Michael N. Koss

Survival Analysis of 200 Pulmonary Neuroendocrine Tumors With Clarification of Criteria for Atypical Carcinoid and Its Separation From Typical Carcinoid

Neuroendocrine tumors of the lung embrace a spectrum from low-grade typical carcinoid (TC), intermediate-grade atypical carcinoid (AC), and high-grade categories of large cell neuroendocrine carcinoma (LCNEC) and small cell carcinoma (SCLC). We studied 200 neuroendocrine lung tumors to critically evaluate the Arrigoni histologic criteria for AC using statistical analysis to delimit more rigorously an intermediate survival for AC between TC and the high-grade tumors of LCNEC and SCLC. Histologic features that might predict prognosis were used for Kaplan-Meier and Cox proportional hazards survival analysis, and an optimal mitotic range for AC was calculated. The optimal mitotic range for AC was 2 to 10 mitoses per 2 mm2 of viable tumor (10 high-power fields). Based on this finding, we collapsed mitoses into three categories (< 2; 2-10; > or = 11) and performed Cox multivariate analysis for all 200 neuroendocrine tumors. Mitotic counts were the only independent predictor of prognosis. Based on this analysis, we propose that AC be defined as a tumor with neuroendocrine morphology, mitotic counts between 2-10 per 2 mm2 of viable tumor (10 high-power fields), or coagulative necrosis. Using these criteria, the 200 neuroendocrine tumors were classified as 51 TC, 62 AC, 37 LCNEC, and 50 SCLC. The 5- and 10-year survival was 87% and 87% for TC, 56% and 35% for AC, 27% and 9% for LCNEC, and 9% and 5% for SCLC, respectively. After stratification for stage, survival for AC was significantly worse than for TC (p < 0.001); for LCNEC and SCLC it was significantly worse than for AC; but the survival for LCNEC was no different than that for SCLC.

Primary germ cell tumors of the mediastinum: II. Mediastinal seminomas - A clinicopathologic and immunohistochemical study of 120 cases

Primary seminomas of the mediastinum are unusual neoplasms that are morphologically indistinguishable from their gonadal counterparts but may have different biologic behavior because they arise at this particular location.

Nodular lymphoid hyperplasia of the lung: a clinicopathologic study of 14 cases.

Nodular lymphoid hyperplasia is a controversial entity in which its existence in the lung has been doubted. The current opinion is that most, if not all, such cases represent extranodal marginal zone B-cell lymphomas masquerading as reactive lesions. We found 14 cases of nodular lymphoid hyperplasia in the files of the Pulmonary Department at the Armed Forces Institute of Pathology from 1974 through 1998. All had clinical histories and hematoxylin-eosin slides. In 12 of 14 with paraffin blocks, we applied immunohistochemical antibodies for CD20, CD3, CD43, CD5, bcl-2, bcl-1, CD45RA, and kappa and lambda immunoglobulin light chains. Molecular genetic analysis was performed on paraffin sections in 10 of 14 by the polymerase chain reaction for rearrangements of the immunoglobulin heavy chain gene and the minor and major break-point regions of the chromosomal translocation t (14;18). There were eight women and six men ranging in age from 19 to 80 years (median, 65 yrs). Most lesions (71%) were incidental findings on routine chest x-rays. Most patients (64%) had a single lesion by chest x-ray whereas the remainder had two to three lesions, except for one patient who had multiple lesions. There was associated regional lymphadenopathy in five of 14 cases (36%) which, on biopsy, proved to be reactive follicular hyperplasia. The only treatment was surgical excision. Of the seven patients with follow-up information from 8 months to 6 years (mean, 30 mos), none had clinical recurrence and no patient died of disease. The histology and immunophenotype of the lesions were strikingly similar, including abundant reactive germinal centers, intense interfollicular polyclonal plasmacytosis, and a variable degree of interfollicular fibrosis. No case showed a molecular rearrangement of the immunoglobulin heavy chain gene or the minor or major break-point region of the t (14;18). We conclude that nodular lymphoid hyperplasia of the lung, although rare, does exist and deserves its place in the spectrum of reactive pulmonary lesions that ranges from follicular hyperplasia to diffuse hyperplasia of the bronchus-associated lymphoid tissue (lymphoid interstitial pneumonitis).

