Expression and localization of thrombomodulin in preneoplastic bronchial lesions and in lung cancer

Thrombomodulin (TM) is an endothelial surface glycoprotein that acts as a natural anticoagulant. It inhibits thrombin and accelerates the activation of the anticoagulant protein C. TM has been detected in dermal keratinocytes, where it is associated with terminal differentiation. It can also be detected in various types of squamous malignant neoplasms and in malignancies of endothelial and mesothelial origin, such as Kaposi's sarcoma or malignant mesothelioma, but is absent in pulmonary adenocarcinomas (AC). Seventy-two lung tumour specimens [33 squamous cell carcinomas (SQCC), 23 AC, 1 large cell carcinoma, 8 small cell lung cancers (SCLC) and 7 multidifferentiated tumours (MT)] were analysed immunohistochemically by staining with an anti-TM antibody in order to assess TM expression. All of the SQCC stained positively for TM. In contrast, only 9 AC and 4 MT and none of the SCLC showed positive anti-TM staining. Seven hyperplastic bronchial epithelial specimens and eight preneoplastic bronchial lesions (five cases of moderate dysplasia, two cases of severe dysplasia and one case of carcinoma in situ) were used as controls.Normal or hyperplastic areas of bronchial epithelium revealed no positive reaction. However, a distinct positive anti-TM staining pattern related to the degree of keratiniziation of dysplastic lesions was seen. The present results suggest that anti-TM immunostaining is a useful marker for squamous cell carcinoma in the differential diagnosis of pulmonary carcinoma, also indicating keratinocyte differentiation in dysplastic bronchial epithelium.     

TTF-1在肺腺癌中的表达及其诊断意义

目的：评价甲状腺转录因子－1（TTF－1）在鉴别肺原发性腺癌与转移性腺癌中的临床病理应用价值。方法：20例肺原发性腺癌：10例高分化，包括3例乳头状、3例腺泡状、3例混合型腺癌和1例细支气管肺泡癌；10例低分化，包括4例黏液腺癌（其中1例为印戒细胞癌）和6例混合型腺癌。另选20例的胃肠道及卵巢腺癌，免疫组化应用TTF－1抗体。结果：95％的肺原发性腺癌表达TTF－1，而胃肠道及卵巢腺癌完全不表达。结论：对于确定肺原发或转移性腺癌的病理诊断。TTF－1是一个有用的特异性抗体，特别是在体积较小的肺活检标本或原发灶不明而仅有肺内转移时。     

Coexistence of papillary and medullary carcinoma of the thyroid gland-mixed or collision tumour? Clinicopathological analysis of three cases

We present three thyroid carcinomas displaying medullary and papillary components. In two cases the papillary component was characterized by typical papillae with a fibrovascular core; in one a follicular variant of papillary carcinoma was found. The papillary component was dominant in two and the medullary in one case. One tumour showed clear-cut borders between the two components, the others displayed an intermingled pattern. Both tumour components were seen in lymph node metastases with immunostaining with antibodies to calcitonin, chromogranin A, carcinoembryonic antigen, other neuroendocrine markers and thyroglobulin. At least two of our cases are true mixed carcinomas probably arising from a common stem cell.     

Spindle cell squamous carcinoma of the thyroid: an unusual anaplastic tumor associated with tall cell papillary cancer.

Five cases of spindle cell squamous carcinoma of the thyroid associated with tall cell papillary carcinoma were examined. The unusual spindle cell squamous carcinoma in these cases resembles those previously described in other sites, including the breast and oropharynx. Three patients demonstrated concurrent spindle cell squamous anaplastic carcinoma and tall cell papillary carcinoma at initial diagnosis, whereas two patients developed concurrent tumor morphologies subsequent to initial diagnoses of only papillary carcinoma. The mean age of the patients was 77 yr, with a female:male ratio of 4:1. Thyroglobulin immunoreactivity was demonstrated in the tall cell papillary component of each case but was absent in both the squamous and spindle cell components. Low molecular weight cytokeratin immunoreactivity was strongly and diffusely present in the tall cell papillary and squamous components, whereas the spindle cell areas demonstrated only focal weak to negative reactivity. Only the squamous cell component demonstrated consistent immunoreactivity with high-molecular-weight keratin antibodies. These unusual tumors have not been previously described in the thyroid, and the association of spindle cell squamous anaplastic carcinoma with tall cell papillary carcinoma in five independent cases may indicate a particular relationship.     

