Nelson G. Ordonez

Anaplastic carcinoma of the thyroid: A clinicopathologic study of 121 cases

One hundred twenty‐one cases of anaplastic carcinoma of the thyroid treated at M. D. Anderson Cancer Center, Houston, were reviewed. Anaplastic carcinoma is a rapidly growing neoplasm with a dismal prognosis. The mean survival of our patients was 7.2 ± 10 months. A significant percentage of our patients (35%) had areas of well‐differentiated thyroid carcinoma elsewhere, supporting the hypothesis that anaplastic thyroid carcinoma arises from preexisting well‐differentiated thyroid carcinoma. Twenty‐four of 30 tumors analyzed (84%) stained for keratin, 28 (93.3%) stained for vimentin, and ten (33%) stained for epithelial membrane antigen. Younger patients lived longer than older patients, and patients whose disease was earlier‐stage at presentation responded better than patients with metastases at presentation. Radical surgery alone did not significantly increase survival duration over less radical surgery. The role of multimodality therapy needs further evaluation.

Micropapillary component in lung adenocarcinoma: A distinctive histologic feature with possible prognostic significance

Micropapillary carcinoma or a micropapillary carcinoma component has been reported in the ovary, breast, and urinary bladder and is generally thought to have prognostic significance. However, little has been written on micropapillary differentiation in lung carcinoma. We studied 35 cases of primary lung adenocarcinoma with a micropapillary component seen at the M.D. Anderson Cancer Center. The micropapillary component in these tumors ranged from focal to prominent and was seen at both primary and metastatic sites. This component was not associated with any particular histologic subtype of lung adenocarcinoma. Of the 15 cases with available material, 14 (93%) stained positive for cytokeratin 7, whereas only two of the 15 cases (13%) stained positive for cytokeratin 20. Thyroid transcription factor-1 immunostaining of tumor nuclei was seen in 12 of the 15 cases (80%). Immunostaining was seen in areas both with and without micropapillary differentiation. Thirty-three of 35 patients (94%) developed metastases, which occurred most commonly in the lymph nodes (n = 26), and also in the lung (n = 17), brain (n = 9 cases), bone (n = 9 cases), and other sites. Most metastases had a prominent micropapillary component, irrespective of the extent of the micropapillary carcinoma component in the primary lung tumor. Adequate clinical follow-up information was available for 29 patients. The mean follow-up was 25 months. At their last follow-up, 16 of 29 patients (55%) were still alive with disease, 5 (17%) were dead of disease, and 8 (28%) were alive with no evidence of disease. We believe that a micropapillary component occurring in lung adenocarcinoma should be reported, as this component may be more likely to metastasize. The presence of this component should alert the clinician to search more carefully for metastases and have a closer follow-up on these patients. It is also important to recognize this component in evaluating a metastasis from an unknown primary site, as it should alert the pathologist to a possible primary in the lung in addition to breast, urinary bladder, and ovary.

Guidelines for pathologic diagnosis of Malignant Mesothelioma: 2017 Update of the consensus statement from the International Mesothelioma Interest Group

