Multilocular thymic cyst associated with Sjögren's syndrome.

A 61-year-old woman, who had been diagnosed as having Sjögren's syndrome, developed an anterior mediastinal mass. She was diagnosed with Sjögren's syndrome with thymoma, preoperatively. Extended thymectomy was performed. Macroscopically, the mediastinal mass showed thick-walled multiloculated cavities filled with turbid yellow fluid. Microscopically, the cyst lining was continuous with thymic lobules in the wall with inflammatory process, cholesterol granuloma formation, and prominent lymph follicular hyperplasia. She was diagnosed with multilocular thymic cysts associated with Sjögren's syndrome.

Clinicopathologic and DNA cytometric analysis of carcinoid tumors of the thymus.

Twelve cases of carcinoid tumors of the thymus were reviewed in terms of clinicopathologic, histochemical, and immunohistochemical features and DNA ploidy patterns. The collective consisted of nine male and three female patients, aged 34 to 74 years, of whom five (42%) had symptoms. Eleven patients underwent surgical resection, and one with systemic metastases was autopsied. In the 11 resected patients, tumors had invaded surrounding structures in four cases, and mediastinal lymph node metastases were detected in six. Recurrence occurred in two of the resected patients (18%), and the 5-year survival rate was 82%. Histologically, all tumors showed an organoid growth pattern with delicate fibrovascular stroma. In addition, three tumors had unusual morphologic features such as combined features of carcinoid tumor and thymoma and solid growth pattern with occasional large tumor cells. Mitotic counts ranged from 1 to 14 per 10 high-power fields with a mean count of 4.9. Central necrosis within solid nests was observed in nine tumors. Classification of this series using the WHO histologic classification system resulted in categorization of all 12 tumors as atypical carcinoids. All tumors were positive for Grimelius staining and for cytokeratin. Immunohistochemical staining documented the presence of moderately to strongly positive neuroendocrine markers such as neuron-specific enolase, chromogranin A, synaptophysin, and neural cell adhesion molecule. No correlation between proliferative activity based on the Ki67 labeling index and prognosis or lymph node metastasis was found. Concerning DNA ploidy patterns, only one tumor with multiple lymph node metastases was considered to be aneuploid. In conclusion, although all of our cases were histologically classified as atypical carcinoid tumors of the thymus, most were diploid, and the patients enjoyed a relatively good prognosis.

The new World Health Organization classification of lung tumours.

Tumour classification systems provide the foundation for tumour diagnosis and patient therapy and a critical basis for epidemiological and clinical studies. This updated classification was developed with the aim to adhere to the principles of reproducibility, clinical significance, and simplicity in order to minimize the number of unclassifiable lesions. Major changes in the revised classification as compared to the previous one (WHO 1981) include the addition of two pre-invasive lesions to squamous dysplasia and carcinoma in situ; atypical adenomatous hyperplasia and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. Another change is the subclassification of adenocarcinoma: the definition of bronchioalveolar carcinoma has been restricted to noninvasive tumours. There has been substantial evolution of concepts in neuroendocrine lung tumour classification. Large cell neuroendocrine carcinoma (LCNEC) is now recognized as a histologically high grade non small cell carcinoma showing histopathological features of neuroendocrine differentiation as well as immunohistochemical neuroendocrine markers. The large cell carcinoma class has been enriched with several variants, including the LCNEC and the basaloid carcinoma, both with a dismal prognosis. Finally, a new class was defined called carcinoma with pleomorphic, sarcomatoid, or sarcomatous elements, which brings together a number of proliferations characterized by a spectrum of epithelial to mesenchymal differentiation. Immunohistochemistry and electron microscopy are invaluable techniques for diagnosis and subclassification, but our intention was to render the classification simple and practical to every surgical laboratory, so that most lung tumours could be classified by light microscopic criteria.

Pulmonary atypical carcinoid: predictors of survival in 106 cases.

