Human Pathology

Masthead

2010-03-01

Editorial Board

2010-03-01

Information for Authors

2010-03-01

In this Issue

2010-03-01

Contributions of pediatrics and pediatric pathology to the body of knowledge regarding human disease

Christian Nezelof, Thomas A. Seemayer, Julia A. Bridge — 2009-09-09

Summary: A century or so ago, pediatrics and pediatric pathology did not exist. Then, many fetuses/newborns died in utero or shortly after birth. With time, the issue of sepsis was addressed, and a greater number of newborns survived. Gradually, in this soil, the disciplines of pediatrics and pediatric nursing arose, as some recognized that infants were not merely small adults but were, in fact, quite different. Years later, pediatric pathology developed as a field of exploration. Today, pediatric pathology is a specialty, as witnessed by training programs, societies devoted to research and education, an expanding number of textbooks and innovative research. Pediatric pathology is distinct from adult pathology, as seen by the diversity of malformations and metabolic diseases stemming from mutations, the immaturity of the newborn's immune system, and the types of neoplasms germane to infants and children. Much of the progress in these areas was facilitated by the simultaneous emergence of cytogenetics and molecular biology and their powerful tools of investigation. The latter were applied in a synergistic fashion to a major extent in maternity clinics and children's hospitals by, among others, molecular biologists, clinical geneticists, cytogeneticists, pediatricians, and pediatric pathologists. This article describes a select but small number of the many contributions of pediatrics and pediatric pathology to the current body of medical knowledge.

Clinically occult interstitial fibrosis in smokers: classification and significance of a surprisingly common finding in lobectomy specimens

2009-12-14

Summary: This study reports the presence of surprisingly frequent and often severe interstitial fibrosis in cigarette smokers with no clinical evidence of interstitial lung disease. Twenty-three lobectomy specimens excised for neoplasms, including 20 from smokers, were extensively sampled, and examined semi-quantitatively for interstitial fibrosis, fibroblast foci, peribronchiolar metaplasia, honey-comb change, emphysema, and respiratory bronchiolitis. Interstitial fibrosis involving greater than 25% of slides was identified in 12 of 20 smokers (60%), but in none of the three never-smokers. Three cases were classified as specific forms of interstitial lung disease, including one each of usual interstitial pneumonia, Langerhans cell histiocytosis, and asbestosis. The remaining 9 cases did not fit with a named interstitial lung disease and were considered to represent examples of smoking-related interstitial fibrosis. This lesion was characterized by varying degrees of alveolar septal widening by collagen deposition along with emphysema and respiratory bronchiolitis. The fibrosis occurred both in subpleural and in deeper parenchyma. It surrounded enlarged airspaces of emphysema, but it also involved non-emphysematous parenchyma. Clinical progression was not documented in any case, although follow-up was short. These observations highlight the spectrum of unexpected fibrosis that is frequently encountered in lobectomy specimens from cigarette smokers. Additional investigation will be required to determine the clinical significance of smoking-related interstitial fibrosis and its relationship, if any, to other smoking-related diseases. It is important, however, that smoking-related interstitial fibrosis be distinguished from specific forms of fibrosing lung disease that may be associated with poor prognoses, especially usual interstitial pneumonia.

Papillary squamous intraepithelial lesions of the uterine cervix: human papillomavirus-dependent changes in cell cycle expression and cytologic features

Cher-Wei Liang, Ming-Chieh Lin, Chen-Hsiang Hsiao, Yi-Ting Lin, Kuan-Ting Kuo — 2009-12-02