Granular cell tumors of the lung: Clinicopathologic study of 20 cases

Granular cell tumor (GCT) of the lung is a rare neoplasm comprising 6-10% of all GCT. Since it was first described in the bronchus by Kramer in 1939, less than 80 cases have been reported. We present the clinicopathologic features of 23 GCT from 20 patients. The patients ranged in age from 20 to 57 years (median, 45 years) and included 10 males and 10 females. Of the 19 patients with available histories, nine (47%) were incidental findigns and 10 (53%) had obstructive symptoms [pneumonia, 7 (37%); atelectasis, 3 (16%)]. Three (16%) had hemoptysis, and one (5%) had weight loss. The GCT were solitary in 15 patients (75%) and multiple in five others (25%). One patient had three endobronchial lesions, and another had one endobronchial and one peripheral pulmonary lesion. Three of the patients had multiple cutaneous GCT (15%). Grossly, they were polypoid or nodular, tan-yellow, and firm. Histologically, the endobronchial GCT consisted of submucosal infiltrates of round to oval cells with abundant granular cytoplasm. The tumor often infiltrated into peribronchial tissue and in one case focally infiltrated an adjacent lymph node. Hyalinized thickening of the subepithelial basement membrane was common; the overlying epithelium often showed squamous metaplasia or ulceration. In those patients with available follow-up, the clinical behavior of lung GCT was benign. Our experience supports a conservative approach to therapy in most cases unless there has been extensive postobstructive lung injury. Potential conservative therapeutic approaches include bronchoscopic extirpation, laser therapy, or sleeve resection. The histogenesis of GCT is not known, although most studies suggest a peripheral nerve sheath origin. Our immunohistochemical results with positive staining for antibodies to S100 (4/4), NSE (3/3), vimentin (4/4), and actin (4/4, focal) are consistent with this concept.

Primary germ cell tumors of the mediastinum: III. Yolk sac tumor, embryonal carcinoma, choriocarcinoma, and combined nonteratomatous germ cell tumors of the mediastinum - A clinicopathologic and immunohistochemical study of 64 cases

Yolk sac tumor (YST), embryonal carcinoma (EC), choriocarcinoma (CC), and combined germ cell tumors (CGCTs) of the mediastinum are uncommon neoplasms. Only sporadic cases have been documented in the literature; therefore, the clinical behavior of these tumors when located in the mediastinum remains relatively unknown.

Lymphomatoid granulomatosis: A clinicopathologic study of 42 patients

&NA; We studied the histological and clinicopathological findings in 42 patients who had lymphomatoid granulomatosis (LYG). In addition to small round lymphocytes, small to intermediate lymphocytes with serpentine nuclei, large immature mononuclear lymphoid cells, abundant histiocytes, and vascular invasion by the cell infiltrate were observed in all cases. Fifty percent of lesions had occasional “atypical” cells with multi‐lobed nuclei. Three of four follow‐up autopsies showed large cell lymphoma, while one other autopsy and the single repeat biopsy showed increased numbers of large immature mononuclear lymphoid cells. Patients were most frequently men 40–60 yr old who had a history of pulmonary symptoms, such as cough or chest pain, and who showed multiple bilateral lung nodules without hilar adenopathy in the chest x‐ray. Thirteen patients (38%) died of disease, 11 of them within 12 mth of initial diagnosis. The presence of neurological signs and symptoms, increased mitoses, or increased numbers of atypical multi‐nucleated cells in the initial biopsy were not statistically significant predictors of survival.

Thymomas presenting as pleural tumors: Report of eight cases

Eight cases of thymomas presenting as pleural-based lesions are presented. The patients are five men and three women between the ages of 38 and 71 years (mean 54.5). Histologically, six tumors showed morphologic features indistinguishable from classical mediastinal thymomas, namely lobulation produced by fibrous bands and a biphasic cell population composed of epithelial cells admixed with small lymphocytes. One case showed prominent spindle cell configuration and marked vascularization resulting in a hemangiopericytomalike appearance; in another case, the epithelial component was associated with cystic structures. The radiographic findings were diffuse pleural thickening with encasement of the lung in four cases; an ill defined mass involving the right diaphragmatic pleura with engulfment of the left lower lobe in one case; diffuse pleural thickening along the mid lateral axillary line in one case; and left-sided pleural masses involving the diaphragmatic and chest wall pleural surfaces in another. In the remaining case, a massive unilateral left pleural effusion obscured the underlying lesion. Clinically, the patients presented with varied symptoms, including shortness of breath, fever, and weight loss. Follow-up information was obtained in four patients. One patient died 1 month after initial diagnosis, but no details of the cause of death were available. Another had metastasis to the groin 1 year after diagnosis. The other two patients were alive and well 2–10 years after the initial diagnosis.

Alveolar adenoma: A histochemical, immunohistochemical, and ultrastructural analysis of 17 cases

Alveolar adenoma of lung is a rare benign neoplasm of uncertain histogenesis. Its rarity hampers characterization of its epithelial and mesenchymal elements. Clinical and histopathologic features of 17 alveolar adenomas were reviewed. Histochemistry was performed on 10 cases, ultrastructural analysis on two, and immunohistochemistry on six cases for pneumocyte markers, thyroid transcription factor (TTF-1), surfactant protein markers pro-SP-B and pro-SP-C, and the Clara cell marker, CC10. Immunohistochemistry was performed in nine cases for desmin, smooth muscle actin, muscle-specific actin, cytokeratin, proliferating cell nuclear antigen (PCNA), factor VIII, and carcinoembryonic antigen. The mean age was 53 years. Seven cases occurred in men, and nine occurred in women. The age and sex were not known for one patient. The tumors were coin lesions on chest radiographs in asymptomatic patients except for one (cough). The mean size was 2.2 cm. The tumors were well demarcated with multiple cystic spaces containing granular material. Mostly type 2 pneumocytes lined the cystic spaces with fewer type 1 cells and no Clara cells. This was confirmed by staining for TTF-1, pro-SP-B, and pro-SP-C and by ultrastructure. CC10 was negative in all cases. The stroma varied from prominent spindle cells with a myxoid matrix to thin alveolar septa. The interstitial spindle cells resembled fibroblasts by immunohistochemistry and ultrastructure. Follow-up data available in five cases showed no recurrence at 2, 2, 5, 8, and 13 years. In summary, alveolar adenoma is a benign neoplasm consisting of an intimate admixture of alveolar epithelial and septal mesenchymal tissue. Most of the epithelial cells are type 2 pneumocytes, and the interstitial stromal cells are fibroblasts or fibroblast-like cells. Recognition of its characteristic morphological appearance allows for its distinction from other benign lesions of the lung.