Expression of epithelial and neural antigens in small cell and non small cell lung carcinoma

Seventy-one lung carcinomas from 66 different patients were stained with a panel of monoclonal antibodies. Twenty-nine were small cell lung carcinoma (SCLC), 15 adenocarcinomas, 17 squamous carcinomas and 10 large cell carcinomas. Three of the monoclonal antibodies recognize different cytokeratins, three recognize other epithelial antigens and one recognizes a neural antigen. Both formalin-fixed and cryopreserved tumours were studied using an indirect immunoperoxidase method. 23/29 SCLC reacted with all but one of the antibodies which recognize epithelial antigens. This staining was similar to that seen in non small cell lung carcinomas (NSCLC) and provides further evidence that SCLC are true epithelial tumours. All but one of the SCLC stained with the antibody recognizing a neural antigen. This antibody did not stain squamous or adenocarcinomas. However, four of the large cell carcinomas stained well with this antibody, suggesting that SCLC and some large cell carcinomas share a common pathway of differentiation. There were variations of staining seen both within and between tumours. This has obvious implications if immunotargetting with monoclonal antibodies is to be used diagnostically or therapeutically.     

Small cell carcinoma of the lung and large cell neuroendocrine carcinoma interobserver variability

den Bakker M A, Willemsen S, Grünberg K, Noorduijn L A, van Oosterhout M F M, van Suylen R J, Timens W, Vrugt B, Wiersma‐van Tilburg A & Thunnissen F B J M
(2010) Histopathology 56, 356–363 Small cell carcinoma of the lung and large cell neuroendocrine carcinoma interobserver variability Aims: To test the hypothesis that the published morphological criteria permit reliable segregation of small cell carcinoma of the lung (SCLC) and large cell neuroendocrine carcinoma (LCNEC) cases by determining the interobserver variation. Methods and results: One hundred and seventy cases of SCLC, LCNEC and cases diagnosed as neuroendocrine lung carcinoma before LCNEC had been established as a diagnostic category were retrieved from the archives of the assessor’s institutes. A representative haematoxylin and eosin section from each case was selected for review. Batches of cases were circulated among nine pathologists with a special interest in pulmonary pathology. Participants were asked to classify the cases histologically according to the 2004 World Health Organization (WHO) criteria. The diagnoses were collected and κ values calculated. Unanimity of diagnosis was achieved for only 20 cases; a majority diagnosis was reached for 115 cases. In 35 cases no consensus diagnosis could be reached. There was striking variability amongst assessors in diagnosing SCLC and LCNEC. The overall level of agreement for all cases included in this study was fair (κ = 0.40). Conclusions: Using non‐preselected cases, the morphological WHO criteria for diagnosing SCLC and LCNEC leave room for subjective pathological interpretation, which results in imprecise categorization of SCLC and LCNEC cases.     

Small cluster invasion: a possible link between micropapillary pattern and lymph node metastasis in pT1 lung adenocarcinomas

Lung adenocarcinomas with micropapillary pattern (MPP) are associated with frequent nodal metastasis. However, little is known about the mechanisms that underlie MPP-associated nodal metastasis. In this study, we investigated how small micropapillary clusters of carcinoma cells present in tumoral alveolar spaces lead to increased lymph node metastasis. We analyzed 146 cases of pT1 lung adenocarcinomas with reference to the presence of MPP, small cluster invasion (SCI), and lymphatic involvement. SCI was defined as markedly resolved acinar–papillary tumor structures with single or small clusters of carcinoma cells invading stroma within fibrotic foci. The MPP-positive group (88/146 cases) was associated with significantly more frequent nodal metastasis and significantly worse survival. Moreover, SCI was significantly more frequent in the MPP-positive group (71/88 cases) than MPP-negative group (10/58 cases) and was significantly associated with lymphatic involvement (p < 0.0001) and nodal metastasis (p = 0.0073). The SCI-positive group showed significantly worse survival (5-year survival, 70%) than the SCI-negative group (91%, p = 0.0017). Carcinoma cells undergoing SCI demonstrated the same characteristic MUC-1 expression on the outer surface of cell clusters as those undergoing MPP. Thus, SCI could link MPP to nodal metastasis; carcinoma cells with MPP tend to undergo SCI in scars and invade lymphatics in pT1 lung adenocarcinomas.     

