Ronald M. Przygodzki

Mucinous cystic neoplasm (mucinous cystadenocarcinoma of low-grade malignant potential) of the pancreas : a clinicopathologic study of 130 cases

Mucinous cystic neoplasms (MCNs) of the pancreas are uncommon tumors. The classification and biologic potential of these neoplasms remain the subject of controversy. Attempts to classify these tumors in a similar manner to ovarian MCNs remains controversial, as even histologically benign-appearing pancreatic MCNs metastasize and are lethal. One hundred thirty cases of MCNs were identified in the files of the Endocrine Pathology Tumor Registry of the Armed Forces Institute of Pathology from the years 1979 to 1993. The pathologic features, including hematoxylin and eosin staining, histochemistry, immunohistochemistry (IHC), cell cycle analysis, and K-ras oncogene determination were reviewed. These findings were correlated with the clinical follow-up obtained in all cases. There were 130 women, aged 20-95 years (mean age at the outset, 44.6 years). The patients had vague abdominal pain, fullness, or abdominal masses. More than 95% of the tumors were in the pancreatic tail or body and were predominantly multilocular. The tumors ranged in size from 1.5 to 36 cm in greatest dimension, with the average tumor measuring >10 cm. A spectrum of histomorphologic changes were present within the same case and from case to case. A single layer of bland-appearing, sialomucin-producing columnar epithelium lining the cyst wall would abruptly change to a complex papillary architecture, with and without cytologic atypia, and with and without stromal invasion. Ovarian-type stroma was a characteristic and requisite feature. Focal sclerotic hyalinization of the stroma was noted. This ovarian-type stroma reacted with vimentin, smooth muscle actin, progesterone, or estrogen receptors by IHC analysis. There was no specific or unique epithelial IHC. K-ras mutations by sequence analysis were wild type in all 52 cases tested. Ninety percent of patients were alive or had died without evidence of disease (average follow-up 9.5 years), irrespective of histologic appearance; 3.8% were alive with recurrent disease (average 10 years after diagnosis); and 6.2% died of disseminated disease (average 2.5 years from diagnosis). Irrespective of the histologic appearance of the epithelial component, with or without stromal invasion, pancreatic MCNs should all be considered as mucinous cystadenocarcinomas of low-grade malignant potential. Pancreatic MCNs cannot be reliably or reproducibly separated into benign, borderline, or malignant categories.

Global Host Immune Response: Pathogenesis and Transcriptional Profiling of Type A Influenza Viruses Expressing the Hemagglutinin and Neuraminidase Genes from the 1918 Pandemic Virus

ABSTRACT To understand more fully the molecular events associated with highly virulent or attenuated influenza virus infections, we have studied the effects of expression of the 1918 hemagglutinin (HA) and neuraminidase (NA) genes during viral infection in mice under biosafety level 3 (agricultural) conditions. Using histopathology and cDNA microarrays, we examined the consequences of expression of the HA and NA genes of the 1918 pandemic virus in a recombinant influenza A/WSN/33 virus compared to parental A/WSN/33 virus and to an attenuated virus expressing the HA and NA genes from A/New Caledonia/20/99. The 1918 HA/NA:WSN and WSN recombinant viruses were highly lethal for mice and displayed severe lung pathology in comparison to the nonlethal New Caledonia HA/NA:WSN recombinant virus. Expression microarray analysis performed on lung tissues isolated from the infected animals showed activation of many genes involved in the inflammatory response, including cytokine, apoptosis, and lymphocyte genes that were common to all three infection groups. However, consistent with the histopathology studies, the WSN and 1918 HA/NA:WSN recombinant viruses showed increased up-regulation of genes associated with activated T cells and macrophages, as well as genes involved in apoptosis, tissue injury, and oxidative damage that were not observed in the New Caledonia HA/NA:WSN recombinant virus-infected mice. These studies document clear differences in gene expression profiles that were correlated with pulmonary disease pathology induced by virulent and attenuated influenza virus infections.

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.

