John J. Brooks

Invasive thymoma: the role of mediastinal irradiation following complete or incomplete surgical resection.

To evaluate the role of mediastinal irradiation (RT) following surgery for invasive thymomas, a clinical and pathologic review of 117 patients with the diagnosis of thymoma was completed. Fourteen cases were excluded because of the lack of histologic criteria for a thymic tumor, and the remaining 103 were classified according to a staging system as follows: stage I, completely encapsulated (43); stage II, extension through the capsule or pericapsular fat invasion (21); stage III, invasion of adjacent structures (36); and stage IV, thoracic dissemination or metastases (3). The 5-year actuarial survival and relapse-free survival rates were 67% and 100% for stage I, 86% and 58% for stage II, and 69% and 53% for stage III. No recurrences occurred among stage I patients after total resection without RT. However, eight of 21 patients with invasive (stage II or III) thymomas had mediastinal recurrence as the first site of failure following total resection without RT. The 5-year actuarial mediastinal relapse rate of 53% in this group compares unfavorably with the mediastinal relapse rate seen among stage II or III cases following total resection with RT (0%) or following subtotal resection/biopsy with RT (21%). Despite attempted salvage therapy, five of eight patients with mediastinal relapse following total resection alone died of progressive disease. No significant difference was observed in the local relapse rate, overall relapse rate, or survival between those patients undergoing biopsy and RT v subtotal resection and RT for invasive thymomas (stages II and III). Total resection alone appears to be inadequate therapy resulting in an unacceptably high local failure rate with poor salvage therapy results.

Renal carcinomas with the t(6;11)(p21;q12): Clinicopathologic features and demonstration of the specific alpha-TFEB gene fusion by immunohistochemistry, RT-PCR, and DNA PCR

A highly distinctive subset of renal neoplasms of children and young adults contains a t(6;11)(p21;q12), a translocation recently been shown to result in fusion of Alpha, a gene on 11q12, with the transcription factor gene TFEB on 6p21. To define the clinicopathologic spectrum of this nascent entity and to establish immunohistochemical (IHC) and molecular methods for the detection of the specific Alpha-TFEB fusion, we studied 7 renal neoplasms that showed the t(6;11) by cytogenetic or molecular analysis (patient age: range, 9-33 years; mean, 17 years). While all tumors were confined to the kidney, 3 tumors demonstrated vascular invasion. In limited follow-up, none has metastasized. We postulated that the Alpha-TFEB gene fusion may result in deregulated expression of TFEB protein that would be detectable by IHC. Using a polyclonal antibody to TFEB on formalin-fixed, paraffin-embedded tissue sections, we found that all 7 renal neoplasms with the t(6;11) demonstrated moderate (2 cases) or strong (5 cases) nuclear TFEB immunoreactivity. In contrast, none of 1089 other tumors (of 74 histologic types from 16 sites) labeled significantly for TFEB. Nuclear immunoreactivity for TFEB in normal tissues was extremely rare, limited to weak labeling of scattered benign lymphocytes. We also show that the Alpha-TFEB fusion RNAs are highly variable in size and structure, making detection by reverse-transcriptase polymerase chain reaction (RT-PCR) less reliable than for other gene fusions. Because Alpha is an intronless gene and therefore lacks splice signals, we hypothesized that DNA PCR and RT-PCR products would be identical, allowing for the use of more robust molecular assays based on genomic DNA. Indeed, in 2 cases with available frozen tissue, we showed the genomic Alpha-TFEB junction detected by DNA PCR to be identical to the Alpha-TFEB fusion mRNA detected by RT-PCR. In summary, renal neoplasms with the t(6;11) are a distinctive neoplastic entity with many similarities to the Xp11 translocation carcinomas, and together with the latter form a growing “MiTF/TFE family” of translocation carcinomas. Nuclear immunoreactivity for TFEB protein is a highly sensitive and specific diagnostic marker for these renal neoplasms. Finally, the special molecular features of the Alpha-TFEB gene fusion allow its molecular detection by DNA PCR as a robust alternative to RT-PCR in clinical tumor samples.

Primary Gastric Lymphomas A Clinicopathologic Study of 58 Cases with Long-Term Follow-up and Literature Review

A large series of primary gastric lymphomas with long‐term follow‐up (average, 12.8 years) is reported. A number of factors known to affect nodal lymphoma were examined. Five‐and ten‐year survival rates were 57 and 46%, respectively. Statistically significant favorable prognostic variables were smaller tumor size (≤7 cm), superficial mural invasion (submucosal only), and pathologic Stage I disease; these variables were intimately interrelated. A favorable influence on survival was discerned concerning histologic type and nodular histology, although still below statistical significance. No significant relation to survival was observed concerning clinical weight loss or palpable mass, vascular invasion, mode of therapy, or histologic subtypes of “histocytic” lymphoma. Of patients who succumbed to disease, 75% did so within two years (average, 1.8 years); however, later recurrence and death may occur. An argument for resection of localized disease is presented. Mitotic index and nuclear diameter were of diagnostic importance, and associated lesions such as pseudolymphomas are discussed in relation to pathogenesis. Histologic variation within tumors suggested visualization of clonal development in non‐Hodgkins lymphomas.