Rosette formation in non Hodgkin's lymphoma in the bone marrow--a case report

This is a case report of rosette formation in non-Hodgkin's lymphoma in the bone marrow. A 66 year old female on treatment for metastatic papillary carcinoma thyroid and non-Hodgkin's lymphoma of the nodular small cleaved cell type was found to have bone marrow infiltration by a low grade B cell lymphoma. Bone marrow aspirate, imprint and trephine biopsy showed rosettes of the abnormal lymphoid cells. The associations of papillary carcinoma thyroid, hyperglobulinemia and retroperitoneal fibrosis in this case which explain the histogenesis of rosette formation are discussed.     

Papillary adenoma of the lung. Histological and ultrastructural findings in two cases.

Two cases of papillary adenoma of the lung are presented along with results of histological and ultrastructural examinations. The tumors were encountered in two asymptomatic patients in a mass-survey chest X-ray examination. The chest X-ray films showed the tumors as well demarcated small lesions. Histologically, both tumors arose in the bronchioles and consisted of cuboidal cells resembling type II pneumocytes showing papillary growth with accompanying edematous connective tissue. Several tumor cells each possessed a large eosinophilic intranuclear inclusion. In case 1, ciliated cells and Clara-like cells were also present in the tumor. Ultrastructurally, most of the tumor cells had various numbers of lamellar bodies in their cytoplasm, indicative of type II pneumocytes, and some of case 1 showed features of Clara cells and ciliated cells. The intranuclear inclusions appeared as aggregates of tubular structures or had lamellar body-like features. These findings are identical to those of papillary adenoma arising from the bronchiole.     

Metastatic potential of encapsulated (intracystic) papillary carcinoma of the breast: a report of 2 cases with axillary lymph node micrometastases

Intracystic papillary carcinoma of the breast has rarely been reported to be associated with metastases. Presented are 2 cases, both of which showed micrometastatic carcinoma in axillary lymph nodes; neither demonstrated stromal invasion. Nearly complete absence of a myoepithelial cell layer around the periphery of the lesions was noted. One case showed 3 separate foci of micrometastatic carcinoma in 1 of 3 sentinel lymph nodes; the second showed micrometastases in 2 of 11 axillary lymph nodes. The clinical significance of micrometastases in lymph nodes associated with intracystic papillary carcinoma is unknown. The term encapsulated papillary carcinoma has been proposed to name papillary carcinomas that are surrounded by a fibrous rim, but which show a scant or absent myoepithelial cell component. The current 2 cases offer evidence to support the use of this term for particularly large encysted lesions. Sentinel lymph node biopsy may be prudent in such cases.     

Pulmonary neuroendocrine tumors: An entity in search of cytologic criteria

Pulmonary neuroendocrine tumors (PNET) are histologically subclassified into typical carcinoid (TC), atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC), and small cell carcinoma (SCLC). The criteria for subclassification in cytological specimens are not well defined. In this study, we reviewed histologically confirmed 18 TC, 8 AC, 10 LCNEC, and 10 SCLC cytologic specimens from 45 patients. The following features were reviewed: small clusters, geographic sheets, trabecular structures, pseudo‐rosettes, single cells, doublets, triplets or short cords, papillary‐like structures, capillary vasculatures, necrosis, smear background, cell size, cell pleomorphism, amount of cytoplasm, plasmacytoid cells, spindle cells, nuclear atypia, molding, palisading and smearing, chromatin textures, nucleoli, and mitotic figure count. Based on our results, geographic clusters and necrosis were often seen in LCNEC and SCLC; while AC only showed scattered single cell necrosis. TC and AC commonly exhibited trabecular structures. Papillary‐like structures and capillary vasculature were only present in TC, AC, and LCNEC. Cells forming doublets, triplets, and short cords were more commonly seen in SCLC and rarely seen in other entities. Plasmacytoid and spindle cells were only seen in TC and AC. Nuclear smearing was not identified in TC, rare in AC, focally present in LCNEC and obvious in SCLC. Mitotic figures were nearly absent in TC, ≤5/10 HPF in AT, and ≥10/10 HPF in SCLC. LCNEC showed a wide span of mitotic count ranging between 2 and 16/10 HPF. In this study, we propose a set of cytological features that are essential for subclassification of PNETs in cytologic specimens. Diagn. Cytopathol. 2013;41:689–696. © 2013 Wiley Periodicals, Inc.     