Adenosquamous Carcinoma Of The Pancreas: A Clinicopathologic Series Of 25 Cases

Background: Adenosquamous carcinoma is a rare aggressive subtype of pancreatic adenocarcinoma. We describe the clinical, pathologic, and molecular characteristics of 25 of these lesions, the largest series to date. Methods: Twenty-five cases of adenosquamous carcinoma of the pancreas diagnosed between 1961 and 1994 were retrieved from the files of the Endocrine Registry of the Armed Forces Institute of Pathology. Histologic features were reviewed, histochemical, immunohistochemical, and molecular (k-ras) studies were performed, and patient follow-up was obtained. Results: The patients included 17 men and eight women, aged 28 to 82 years (mean, 65.4 y). The patients usually experienced weight loss (n = 17) or painless jaundice (n = 11), while also presenting with other abdominal symptoms. The tumors affected the head most frequently (n = 17), followed by the tail (n = 9) or body (n = 4). Five cases involved more than one anatomic region of the pancreas. Microscopically, all tumors demonstrated dual differentiation toward adenocarcinoma and squamous cell carcinoma. All cases tested were immunoreactive with keratin (AE1:AE3 and CK1), whereas other keratin markers were variably expressed: CK5/6 (88%), CK7 (68%), Cam5.2 (41%), and CK20(26%). CA-19–9 (84%) and CEA (74%) were positive in the majority of the cases. K-ras oncogene mutations were identified in seven of 13 cases. All patients died from their disease an average of 5.8 months after diagnosis (range, 1 to 33 months). Conclusions: Adenosquamous carcinoma of the pancreas represents a distinct clinical and pathologic entity, demonstrating the expected immunoprofile and k-ras oncogene mutation of a ductal origin, with a worse prognosis than ductal adenocarcinoma.

Autopsy series of 68 cases dying before and during the 1918 influenza pandemic peak

The 1918 to 1919 “Spanish” influenza pandemic virus killed up to 50 million people. We report here clinical, pathological, bacteriological, and virological findings in 68 fatal American influenza/pneumonia military patients dying between May and October of 1918, a period that includes ∼4 mo before the 1918 pandemic was recognized, and 2 mo (September–October 1918) during which it appeared and peaked. The lung tissues of 37 of these cases were positive for influenza viral antigens or viral RNA, including four from the prepandemic period (May–August). The prepandemic and pandemic peak cases were indistinguishable clinically and pathologically. All 68 cases had histological evidence of bacterial pneumonia, and 94% showed abundant bacteria on Gram stain. Sequence analysis of the viral hemagglutinin receptor-binding domain performed on RNA from 13 cases suggested a trend from a more “avian-like” viral receptor specificity with G222 in prepandemic cases to a more “human-like” specificity associated with D222 in pandemic peak cases. Viral antigen distribution in the respiratory tree, however, was not apparently different between prepandemic and pandemic peak cases, or between infections with viruses bearing different receptor-binding polymorphisms. The 1918 pandemic virus was circulating for at least 4 mo in the United States before it was recognized epidemiologically in September 1918. The causes of the unusually high mortality in the 1918 pandemic were not explained by the pathological and virological parameters examined. These findings have important implications for understanding the origins and evolution of pandemic influenza viruses.

Primary Mediastinal Seminomas: Evidence of Single and Multiple KIT Mutations

Primary mediastinal seminomas (MS) are rare tumors that are histologically similar to their testicular counterparts. Reports document KIT mutations in gastrointestinal stromal tumors, mastocytosis, and germ cell tumors. Although rare exon 17 mutations have been reported in gonadal seminomas, their mediastinal counterparts have not been studied. To determine whether primary MS harbor KIT mutations, eight formalin-fixed, paraffin-embedded primary MS were microdissected; KIT exons 11 and 17 were sequenced. Four (50%) of the eight cases demonstrated KIT exon 17 mutations. Two of the cases showed single monoallelic base pair alterations; one of these mutations were silent. The other two cases each demonstrated two monoallelic point mutations. In each case, one of these mutations results in protein sequence alteration, and the other is silent. Sequencing of cloned PCR products showed both the silent and amino acid–altering mutations to be found on the same allele (cis). The codon 816 mutation previously identified in mastocytosis and gonadal germ cell tumors was not observed. Non-neoplastic tissues from these patients did not demonstrate KIT mutations; exon 11 mutations were not seen in either tumors or normal tissues. Only the three cases in which amino acid–altering mutations were observed showed a predominantly cytoplasmic CD177 KIT immunohistochemical staining, whereas the one non–amino acid mutating and all wild-type cases were immunonegative. Our findings demonstrate a unique KIT sequence and expression pattern among MS. KIT sequencing may assist in differentiating primary from metastatic MS.