CONTEXT - Malignant mesothelioma (MM) is an uncommon tumor that can be difficult to diagnose. OBJECTIVE - To provide updated, practical guidelines for the pathologic diagnosis of MM. DATA SOURCES - Pathologists involved in the International Mesothelioma Interest Group and others with an interest and expertise in the field contributed to this update. Reference material included up-to-date, peer-reviewed publications and textbooks. CONCLUSIONS - There was discussion and consensus opinion regarding guidelines for (1) distinguishing benign from malignant mesothelial proliferations (both epithelioid and spindle cell lesions), (2) cytologic diagnosis of MM, (3) recognition of the key histologic features of pleural and peritoneal MM, (4) use of histochemical and immunohistochemical stains in the diagnosis and differential diagnosis of MM, (5) differentiating epithelioid MM from various carcinomas (lung, breast, ovarian, and colonic adenocarcinomas, and squamous cell and renal cell carcinomas), (6) diagnosis of sarcomatoid MM, (7) use of molecular markers in the diagnosis of MM, (8) electron microscopy in the diagnosis of MM, and (9) some caveats and pitfalls in the diagnosis of MM. Immunohistochemical panels are integral to the diagnosis of MM, but the exact makeup of panels employed is dependent on the differential diagnosis and on the antibodies available in a given laboratory. Depending on the morphology, immunohistochemical panels should contain both positive and negative markers for mesothelial differentiation and for lesions considered in the differential diagnosis. Immunohistochemical markers should have either sensitivity or specificity greater than 80% for the lesions in question. Interpretation of positivity generally should take into account the localization of the stain (eg, nuclear versus cytoplasmic) and the percentage of cells staining (>10% is suggested for cytoplasmic and membranous markers). Selected molecular markers are now being used to distinguish benign from malignant mesothelial proliferations. These guidelines are meant to be a practical diagnostic reference for the pathologist; however, some new pathologic predictors of prognosis and response to therapy are also included.

Small cell carcinoma of the prostate part I a clinicopathologic study of 20 cases

Clinical information and histological slides of 20 cases of small cell carcinoma of the prostate seen at The University of Texas M. D. Anderson Hospital and Tumor Institute at Houston over a 23‐year period were reviewed. Patients ages ranged from 30 to 89 years (median, 67 years). In nine cases, pure adenocarcinoma of the prostate preceeded recognition of the small cell component by 7 months to 8 years (median, 18 months); five of these were initially at Stage A. There was a small cell component at presentation in 11 cases (10, Stage D). Small cell carcinoma was merging with the adenocarcinoma in 11 cases and represented 30% to 90% of total tumor volume. Eleven of 20 patients died of their disease. Those presenting initially with a pure adenocarcinoma survived between 7 months and 9 years (median, 24 months). After the recognition of the small cell carcinoma component, regardless of a prior history of adenocarcinoma, death followed within 1.5 years (median, 5 months). This study suggests a biologic difference in behavior in prostatic carcinoma containing a small cell carcinoma component. The small cell component may manifest early or late in the disease.

Guidelines for pathologic diagnosis of malignant mesothelioma: A consensus statement from the International Mesothelioma Interest Group

CONTEXT Malignant mesothelioma (MM) is an uncommon tumor that can be difficult to diagnose. OBJECTIVE To develop practical guidelines for the pathologic diagnosis of MM. DATA SOURCES A pathology panel was convened at the International Mesothelioma Interest Group biennial meeting (October 2006). Pathologists with an interest in the field also contributed after the meeting. CONCLUSIONS There was consensus opinion regarding (1) distinguishing benign from malignant mesothelial proliferations (both epithelioid and spindle cell lesions), (2) cytologic diagnosis of MM, (3) key histologic features of pleural and peritoneal MM, (4) use of histochemical and immunohistochemical stains in the diagnosis and differential diagnosis of MM, (5) differentiating epithelioid MM from various carcinomas (lung, breast, ovarian, and colonic adenocarcinomas and squamous cell and renal cell carcinomas), (6) diagnosis of sarcomatoid mesothelioma, (7) use of molecular markers in the differential diagnosis of MM, (8) electron microscopy in the diagnosis of MM, and (9) some caveats and pitfalls in the diagnosis of MM. Immunohistochemical panels are integral to the diagnosis of MM, but the exact makeup of panels used is dependent on the differential diagnosis and on the antibodies available in a given laboratory. Immunohistochemical panels should contain both positive and negative markers. The International Mesothelioma Interest Group recommends that markers have either sensitivity or specificity greater than 80% for the lesions in question. Interpretation of positivity generally should take into account the localization of the stain (eg, nuclear versus cytoplasmic) and the percentage of cells staining (>10% is suggested for cytoplasmic membranous markers). These guidelines are meant to be a practical reference for the pathologist.