Proliferation and cellular phenotype in lymphomatoid granulomatosis: Implications of a higher proliferation index in B cells

Pulmonary involvement by lymphomatoid granulomatosis (LYG) is characterized by nodules of a polymorphous lymphoreticular infiltrate with necrosis, angioinvasion, and variable numbers of large, atypical cells. Using combined immunohistochemistry, the authors compared the expression of a marker of proliferation (DNA topoisomerase IIalpha) between B cells, T cells, and histiocytes. Sixteen cases of LYG were stained by combined immunohistochemistry for DNA topoisomerase IIalpha and CD-20, CD-3, CD-68, and CD-57. A proliferation index was determined for B cells, T cells, histiocytes, and natural killer cells by dividing the number of cells with coexpression of DNA topoisomerase IIalpha and CD-20, CD-3, CD-68, or CD-57 by the total number of CD-20+, CD-3+, CD-68+, or CD-57+ cells, respectively. A significantly higher proliferation index was present in B cells compared to T cells, histiocytes, or natural killer cells (p < 0.002). The average proliferation index for B cells was 0.25+/-0.24 (range, 0.00-0.76), for T cells was 0.02+/-0.01 (range, 0.00-0.04), for histiocytes was 0.00+/-0.01 (range, 0-0.02), and for natural killer cells was 0.00+/-0.00 (range, 0.0-0.02). The average proliferation index of CD-20+ cells was greater in grade III LYG (0.36) than in grade II LYG (0.17) or the single case of grade I LYG (0.00). The authors conclude that (1) there is a spectrum of B-cell proliferation in LYG that roughly correlates with histologic grade, (2) T cells, histiocytes, and natural killer cells do not proliferate but are recruited, and (3) the average B-cell proliferation index in grade III LYG is similar to that observed in large cell non-Hodgkins B-cell lymphomas. These observations provide a possible rationale for the use of chemotherapy for grade III LYG and observation or immunologic adjuvants for LYG with grade I or grade II histology.

Primary intrapulmonary thymoma: A clinicopathologic and immunohistochemical study of eight cases

We describe eight cases of primary intrapulmonary thymoma occurring in seven women and one man between the ages of 25 and 77 years. Clinically, all patients had initial radiographic findings of a parenchymatous intrapulmonary mass without evidence of mediastinal involvement either radiologically or at surgery. The lesions varied from 0.5 to 10 cm in greatest diameter. Five tumors were located close to the hilum, while the other three were discovered deep within the lung and in subpleural locations. In one case, the lesion appeared to arise endobronchially and infiltrate the surrounding parenchyma. In another case, in addition to the main hilar mass, there were two smaller tumor nodules found deep within the same lung. Histologically, the lesions were characterized by the classic biphasic cellular composition of thymomas, i.e., an admixture in varying proportions of epithelial cells and lymphocytes. Four cases were characterized by sheets of lymphocytes admixed with scattered epithelial cells that were separated by fibrous bands into lobules. Three cases were composed predominantly of sheets of epithelial cells admixed with scattered small lymphocytes and containing prominent perivascular spaces. In two of these cases, focal areas of spinding of the cells were noted. One case was composed predominantly of a spindle cell proliferation with perivascular spaces and numerous small lymphocytes. Immunohistochemical stains for keratin and epithelial membrane antigen in six cases highlighted the epithelial cells scattered against the lymphoid cell background. Seven patients were treated by surgery. In one patient the tumor was deemed inoperable at the time of exploration owing to extensive pleural infiltration and was treated by postoperative radiation; the lesion recurred locally in the pleura 8 years later. Clinical follow-up in three patients after-surgical excision showed them to be alive and well without evidence of disease at 10 months, 2 years, and 8 years, respectively. Two of the patients had been followed clinically for 2 and 4 years following discovery of their lung masses on routine chest radiograph before resection of their tumors. Two patients died of unrelated conditions; in one of them, the lesion had been followed clinically for 6 years before surgery; this patient died 6 months later from coronary artery disease, without evidence of recurrence or metastasis. Our findings suggest that intrapulmonary thymomas are slow-growing tumors that may respond well to surgical resection when confined to the lung. As with their mediastinal counterparts, invasive tumors will require additional treatment for the possibility of recurrence of metastasis.