Malignant “Triton” tumors. Natural history and immunohistochemistry of nine new cases with literature review

Malignant schwannomas with rhabdomyoblastic differentiation have been termed malignant “Triton” tumors (MTT). To define the natural history of MTT, we have analyzed our experience (9 cases, the largest series reported) in combination with the 27 previously described in the literature (total 36 cases). This study was initiated due to the unusual presentation of MTT as a polypoid esophageal mass. Rhabdomyoblastic differentiation in these tumors was confirmed using myoglobin immunohistochemistry. Two groups of patients were identified: those with Von Recklinghausens Neurofibromatosis (Group I, VRN cases); and those without (Group II, sporadic, non‐VRN cases). Group I patients accounted for over 70% of cases and displayed a marked male predominance, young age, and common head and neck presentation. By contrast, Group II patients were older, had a female predominance, and tumors frequently located on the trunk. Both groups fared equally poorly: local recurrence was common and the 5‐year survival rate for all cases was 12%. Our data support the view that the natural history of MTT, whether in VRN patients or not, is much more aggressive than sporadic malignant schwannoma and similar to VRN sarcomas in general. This poor outlook could not be attributed to site; rather, it appeared to reflect the high frequency of Grade III histology in this disease.

Malignancy arising in extragonadal endometriosis. A case report and summary of the world literature

A case of clear cell carcinoma arising in endometriosis of the retroperitoneum is presented. It occurred 5 years after supracervical hysterectomy and bilateral salpingo‐oophorectomy and following 4 years of estrogen therapy. The literature concerning malignancy developing in extragonadal endometriosis has been reviewed and is summarized as follows: 1) 45 cases have been compiled, of which 32 were carcinomas and 13 sarcomas; 2) adenocarcinoma was the most common histologic type, although virtually every tumor of müllerian derivation has been described; 3) the typical patient was nulliparous and perimenopausal; 4) the rectovaginal septum was the most common site, and in general the frequency of malignancy in a given site parallels the frequency of endometriosis in that location; 5) simultaneous tumors of the uterus or ovary were present in seven cases (15%); 6) prognosis appeared affected by site and histologic type; 7) a history of prior pelvic irradiation to effect castration was present in three (9%) of the patients with adenocarcinoma; and 8) four (12%) of the patients with adenocarcinoma were subjected to exogenous estrogens or estrogen‐secreting ovarian tumors. Cancer 40:3065‐3073, 1977.

Thyroid transcription factor-1 expression prevalence and its clinical implications in non-small cell lung cancer: a high-throughput tissue microarray and immunohistochemistry study.

Thyroid transcription factor 1 (TTF-1), a homeodomain-containing transcription factor, plays a pivotal role in lung development, cell growth, and differentiation processes. The current literature reports considerable variation in frequency of TTF-1 protein expression in human non-small cell lung cancer (NSCLC). TTF-1 expression has not been extensively investigated as a prognostic marker in NSCLC. To assess the prevalence of TTF-1 expression, and to evaluate its potential role in disease prognosis, 140 stage I-IIIA NSCLCs with long-term follow-up were studied under uniform conditions using high-density tissue microarray (TMA) combined with immunohistochemistry. Patient survival and association of TTF-1 expression with clinicopathologic parameters were analyzed. One hundred twenty-six tumor samples were fully assessable after tissue processing. Sixty-four samples (50.8%) expressed TTF-1 and 62 (49.2%) displayed no expression. TTF-1 expression was significantly (P < 0.001) correlated with histological subtype: 51 adenocarcinomas (AdCs) (51 of 75; 68%) versus 9 squamous cell carcinomas (SCCs) (9 of 43; 21%) were TTF-1 positive. TTF-1 expression, performance status, nodal status, and tumor stage were significantly related to patient survival. In multivariate analysis, positive TTF-1 expression tended to favor a better patient outcome (P = 0.05). Overall, NSCLC patients with positive TTF-1 expression had a median survival of greater than 57.3 months, whereas those with negative expression had a median survival of 39.4 +/- 5.2 months (log-rank test, P = 0.0067). In this study we found that TTF-1 is predominately expressed in adenocarcinoma. The loss of TTF-1 expression was associated with aggressive behavior of NSCLCs. The results from this study strongly indicate that further investigation is warranted to better define the role of TTF-1 as a prognostic factor in this malignancy.