Pulmonary neuroendocrine tumors (NE) include a spectrum of tumors from typical carcinoid (TC) to atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC), and small cell carcinoma (SCLC). Little is known about prognostic predictors for AC because of its rarity. Survival analysis was performed on 106 ACs with clinical follow-up from the AFIP and the Pathology Panel of the International Association for the Study of Lung Cancer (IASLC). The tumors fulfilled the 1999 WHO/IASLC criteria for AC of a NE tumor with a mitotic rate of 2 to 10 per 2 mm(2) of viable tumor or coagulative necrosis. Multiple clinical and histologic features were analyzed by Kaplan-Meier and Cox regression analysis. Of the clinical features, higher stage (P = .003) and a tumor size of 3.5 cm or greater (P = .003) were associated with a worse prognosis. Features that were histologically unfavorable by univariate analysis were mitotic rate (P =.002), pleomorphism (P = .018), and aerogenous spread (P =.007). Histologically favorable features by univariate analysis were the presence of palisading (P = .008), papillary (P = .039), pseudoglandular (P =.026), and rosette (P = .022) patterns. Female gender showed a trend toward a poorer prognosis (P =.085) and was included in the multivariate model. Multivariate analysis stratified for stage showed mitoses (P<.001), a tumor size of 3.5 cm or greater (P =.017), and female gender (P =.012) to be the only negative independent predictors of prognosis and the presence of rosettes (P = .016) to be the only independent positive predictor. We further divided the AC into subgroups of low (2 to 5 mitoses/2 mm(2)) and high (6 to 10 mitoses/2 mm(2)) mitotic rate and compared the survival with TC and with LCNEC. Within the category of AC, the patients with a higher mitotic rate had a significantly worse survival than those with a lower mitotic rate (P<.001) stratified for stage. Five- and 10-year survival rates for AC (61% and 35%, respectively) stratified for stage were significantly worse than for TC and better than that for LCNEC and SCLC. Chemotherapy or radiation therapy was given in 12 of 52 and 14 of 52 cases, respectively, but the data were insufficient to evaluate tumor response. We conclude that AC is an aggressive neuroendocrine neoplasm with survival intermediate between TC and LCNEC and SCLC. Higher mitotic rate, tumor size of 3.5 cm or greater, female gender, and presence of rosettes are the only independent predictors of survival. Surgical resection remains the treatment of choice, and the role of chemotherapy and radiation therapy remains to be proven.

Histopathologic prognostic factors in resected adenocarcinomas: is nuclear DNA content prognostic?

BACKGROUND: The pathobiological characteristics of lung adenocarcinoma are still unclear. To identify the factors that may affect the survival of patients undergoing pulmonary resections for adenocarcinoma of the lung, univariate and multivariate analyses were performed for 17 variables of the host, histopathology, nuclear DNA content (NDC), and morphometry of nucleus (nuclear area [NA]) of tumor cells. METHODS: Seventy-two consecutive patients who underwent resection at the National Cancer Center in Tokyo were studied. They consisted of 45 men and 27 women with an average age of 61.7 years (range, 27 to 83 years). For these patients, NDC and NA were prospectively measured by cytofluorometry and morphometry, respectively. For univariate analysis, 17 factors were studied, including age, sex, TNM stage, diameter of the tumor, pleural involvement, degree of differentiation, scar grade, nuclear atypia, mitotic index, histogram pattern of NDC, mean NDC, number of aneuploid stem cell lines, and mean and SD of NA. A multivariate analysis was performed with Cox's regression model for 16 variables. RESULTS: In the univariate analysis, 12 factors were significantly related to postoperative survival, including TNM stage, diameter, pleural involvement, nuclear atypia, mitotic index, mean NA, mean NDC, number of aneuploid stem cell lines, and the DNA histogram pattern. In the multivariate analysis, M, T, and the histogram pattern of NDC were significantly associated with survival while N showed a strong, but not significant, association. CONCLUSIONS: Multivariate analysis of histopathologic prognostic factors indicated that the TNM stage, as well as each component independently, still provided the greatest prognostic value in resected adenocarcinomas of the lung. Among other factors, only NDC significantly affected survival. The importance of NDC measurement should be stressed for predicting the survival after surgical resection more accurately and for selecting patients with a higher risk of recurrence.

Two cases of repeatedly recurrent atypical thymoma.

