal antibodies, in normal lung and in small (less than 2 cm in diameter) adenocarcinoma of the lung with a bronchioloalveolar growth pattern at the periphery. Small adenocarcinomas were histopathologically classified into three subtypes: bronchioloalveolar carcinoma (BAC) without collapse, BAC with collapse, and adenocarcinoma with bronchioloalveolar features. In normal lung, alveolar BM was composed of alpha1(IV)/alpha2(IV) chains and alpha3(IV)/alpha4(IV)/alpha5(IV) chains. In non-collapsed areas of BAC, alveolar BM was composed of linear alpha1(IV)/alpha2(IV) chains and discontinuous alpha3(IV)/alpha4(IV)/alpha5(IV) chains. In collapsed areas of BAC, alveolar BM was composed of linear and thick alpha1(IV)/alpha2(IV) chains only, because of the complete loss of alpha3(IV)/alpha4(IV)/alpha5(IV) chains. In invasive areas of adenocarcinoma with bronchioloalveolar features, alpha1(IV)/alpha2(IV) chains around the cancer cell nests were disrupted, in addition to the complete loss of alpha3(IV)/alpha4(IV)/alpha5(IV) chains. In conclusion, during the process of stromal invasion of lung adenocarcinoma, type IV collagen of alveolar BM is remodelled from the complete type, composed of alpha1(IV)/alpha2(IV)/alpha3(IV)/alpha4(IV)/alpha5(IV) chains, to the incomplete type, composed of only alpha1(IV)/alpha2(IV) chains, before the disruption of alpha1(IV)/alpha2(IV) chains. These findings may help to clarify the molecular mechanisms of cancer invasion.     

Anaplastic spindle cell carcinoma, arising in a background of an ovarian mucinous cystic tumor: a case report with clinical follow up, review of the literature

Anaplastic carcinoma (AC) of spindle cell type is an exceedingly rare ovarian malignant neoplasm. The histo-genesis of these tumors is still controversial. Although it was first thought to carry an invariably unfavorable prognosis, recent data indicates that this does not apply to stage Ia tumors. To date, there have been less than ten cases of anaplastic spindle cell carcinoma reported in the medical literature. Furthermore, our case is the first time this tumor has been described in a 40-year-old female with malignant spindle cells merging with conventional high grade adeno-carcinoma. The differential diagnosis of spindle cell proliferation in the ovary will be discussed and their distinction using a panel of immunohistochemical stains. This report demonstrated that the findings of malignant spindle cell proliferation does not imply this entity to be carcinosarcoma. The distinction of AC from true sarcomas is important because of the poorer prognosis of the later compared with the quite favorable behavior of AC. However, such existence necessitates a careful tissue sampling for the logical distinction between AC and carcinosarcoma, which is critical for planning further management and ultimately the predictor of prognosis.     

Immunolocalization of glycodelin in human adenocarcinoma of the lung, squamous cell carcinoma of the lung and lung metastases of colonic adenocarcinoma

Glycodelin (Gd), which is localized in cells of bronchial epithelium, type II pneumocytes and alveolar macrophages in rats and humans, plays an important role in the pulmonary immune response in asthmatic inflammation. In this study, sections of paraffin-embedded tumor adjacent lung tissue and sections of adenocarcinoma of the lung, squamous cell carcinoma of the lung and metastases of colonic adenocarcinoma were investigated for the distribution and expression of Gd using a polyclonal anti-Gd antibody. Glycodelin protein is located in the cytoplasm of bronchial epithelial cells, pneumocytes and alveolar macrophages. Furthermore, Gd is expressed in adenocarcinoma and squamous cell carcinoma of the lung as well as in lung metastases of colonic adenocarcinoma. Densitometric analyses showed a significantly increased expression of glycodelin protein in cancer tissue compared to tumor adjacent lung tissue. The Gd protein level was 1.7–2.6-fold increased in lung carcinoma compared to tumor adjacent lung tissue. The Gd protein level did not differ from each other between the investigated types of cancer tissue. Because these data validate the recent findings of Gd mRNA expression, it may be concluded that glycodelin plays an important role in the pathogenesis of lung cancer and lung metastases.