Alveolar soft part sarcoma. A clinicopathologic and immunohistochemical study

The histogenesis of alveolar soft part sarcoma (ASPS) has been investigated since its description. Twenty ASPS cases were analyzed for immunohistochemical content, with emphasis directed toward the paraganglial, Schwann cell, and muscle theories of histogenesis. In addition, the cases were examined for possible prognostic clinical features. The clinical characteristics of the patients were similar to those reported previously concerning (1) average age (23 years); (2) male:female ratio (1:1); and (3) predominant primary site (lower extremity, nine cases). Despite a local recurrence rate of 20% and a metastatic rate of 68% (including four at presentation), the natural history was often indolent and relapse commonly occurred very late. The average follow‐up period was 10.1 years. While the overall 5‐year survival was 67%, only seven of 18 patients were alive without disease at last follow‐up (1.7‐32 years), and one patient died of tumor after a 28‐year disease‐free interval. Neither tumor size nor site appeared to affect prognosis. The tumors were analyzed immunohistochemically for neurofilament, S‐100 protein, met‐enkephalin, leu‐enkephalin, acetylcholinesterase, α1‐antichymotrypsin, Factor VIII‐related antigen, serotonin, lysozyme, neuron‐specific enolase, myoglobin, cytokeratins, desmin, and vimentin. Except for weak vimentin immunoreactivity, no other antigenic expression was detected despite multiple repeated experiments with several antibodies. S‐100 protein which is present in virtually all granular cell tumors was absent in the cases of ASPS. The lack of detectable expression of neurofilament, met‐enkaphalin and leu‐enkaphalin, and neuron‐specific enolase is interpreted as evidence against the paraganglial theory of histogenesis. Similarly, the repeated absence of the muscle proteins, desmin and myoglobin, in contrast to a previous report, is interpreted as evidence against a myogenic origin.

Non‐hodgkin's lymphomas: A clinicopathologic study of 293 cases

Retrospective clinicopathologic study of 293 cases of non‐Hodgkins lymphomas was performed. Nodularity was quantitatively graded 0 through +4. Higher degrees of nodularity were associated with improved survival. Comparing nodular and diffuse groups, nodularity was associated with improved survival for each cell type except mixed lymphoma. Within nodular and diffuse groups survival advantage was shown to be related to cell type. In NLPD and NM, male sex and systemic symptoms adversely affected survival. In DLPD and DM, advanced clinical stage, old age, and systemic symptoms were associated with poor outlook, sex having no significant effect. In DH, only the absence of systemic symptoms was beneficial; clinical stage, sex, and age showed no effect on the poor outcome. No survival advantage was observed for cases with histologic evidence of nodular fibrosis. Vascular invasion was demonstrated in 18% of nodular and 27% of diffuse lymphomas and was most common in mixed and histiocytic types. However, survival was adversely affected only in histiocytic lymphomas. No direct association between vascular invasion and wide‐spread dissemination was observed. The results suggest that only cases with well developed histologic nodularity have improved survival over diffuse lymphoma, and affirm the prognostic value of the pathologic classification of Rappaport.

MCM2 Is an Independent Predictor of Survival in Patients With Non–Small-Cell Lung Cancer

PURPOSE Minichromosome maintenance protein 2 (MCM2) is a component of the prereplicative complex. It is essential for eukaryotic DNA replication and is only expressed in proliferating cells. The prognostic utility of MCM2 compared with Ki-67, another marker of proliferating cells, on survival of patients with non-small-cell lung cancer (NSCLC) was studied. PATIENTS AND METHODS We examined the immunohistochemical expression of MCM2 and Ki-67 in primary pathologic tumor specimens from 221 NSCLC patients. For each marker, the fraction of tumor cells with positive staining was assessed as a percentage and categorized into four groups: 0% to 24%, 25% to 49%, 50% to 74%, and > or = 75%. MCM2 and Ki-67 immunoreactivities were compared with each other, and associations with pathologic and clinical parameters predictive of survival were analyzed with the chi(2) test. Cox regression models were used to assess associations between MCM2 and Ki-67 and survival while controlling for confounders. RESULTS Independent variables significantly associated with survival were tumor stage, performance status, and staining category. Patients with less than 25% MCM2 immunoreactivity had a longer median survival time than patients with > or = 25% MCM2 immunoreactivity (46 v 31 months; P =.039) and a lower relative risk (RR) of death (RR, 0.55, 95% confidence interval, 0.34 to 0.88). There was no significant association between survival and Ki-67 expression. CONCLUSION Immunostaining of tumor cells for MCM2 is an independent prognostic parameter of survival for patients with NSCLC. Interpretable results can be obtained on more than 96% of paraffin-embedded specimens, and approximately 35% will be in the favorable subgroup, with less than 25% positively stained tumor cells. Whether MCM2 is predictive of response to therapy needs to be studied.

Immunohistochemistry of soft tissue tumors. Myoglobin as a tumor marker for rhabdomyosarcoma

Myoglobin, found exclusively in striated muscle, can be considered a fetal antigen. This study investigated its usefulness as a tumor marker for rhabdomyosarcoma (RMS) using an immunoperoxidase technique. Eighty‐nine percent (89%) or 27 rhabdomyosarcomas contained immunoreactive myoglobin. In contrast, all other soft tissue tumors (54), carcinomas (10), and numerous normal tissues including smooth muscle were negative. Among RMS, staining correlated directly with cytoplasmic differentiation regardless of histologic type. Importantly, six of nine small cell RMS with no initially appreciated cytoplasm were positive, although focally. Since the three negative RMS had only limited tissue available for study, it remains possible that all RMS would exhibit rare positivity if sizeable specimens were tested. Myoglobin should be considered an extremely sensitive and specific tissue tumor marker for rhabdomyosarcoma of considerable clinical importance. Cancer 50:1757‐1763, 1982.