Tumor-to-tumor metastasis to follicular variant of papillary carcinoma of thyroid.

OBJECTIVE: To describe and document tumor-to-tumor metastases in the thyroid gland. METHODS AND RESULTS: In this series we describe 3 cases of tumor-to-tumor metastasis in which the recipient tumor was a follicular variant of papillary thyroid carcinoma. The donor tumors and sites were small cell carcinoma of the lung, neuroendocrine carcinoma probably of pancreatic origin with initial presentation as liver metastasis, and clear cell carcinoma of the kidney with metastasis to liver and pancreas. The donor tumor cells infiltrated the substance of the follicular variant of papillary thyroid carcinoma, the nontumorous thyroid parenchyma, and the lymphovascular spaces. Small cell carcinoma and neuroendocrine carcinoma showed positive reactivity for neuroendocrine markers and were negative for thyroglobulin and calcitonin. The follicular variant of papillary thyroid carcinoma showed positivity with thyroglobulin and cytokeratin 19. CONCLUSIONS: Although tumor-to-tumor metastases in thyroid gland are exceedingly rare, one should be aware of this phenomenon as the metastatic lesion may simulate a thyroid primary. History of a previous tumor and immunohistochemical stains can be helpful in distinguishing between primary and metastatic thyroid neoplasms.     

Small cell carcinomas of the lung express the Bcl-2 protein.

In our laboratory, we observed that a case of small cell carcinoma of the lung (SCLC) stained with a monoclonal antibody (Dako Corp., Bcl-2-124) against the Bcl-2 protein. To determine how common this reaction was, and whether it was specific for SCLC, we stained formalin-fixed, paraffin-embedded tissues from 23 cases of SCLC and 20 cases of squamous cell carcinoma of the lung for Bcl-2. Fifteen of the 23 SCLC cases stained positively for the Bcl-2 oncogene protein. In contrast, weak staining was observed in only three of the squamous cell carcinomas (chi 2-test; P = 0.001). In addition, four small cell carcinoma cell lines (H69, H146, H209, and WB) were tested by immunohistochemistry and flow cytometry for expression of this protein; all four were positive. In these and three other (H128, H432, and H510) SCLC lines, Northern blots of polyadenylated RNA revealed expression of the 6-kb Bcl-2 mRNA. Moreover, Western blots of extracts from these cell lines revealed the characteristic 26-kd band for Bcl-2 protein. In a single cell line, H82, which has previously been characterized as a variant SCLC, we failed to detect expression of the Bcl-2-specific mRNA and protein. We therefore conclude that most cases of SCLC of the lung express the Bcl-2 oncoprotein, which could play a role in the pathogenesis of this disease.     

Significant high expression of cytokeratins 7, 8, 18, 19 in pulmonary large cell neuroendocrine carcinomas,compared to small cell lung carcinomas

The aim of the present study was to clarify protein profiling in small cell lung carcinoma (SCLC) and pulmonary large cell neuroendocrine carcinoma (LCNEC). The proteomic approach was used, and involved cell lysate from two cell lines (N231 derived from SCLC and LCN1 derived from LCNEC), with 2‐D gel electrophoresis (2‐DE). In the present study, 25 protein spots with greater than twofold quantitative differences between LCN1 and N231 cells on 2‐DE gels were confirmed. Within the 25 identified proteins, cytokeratins (CK) 7, 8, 18 and 19 were upregulated in LCN1 cells compared with N231 cells. The expression of CK7, 8, 18, and 19 was further studied on immunohistochemistry with 81 formalin‐fixed and paraffin‐embedded pulmonary carcinomas, which included 27 SCLC, 30 LCNEC, 14 adenocarcinomas, and 10 squamous cell carcinomas. Although the expression of CK7, 8, 18, and 19 was observed in all histological types, the mean immunostaining scores of CK7, 8, 18, and 19 were significantly higher in LCNEC than in SCLC (P < 0.001, P < 0.001, P < 0.01 and P < 0.001, respectively). These data suggest that the biological characteristics of LCNEC and SCLC may be different and the expression of CK may serve as differential diagnostic markers.     