Two cases of repeatedly recurrent thymoma with myasthenia gravis are detailed here. A 41-year-old woman had 5 recurrent thymomas, including local recurrences and lumbar and lung metastases; she was alive at the time of this writing, which was 22 years after her first surgery. A 36-year-old man had 3 recurrent thymomas, including local recurrence, dissemination, and lung metastasis; he was alive at the time of this writing, which was 16 years after his first surgery. Both recurrent lesions were diagnosed as "atypical thymoma" with moderate nuclear atypia. The patients with atypical thymoma must be followed up carefully due to a possible recurrence. Surgical treatment with chemoradiotherapy can lengthen their survival.

Fibrotic focus in infiltrating ductal carcinoma of the breast: a significant histopathological prognostic parameter for predicting the long-term survival of the patients.

The presence of fibratic fows (FF) in infiltrating ductal carcinoma (IDC) has been shown to be an important histological factor associated with high tumor aggressiveness, or early tumor recurrence or death. However, the clinicopathological significance of FF for predicting the long-term survival of the patients with IDC has not been fully investigated. In order to elucidate this aspect, we divided 140 IDCs with at least 10 years of follow up into tumors with FF and those without. IDC with FF showed significantly higher histologic grade (P=0.02), higher frequency of tumor necrosis (P=0.02), higher frequency of cases with more than three positive lymph node metastases (P=0.04), higher T classification (P=0.009), and higher pathological stage (P=0.0002) than those without FF. Relative risk (RR) of tumor recurrence and death was significantly higher in tumors with FF than in those without (RR=4.5, P < 0.00001 and RR=5.6, P < 0.00001, respectively). In cases of early stage cancer (stages I, IIA, and IIB), or in those with less than four lymph node metastases, IDCs with FF demonstrated a significantly higher risk than those without. Multivariate adjustments for other pathological factors did not change the RRs significantly. These results indicate that in long-term follow up the presence of FF is a significant prognostic parameter for IDC, and therefore strongly suggest that IDCs must be divided into those with and without FF.

Analysis of loss of heterozygosity in small adenocarcinomas of the lung.

BACKGROUND: Despite the many studies of genetic alterations in advanced lung carcinomas, few reports have analyzed early stage adenocarcinoma of the lung. METHODS: We focused on small pulmonary adenocarcinomas, classified according to recently proposed histological criteria (Noguchi M., et al. Cancer 1995;75:2844-52) which divided adenocarcinomas 2 cm or less in diameter into two groups; one showing replacing growth of the pulmonary alveolar structure [A, localized bronchioloalveolar carcinoma (LBAC); B, LBAC with alveolar collapse; C, LBAC with active fibroblastic proliferation] and the other showing non-replacing growth (D, poorly differentiated adenocarcinoma). Ninety-four small pulmonary adenocarcinomas, including 40 of type A and B, 30 of type C and 24 of type D, were examined for loss of heterozygosity (LOH) using microsatellite markers. RESULTS: The frequencies of LOH were 19.8% in types A and B, 26.8% in type C and 32.7% in type D tumors. There were no significant differences in the frequency of LOH on chromosomes 2p, 3p, 9p and 17q among tumor types. However, on 17p, the frequency of LOH was significantly lower for types A and B than for type C or D. Three out of six type C tumors which were positive for LOH at several loci showed different LOH patterns in two areas (central and peripheral regions). CONCLUSIONS: Allelic losses were detected in very early adenocarcinomas and the frequency of LOHs on chromosome 17p increased during malignant progression of the tumor. Heterogeneous genetic alterations were demonstrated even in small pulmonary adenocarcinomas.

Papillary carcinoma of the thymus: report of four cases of a new microscopic type of thymic carcinoma.

We describe four cases of papillary carcinoma arising in the thymus. Three showed low-grade atypia and were associated with spindle cell-type thymoma. The fourth case showed high-grade atypia and had no evidence of an association with thymoma. Two of three low-grade cases invaded the lung and showed extensive lymphatic permeation. Cyst formation was seen in one case. Immunohistochemically, the tumor cells were positive for carcinoembryonic antigen (CEA), Leu-M1, Ber-EP4, calretinin (2 cases), and CD5 and were negative for thyroglobulin and pulmonary surfactant apoprotein. Ultrastructural findings for the one case studied by electron microscopy gave evidence against a mesothelial origin of the tumor. The histologic similarities and the intimate association with spindle cell thymoma indicate that papillary thymic carcinoma may arise from the papillotubular formations sometimes seen in the former tumor. Papillary thymic carcinoma, a lesion hitherto undescribed, should be considered in the differential diagnosis of anterior mediastinal tumors. Conceivably, it may be the source of some metastatic papillary carcinomas with or without psammoma bodies in cervical lymph nodes, in which no tumor is found in the thyroid gland.