Detection of SYT-SSX Fusion Transcripts in Archival Synovial Sarcomas by Real-Time Reverse Transcriptase-Polymerase Chain Reaction

Synovial sarcomas comprise approximately 5% of soft tissue sarcomas and occur primarily in young adults. The t(X;18) (p11.2;q11.2) has been demonstrated to be highly characteristic of synovial sarcomas, and the resulting SYT-SSX fusion transcripts have been shown to be useful diagnostic markers. We have developed a real-time, reverse transcriptase-polymerase chain reaction (RT-PCR) multiplex assay for the identification of the primary fusion transcript types (SYT-SSX1 and SYT-SSX2) from formalin-fixed, paraffin-embedded (FFPE) tissues. Twenty-nine of 30 (96.7%) histologically diagnosed FFPE synovial sarcomas were positive for the presence of either the SYT-SSX1 or SYT-SSX2 fusion transcripts. Ten of 16 (62.5%) and five of 16 (31.25%) monophasic fibrous synovial sarcomas were positive for SYT-SSX1 and SYT-SSX2, respectively. One of 16 (6.25%) monophasic fibrous synovial sarcomas was negative for either SYT-SSX fusion transcript. Twelve of 14 (85.7%) and 2 of 14 (14.3%) biphasic synovial sarcomas were positive for SYT-SSX1 and SYT-SSX2, respectively. All 13 non-synovial sarcomas tested were negative for SYT-SSX1 and SYT-SSX2 fusion transcripts. This method is a relatively simple and rapid procedure for the detection of the t(X;18)(p11.2;q11.2).

Unique pulmonary presentation of an angiomyolipoma: analysis of clinical, radiographic, and histopathologic features

Extrarenal angiomyolipomas are rare lesions that have been described in the liver, hard palate, skin, uterus, vagina, penis, and spermatic cord. In this report we present the clinical, radiographic, and pathologic findings of an angiomyolipoma of the lung in a 68-year-old woman without tuberous sclerosis or lymphangioleiomyomatosis. To our knowledge, this report is the first description of pulmonary angiomyolipoma. Distinction from other benign and malignant pulmonary mesenchymal lesions depends on recognition of traditional histologic criteria. In contrast to renal angiomyolipomas, study of this case and review of prior reports reveals that extrarenal angiomyolipomas are most often well demarcated, easily resected, and not associated with tuberous sclerosis.

p53 mutation spectrum in relation to GSTM1, CYP1A1 and CYP2E1 in surgically treated patients with non-small cell lung cancer

p53 mutation status was analysed in relation to DNA polymorphisms of GSTM1, CYP1A1 and CYP2E1 from 105 surgically resected non-small cell lung cancer cases. Demographic factors, smoking, occupation, family history, tumour histology, grade and stage were taken into account. p53 mutations, detected either directly by DNA sequencing (P = 0.04, adjusted for smoking) or indirectly by immunostaining (P = 0.06), were overrepresented among CYP1A1 variants. Mutations in exon 8 and transitions at CpG sites in the p53 gene were favoured in this subset. There was no relation between the individual gene polymorphisms or p53 mutations and disease-free survival by Kaplan-Meier analysis. The finding of excess CYP1A1 heterozygotes in individuals with p53 mutations after adjustment for smoking suggests that CYP1A1 activation contributes to lung cancer via p53 inactivation.

Primary mediastinal and testicular seminomas: A comparison of k-ras-2 gene sequence and p53 immunoperoxidase analysis of 26 cases

Primary mediastinal seminomas (MS) are rare tumors. Histologically, they are similar to their counterpart in the gonads. The survival rate has varied from 50% to 85% in different series. However, large series of these tumors primarily in the mediastinum are lacking. At the molecular level, a few reports document K-ras mutations in up to 40% of testicular seminomas (TS), localized predominantly to codon 12. Reports on TS p53 immunohistochemistry (IHC) range from negative to overexpression approaching 90% of cases, and by sequence analysis one small series showed a 23% mutation rate. To date, no analyses have been performed for either K-ras mutations or p53 immunohistochemical expression in primary MS. The authors studied 13 cases each of primary MS and TS from archival formalin-fixed, paraffin-embedded sections in which adequate tumor sampling and clinical history, including serological studies, and histological, histochemical, and IHC staining, were performed to confirm the diagnosis. p53 immunoperoxidase staining using citrate buffer/microwave antigen retrieval was performed. Topographic genotyping was performed on 5-microns-thick tissue sections up to 17 years old, in which the neoplastic cell population was sampled. Additionally, multiple sites within a given cases were sampled to determine clonality of the tumor cell population. Polymerase chain reaction and subsequent sequence analysis of the K-ras-2 exon-1 gene was used for mutation analysis. Focal weak staining with p53 IHC was observed in 4 of 13 (31%) MS and 10 of 13 (77%) TS cases, with all remaining cases being negative (P < .05). Only one MS case (8%) showed K-ras mutation (codon 13 GGC > GAC; glycine > aspartate), which is in contrast to 2 of the TS cases (15%), showing codon 12 mutations. All the remaining cases were wild type. Therefore, primary mediastinal seminomas appear to be different in their K-ras sequence and p53 immunostain profile from TS. Codon mutation type may be useful in determining primary versus metastatic origin of a mediastinal seminoma.