Primary adenocarcinoma of the urinary bladder. A clinicopathologic analysis of 72 cases.

Adenocarcinomas account for approximately 2% of primary epithelial malignancies of the urinary bladder. The clinicopathologic features of 72 cases treated at one institution are reported; 22 cases were evaluated immunohistochemically. Twenty‐four tumors were urachal and 48 nonurachal. The cases were analyzed according to their stage at presentation, histologic type, and mucin staining; they were tested immunohistochemically to determine their reaction to carcinoembryonic antigen, Leu‐M1, prostate‐specific antigen, and prostatic acid phosphatase. Tumor stage was a highly significant predictor of outcome (P = 0.001). Nonurachal tumors tended to have a worse outcome than urachal, but the difference was not statistically significant (P = 0.07). Histologic type was not a significant predictor of outcome (P = 0.10). For adenocarcinoma of the urinary bladder, stage was the most significant predictive factor; separating urachal from nonurachal tumors was important, but mucin histochemistry and immunohistochemistry did not help in this distinction. On occasion, a few tumors may react with some polyclonal antibodies to prostate‐specific antigen; thus these results must be interpreted with caution. In these instances, the possibility of using highly sensitive and specific monoclonal antibodies such as the one employed in this study should be considered.

HER-2/neu gene amplification compared with HER-2/neu protein overexpression and interobserver reproducibility in invasive breast carcinoma

We compared the detection of HER-2/neu gene amplification by fluorescence in situ hybridization (FISH) with detection of HER-2/neu protein overexpression by immunohistochemistry using 2 antibodies on 100 archival invasive breast carcinomas. Protein overexpression for each marker was scored independently by 4 pathologists using standardized criteria, and consensus was compared with results obtained from gene amplification. The concordance rate between FISH and immunohistochemistry was 76% for e2-4001 and 91% for the HercepTest. Of the 37 cases positive by e2-4001, 21 demonstrated no gene amplification; 7 of 24 cases positive by the HercepTest demonstrated no gene amplification. However, 1 of 61 cases negative by e2-4001 showed gene amplification; none of the cases negative by the HercepTest showed amplification. The predictive values of gene amplification based on 0-1+, 2+, and 3+ immunohistochemical staining were best for cases scored as 3+ (75% for e2-4001 and 89% for the HercepTest). Complete agreement among observers for immunohistochemical scoring of e2-4001 and the HercepTest was achieved in 75 and 85 cases, respectively. The pairwise kappa agreement values were substantial for e2-4001 and substantial to almost perfect for the HercepTest. Immunohistochemical staining may be considered a useful screening test. While negative staining almost always correlated with a lack of gene amplification, positive membranous staining, especially 2+, did not predict gene amplification. The low interobserver reproducibility in separating 2+ from 3+ cases necessitates further confirmation by FISH before treatment decisions are made.