Low-grade B cell lymphoma of mucosa-associated lymphoid tissue in the thymus of a patient with rheumatoid arthritis.

The majority of thymic lymphomas are either lymphoblastic lymphoma, large B cell lymphoma or Hodgkin's disease, and other types of non-Hodgkin lymphoma are rare. A case of low-grade B cell lymphoma of mucosa-associated lymphoid tissue (MALT) in the thymus is reported. A 55-year-old Japanese female with a history of rheumatoid arthritis (RA) complained of back pain. A mediastinal tumor was identified by computerized tomography and magnetic resonance imaging, and the thymus was resected through median sternotomy. The solid and nodular tumor had several small satellite extensions and was completely confined to within the thymus. Histologically, monotonous medium-sized centrocyte-like cells occupied the medulla of the thymus and infiltrated Hassall's corpuscles (lymphoepithelial lesions). Immunohistochemically, tumor cells were positive for CD20 and CD79a. IgA and kappa light chain restriction were also found in plasmacytoid cells in the tumor. Clonal rearrangement of the immunoglobulin heavy chain gene was demonstrated by polymerase chain reaction. This case was diagnosed as MALT-type low-grade B cell lymphoma in the thymus. This is the first report of low-grade B cell lymphoma in the thymus associated with RA. As autoimmune diseases are known to be associated with lymphoid neoplasms, it is suggested that the RA played an important role in the development of malignant lymphoma in this case.

Clinicopathological characteristics of primary breast cancer in older geriatric women: a study of 39 Japanese patients over 80 years old.

The number of primary breast cancers occurring in elderly women is increasing in Japan. Optimization of treatment regimens in this age group requires precise evaluation of the biological aggressiveness of these tumors as well as the performance status and extent of tumor spread. In 39 breast cancer patients who were at least 80 years old, we examined several parameters; the form of surgical therapy, the lymph node status, presence or absence of distant metastases, the histological type and grade of atypia, and overexpression of the c-erbB-2 oncoprotein in the cancer cells. They were correlated with the clinical outcome of the patient. Of the 33 patients who underwent a mastectomy and axillary lymph node dissection, five died from cancer recurrence. Only one out of 22 patients without lymph node metastases died from cancer, while four out of the eight patients with metastases to three or more lymph nodes died from cancer recurrence within 2.7 years of surgery. The overall survival curves also differed between patients with low-risk histological tumors or grade 1 or 2 invasive ductal carcinoma and those with grade 3 invasive ductal/lobular carcinoma. Overexpression of c-erbB-2 also affected survival. Regional recurrence occurred in three out of the six patients for whom only lumpectomy or simple mastectomy was performed. These results indicate that, although primary breast cancer occurring in patients over 80 years old was largely of low-grade malignancy, patients with three or more lymph node metastases, invasive ductal/lobular carcinomas of grade 3, or c-erbB-2 overexpression frequently exhibited an aggressive clinical course.

A case of sarcomatoid carcinoma of the thymus.

A 57-year-old woman presented with a 10 x 10 cm anterior mediastinal mass. The tumor had invaded the pericardium, both lungs and the left brachiocephalic vein, and was treated by partial resection and postoperative radiation therapy. Pathological examination of the tumor revealed squamous cell carcinoma with a spindle cell sarcomatous component. Immunohistochemically, keratin and epithelial membrane antigen were positive in both the spindle cell sarcomatous areas and the squamous cell carcinomatous area and thus, a diagnosis of thymic carcinoma of sarcomatoid type was made. The patient died of recurrent disease 1 year after surgery. This case is the seventh reported in the English literature. Because of the poor outcome, adjuvant therapy is recommended.

Nuclear p53 accumulation by small-sized adenocarcinomas of the lung.