40岁以下妇女子宫内膜癌刮宫活检的病理诊断问题

目的 探讨40岁以下妇女子宫内膜癌刮宫活检的病理诊断。方法对20例40岁以下子宫内膜癌患者的临床病理资料进行回顾性分析。结果子宫内膜样腺癌18例,腺鳞癌(腺癌伴鳞状上皮分化)1例,浆液性乳头状癌并透明细胞癌1例。子宫内膜样腺癌的组织学特点是子宫内膜腺体失去极性,细胞核变大、变圆、核仁突出,染色质粗或呈空泡状,同时子宫内膜间质消失,代之为肉芽组织或纤维组织,常有炎性反应。子宫内膜样腺癌多数仅累及浅肌层,皆无转移。1例子宫内膜腺鳞癌呈双侧卵巢转移;1例浆液性乳头状癌有盆腔淋巴结转移。结论40岁以下妇女的子宫内膜癌多数为高分化子宫内膜样腺癌,应注意与子宫内膜不典型增生及不典型息肉状腺肌瘤鉴别。     

Aspiration cytology of cystic carcinoma of the breast

Cystic carcinomas of the breast are rarely encountered in fine-needle aspiration (FNA) biopsies. The most common entities comprise intracystic papillary adenocarcinoma, ductal adenocarcinoma with cystic degeneration including comedo forms of ductal adenocarcinoma in situ, medullary carcinoma, squamous carcinoma, and cystic hypersecretory ductal adenocarcinoma. The cytologic diagnosis is often hampered by sparse cellularity, abundant obscuring blood, necrotic debris, and degenerative changes in diagnostic cells. We report on the cytologic features of 10 cases of cystic carcinoma, including 12 FNA biopsies with radiologic and surgical correlation. The original cytologic diagnoses for these cases were: benign (2 cases), atypical (2 cases), suspicious (3 cases), and positive for malignant cells (3 cases). On repeat FNA, one benign case and one atypical case were reclassified, respectively, as atypical and suspicious for carcinoma. The follow-up diagnoses were 5 intracystic papillary adenocarcinomas and 5 cystic ductal adenocarcinomas. Despite 2 false-negative cases, all cases were adequately managed. Correlation with clinical and radiologic findings and direct sampling of any solid component of these cystic neoplasms are crucial in diagnosis and management.     

Mucin histochemistry of pancreatic duct cell carcinoma, with special reference to organoid differentiation simulating gastric pyloric mucosa.

The present study was undertaken to explore mucins produced in normal, metaplastic, and hyperplastic ductal epithelia as well as in carcinoma tissues of the pancreas, and used a battery of histochemical techniques. Thirty-five cases of ordinary pancreatic duct cell carcinoma and nine cases of duct cell carcinoma, which fulfilled the clinical criteria of "mucin-producing carcinoma of the pancreas," were examined. The results indicated that all lesions of mucinous metaplasia with or without papillary hyperplasia as well as atypical hyperplasia characteristically had gastric mucins and showed organoid differentiation simulating the gastric pyloric mucosa, but never stained for 8-O-acetyl-N-acetylneuraminic acid, which is a histochemical marker of the large intestine. Ordinary duct cell carcinoma also contained gastric mucins and small intestinal mucins and showed organoid differentiation, but rarely had 8-O-acetyl-N-acetylneuraminic acid. Mucin-producing carcinomas were classified into two groups: the ordinary duct cell carcinoma group and a group that showed marked atrophy and extensive fibrosis of the parenchyma, a lack of organoid differentiation and gastric mucins, and an abundance of large and small intestinal mucins. These results suggest that gastrointestinal mucins are useful markers to detect cancer-related lesions and cancers of the pancreas.     

Mixed medullary and follicular cell carcinoma of the thyroid with lymph node metastasis in a 7-year-old child

A 7-year-old boy presented with midline swelling in the neck. On fine-needle aspiration cytology it was diagnosed as papillary carcinoma of the thyroid. The patient underwent total thyroidectomy. Histopathological examination, immunohistochemistry and electron microscopy revealed the presence of two intermingled components: medullary carcinoma and papillary carcinoma. One of the submandibular lymph nodes had metastasis of both the components. The case was diagnosed as 'mixed medullary and follicular cell carcinoma' with papillary carcinoma pattern and lymph node metastasis. Mixed medullary and follicular cell carcinoma with intermingling of medullary and papillary carcinoma components is a rare tumor. In adults, only eight such cases with lymph node metastasis have been published. To the best of the authors' knowledge no pediatric case has previously been reported in the English-language literature.