Value of Mesothelin Immunostaining in the Diagnosis of Mesothelioma

Mesothelin is a cell surface antigen of unknown function that is strongly expressed in mesothelial cells. Although it was reported in 1992 that immunostaining with the K1 anti-mesothelin antibody could be very useful in distinguishing between epithelioid mesotheliomas and pulmonary adenocarcinomas, no further studies have been published on the value of this marker in the diagnosis of mesotheliomas. To determine whether mesothelin can assist in discriminating epithelioid mesotheliomas from lung adenocarcinomas or from other carcinomas metastatic to the serosal membranes, 55 mesotheliomas (44 epithelioid, 3 biphasic, and 8 sarcomatoid), 48 carcinomas of the lung (31 adenocarcinomas, 17 squamous carcinomas), and 86 nonpulmonary adenocarcinomas (14 ovary, 5 peritoneum, 9 endometrium, 11 pancreas, 4 stomach, 16 colon, 12 breast, 9 kidney, 4 thyroid, and 2 prostate) were investigated for mesothelin expression using the recently available 5B2 anti-mesothelin monoclonal antibody. Reactivity was obtained in all 44 (100%) of the epithelioid mesotheliomas, 12 (39%) of the lung adenocarcinomas, and 42 (49%) of the nonpulmonary adenocarcinomas (14 [100%] ovary; 5 [100%] peritoneum; 6 [67%] endometrium; 10 [91%] pancreas; 2 [50%] stomach; 5 [31%] colon; and in none [0] of the breast, kidney, thyroid, or prostate). Three (18%) of the squamous carcinomas of the lung, but none of the sarcomatoid mesotheliomas, exhibited positivity for this marker, nor was any reactivity seen in the spindle cell component of the biphasic mesotheliomas. It is concluded that despite the low specificity of mesothelin for discriminating between epithelioid mesotheliomas and adenocarcinomas, immunostaining for this marker may have some utility in those instances in which the results obtained with the standard panel of immunohistochemical markers used for the diagnosis of mesotheliomas are equivocal. Because mesothelin is a highly sensitive positive marker for epithelioid mesotheliomas, a negative staining for this marker is an indication against such a diagnosis; however, because of its limited utility, it is not recommended for inclusion in the standard panel of immunohistochemical markers used in the distinction between mesotheliomas and adenocarcinomas.

Increased bone mass is an unexpected phenotype associated with deletion of the calcitonin gene

Calcitonin (CT) is a known inhibitor of bone resorption. Calcitonin gene-related peptide-alpha (CGRPalpha), produced by alternative RNA processing of the CT/CGRP gene, has no clearly defined role in bone. To better understand the physiologic role of the CT/CGRP gene we created a mouse in which the coding sequences for both CT and CGRPalpha were deleted by homologous recombination. The CT/CGRP(-/-) knockout (KO) mice procreated normally, there were no identifiable developmental defects at birth, and they had normal baseline calcium-related chemistry values. However, KO animals were more responsive to exogenous human parathyroid hormone as evidenced by a greater increase of the serum calcium concentration and urine deoxypyridinoline crosslinks, an effect reversed by CT and mediated by a greater increase in bone resorption than in controls. Surprisingly, KO mice have significantly greater trabecular bone volume and a 1.5- to 2-fold increase in bone formation at 1 and 3 months of age. This effect appears to be mediated by increased bone formation. In addition, KO mice maintain bone mass following ovariectomy, whereas wild-type mice lose approximately one-third of their bone mass over 2 months. These findings argue for dual roles for CT/CGRP gene products: prevention of bone resorption in hypercalcemic states and a regulatory role in bone formation.

Small cell carcinoma of the prostate. II. Immunohistochemical and electron microscopic studies of 18 cases

To evaluate the histogenesis of small cell carcinoma of the prostate, 18 cases of this tumor (9 pure small cell and 9 combined adeno‐and small cell carcinoma) were studied using immunohistochemical methods. Seven of the small cell components also were assessed by electron microscopic examination. Using neuronspecific enolase (NSE), prostatic acid phosphatase (PAP), and prostate‐specific antigen (PSA) on tissue sections, three distinctive immunostaining patterns of small cell carcinoma components were identified: staining positive for NSE and negative for PSA and PAP (10 cases), staining positive for PSA and PAP and negative for NSE (3 cases), and negative reaction for all three antigens (5 cases). Electron microscopic study demonstrated neurosecretory granules in two cases. Based on the immunostaining and electron microscopic findings, small cell carcinomas of the prostate appear to be a heterogeneous group of tumors. Some of them are neuroendocrine carcinomas whereas others are poorly differentiated adenocarcinomas or, possibly, reserve cell carcinomas. Differences in immunostaining patterns or presence and absence of adenocarcinoma component do not reflect any differences in the uniformly poor prognosis of small cell carcinomas, in which median survival is 7.7 months. The authors believe that, because of such heterogeneity, small cell carcinomas of the prostate arise from multipotential prostatic epithelium and that an origin from specific neuroendocrine cells need not be implicated. Cancer 59:977‐982, 1987.