In order to evaluate the alterations of nuclear p53 accumulation in early stage adenocarcinomas of the lung, nuclear p53 accumulation by small-sized peripheral adenocarcinomas of the lung was examined immunohistochemically. Peripheral adenocarcinomas of the lung, 2 cm or less in diameter, have been classified into two groups; one showing replacing growth of the pulmonary alveolar structure and the other showing non-replacing growth. The former group has been subdivided into three microscopic subtypes: type A, localized bronchioloalveolar carcinoma (LBAC); B, LBAC with foci of pulmonary alveolar structural collapse; and C, LBAC with foci of active fibroblastic proliferation. Type C is thought to be advanced carcinoma, which develops progressively from types A and B. Two of 32 (6%) types A and B carcinomas, 37 of 133 (28%) type C carcinomas and 14 of 35 (40%) non-replacement-type adenocarcinomas showed positive nuclear staining for p53. The positive staining frequency was significantly higher for type C than for types A and B (P < 0.05). These results suggest that nuclear p53 accumulation occurs in the transition from the early to advanced stages of replacement-type adenocarcinoma development and it may be a clinically useful indicator of the degree of tumor malignancy.

Lymph node involvement, recurrence, and prognosis in resected small, peripheral, non-small-cell lung carcinomas: are these carcinomas candidates for video-assisted lobectomy?

To determine the clinicopathologic characteristics of peripheral non-small-cell carcinomas, the cases of 337 patients undergoing major pulmonary resection with complete lymphadenectomy were retrospectively reviewed with regard to lymph node involvement, recurrence, and prognosis. All of the tumors were 3.0 cm or less in diameter and were categorized as T1 (318 patients) or T2 (19). Eighty-eight patients (26.1%) had lymph node involvement: 32 (9.5%) at N1 nodes, 55 (16.3%) at N2 nodes, and 1 (0.3%) at N3 nodes. Although the prevalence of lymph node involvement did not differ significantly with tumor histologic type, it was quite low in squamous cell carcinomas 2.0 cm or less in diameter. Of the 56 N2/3 metastases, 14 (25%) occurred in a "skipping" manner, and all but one had a nonsquamous histologic makeup. Of the 213 patients with a follow-up period of 5 years or more, 59 patients (27.7%) showed cancer recurrence. This occurred at a distant site in 67.8% of the cases. Five-year survival rates based on nodal status were 91.9% (NO), 61.8% (N1), 44.5% (N2), and 0% (N3). Because of the relatively high prevalence of lymph node involvement, complete hilar/mediastinal lymphadenectomy should be routinely done regardless of tumor histologic type and size, as long as patients are at good risk. However, in squamous cell histologic types, mediastinal lymphadenectomy might be dispensable if the tumor is less than 2.0 cm in diameter, or if the hilar node is proved to be tumor-free on pathologic examination of the frozen section during operation. Although video-assisted major pulmonary resection currently has limited application, this new technique may represent a surgical option in resection without complete lymphadenectomy.

Fibrotic focus in invasive ductal carcinoma: an indicator of high tumor aggressiveness.

Histological examination of invasive ductal carcinoma of the breast often demonstrates the presence of an extensive central fibrotic focus (FF). The clinicopathological significance of the FF, or scar, in primary invasive ductal carcinoma is still ambiguous. One hundred and fifty-three cases of invasive ductal carcinoma (IDC) were classified into two groups, those with and those without FF. The differences in frequency of immunohistochemically detected overexpression of c-erbB-2 protein and nuclear accumulation of p53 protein, and the labeling index of proliferating cell nuclear antigen (PCNA), as well as histopathological parameters were compared between these two groups. IDCs smaller than 50 mm with FF showed a higher frequency of high-grade tumors, a higher frequency of lymph node metastasis, and a significantly higher frequency of c-erbB-2 protein overexpression than those without FF. In tumors of 20 mm or less, the incidence of nuclear accumulation of p53 protein was significantly higher in tumors with than those without FF. Tumors with FF showed a significantly higher PCNA labeling index than those without FF, regardless of tumor size. The present results indicate that the presence of FF is an important clinicopathological parameter associated with a higher degree of malignancy in IDCs, especially those smaller than 50 mm. Therefore, dividing IDCs into those with and those without FF appears to be meaningful clinicopathologically.

DNA gyrase gyr A gene mutations in ofloxacin-resistant Staphylococcus aureus.

A total of 106 clinical isolates of Staphylococcus aureus were classified into nine pattern types correlated with gyrA mutations. In 62 strains, mutations were found at a single codon (84, 85, 86 and 88), while 22 strains showed double mutations either at codons 84 and 85 or at codons 84 and 88. The double mutations led to the highest levels of ofloxacin resistance (MIC, > or = 128 microg/ml). All isolates with a single Ser-84--> Leu change had an ofloxacin MIC of 8-128 microg/ml, whereas others showed an MIC range of 8-16 microg/ml. Twenty-two wild type strains and one strain with a single mutation at codon 86 (silent mutation) were ofloxacin-susceptible. Thus, gyrA mutations seem to play a definite role in the high-level of resistance to ofloxacin.

Identification of mycobacteria by nonradioisotopic single-strand conformation polymorphism analysis.

Clinical isolates of mycobacteria were identified to species levels using nonradioisotopic single-strand conformation polymorphism (non-RI SSCP) analysis of 16S rRNA gene fragments amplified by polymerase chain reaction with primers common to all of mycobacterial species. The method is based on a hypervariable region within the 16S rRNA in mycobacteria, which is characterized by species-specific nucleotide sequences. A total of 92 mycobacterial strains (Mycobacterium tuberculosis, M. avium, M. gordonae, M. intracellulare, M. kansasii, M. chelonae, M. nonchromogenicum, M. xenopi, and unidentified strain) were studied. They were classified into nine types of pattern showing single-strand DNA bands having different mobilities. Each strain was shown in the species-specific mobility by non-RI SSCP analysis. The results of non-RI SSCP analysis were identical to those of standard biochemical methods and 16S rRNA sequencing.

The value of PE-10, a monoclonal antibody against pulmonary surfactant, in distinguishing primary and metastatic lung tumours.

A new monoclonal antibody (PE-10) raised against components of pulmonary surfactant has been assessed for its ability to distinguish primary from secondary carcinomas in the lung. We applied this antibody to a series of 107 primary lung carcinomas, 40 adenocarcinomas of other sites, and 26 cases of adenocarcinoma metastatic to lung and pleura. Of the primary lung carcinomas, all the non-mucinous bronchiolo-alveolar carcinomas were positive whereas all the mucinous cases were negative; 60% of other types of adenocarcinoma were positive and 10% of large cell undifferentiated carcinomas, 20% of small cell carcinomas and 40% of atypical carcinoids also showed focal positivity. Squamous cell carcinomas were all negative. Adenocarcinomas of the breast, kidney, large bowel and ovaries were all negative, as were all 26 cases of adenocarcinoma metastatic to the lung and pleura. We conclude that this antibody is highly specific and moderately sensitive for primary tumours of the lung.

Small adenocarcinoma of the lung. Histologic characteristics and prognosis.

BACKGROUND: Although there are many reported prognostic indicators for pulmonary adenocarcinoma, the clinicopathologic characteristics and prognostic factors of early stage adenocarcinoma have not been evaluated fully, except for several studies of nonmucinous and sclerosing bronchioloalveolar carcinoma. METHOD: Two hundred thirty-six surgically resected small peripheral adenocarcinomas measuring 2 cm or less in greatest dimension were reviewed using a simple histologic classification of six types based on tumor growth patterns. RESULTS: Type A (localized bronchioloalveolar carcinoma [LBAC]) (n = 14) revealed replacement growth of alveolar-lining epithelial cells with a relatively thin stroma. In type B (LBAC with foci of structural collapse of alveoli) (n = 14), fibrotic foci due to alveolar collapse were observed in tumors of LBAC. Type C (LBAC with foci of active fibroblastic proliferation) (n = 141) was the largest group in this study, and foci of active fibroblastic proliferation were evident. Type D (poorly differentiated adenocarcinoma), type E (tubular adenocarcinoma) and type F (papillary adenocarcinoma with a compressive growth pattern) (n = 61) showed compressive and expanding growth. Types A and B showed no lymph node metastasis and the most favorable prognosis (100% 5-year survival) of the six types. CONCLUSION: Histologic types A and B are thought to be in situ peripheral adenocarcinoma, whereas type C appears to be an advanced stage of types A and B. Conversely, types D, E, and F are small advanced adenocarcinomas with a less favorable prognosis.