Summary: Most human papillomavirus–associated squamous intraepithelial lesions of the uterine cervix are flat; some have papillary architecture that shows a spectrum of differentiation from low-grade squamous intraepithelial lesions to high-grade squamous intraepithelial lesions. For this subset of lesions, there are few data relating human papillomavirus type to cytology and cell cycle activity. Here, we collected 24 cases of papillary squamous intraepithelial lesions with either low-risk (15 cases) or high-risk (9 cases) human papillomavirus infection. We described their morphology and performed immunohistochemical staining with cell cycle–related markers Ki-67, p53, pRb, and P16INK4a. The Ki-67 labeling index was significantly lower in the low-risk group than in the high-risk group (P < .001). A cut point of less than 50% labeling index detected all but one low-risk group case. Degradation of p53 and pRb was less evident in the low-risk group than in the high-risk group (p53, P < .001; pRb, P = .006). P16INK4a produced an unexpectedly high positive rate of staining in the low-risk group (60%). However, a specific top-heavy distribution pattern was noted, with evident nuclear but faint cytoplasmic staining, whereas the high-risk group showed strong full-thickness nuclear and cytoplasmic staining. The detection of these lesions by smear examination was not reliable, given the wide expression pattern. Papillary structure was evident in none. We conclude that cell cycle–related markers are helpful in distinguishing low- and high-risk lesions. The strong p16INK4a staining in the low-risk group may imply that more cell cycle–controlling pressure is elicited in papillary lesions than in flat lesions. The distribution pattern of p16INK4a staining is important when making a diagnosis; cytology is not effective. Human papillomavirus type, histology, and cell cycle markers could clearly separate these lesions into either a low-risk or a high-risk group, properly designated low-grade squamous intraepithelial lesions or high-grade squamous intraepithelial lesions in current management algorithms. Thus, the previously used terms papillary immature metaplasia and immature condyloma, although descriptive for low-risk group lesions, are confusing and should be discarded.

Fluorescence in situ hybridization analysis of extraskeletal myxoid chondrosarcomas using EWSR1 and NR4A3 probes

2009-09-23

Summary: Extraskeletal myxoid chondrosarcomas (EMCs) are characterized histologically by a cord-like or lace-like arrangement of small round cells or short spindle cells with eosinophilic cytoplasm distributed in a rich myxoid matrix. Atypical cases of EMC have also been described, with areas of poor mucus production and high cellularity and a transition to typical EMC. Most cases of EMC harbor the chromosomal reciprocal translocation t(9;22) (q22;q12) and the resultant fused gene, Ewing sarcoma region 1-nuclear receptor subfamily 4, group A, member 3 (EWSR1-NR4A3). Other translocations, such as those involving the NR4A3 gene, have also been noted, although these occur at a lower frequency. On this basis, we conducted a fluorescence in situ hybridization (FISH) analysis of 18 cases of EMC in which patients presented with typical or atypical (areas of high cellularity) histologic features of EMC. We used an EWSR1 probe and a newly prepared NR4A3 probe to evaluate the usefulness of FISH in the pathologic diagnosis of EMC. FISH analysis using the EWSR1 or NR4A3 probe showed split signals in 83% (15/18) of the cases, regardless of the presence of typical/atypical histologic features. Gene rearrangement of EWSR1 was noted in 72% (13/18) of the cases, and rearrangement of NR4A3 was noted in 61% (11/18) of the cases. The NR4A3 rearrangement was detected in 2 cases not carrying any EWSR1 rearrangement, as determined by reverse transcription-polymerase chain reaction. These results suggest that FISH analysis of formalin-fixed, paraffin-embedded specimens using EWSR1 and NR4A3 probes is useful and convenient and may provide an ancillary method for the diagnosis of EMC.

Overexpression of A disintegrin and metalloproteinase 28 is correlated with high histologic grade in conventional chondrosarcoma

2009-11-09

Summary: Low-grade chondrosarcoma and enchondroma are occasionally difficult to differentiate solely by reference to clinicoradiologic and histologic findings. The A disintegrin and metalloproteinases are a new gene family of proteins having a metalloprotease domain with matrix metalloproteinases and play an important role in the chondrocyte development process. Therefore, we analyzed the expression of A disintegrin and metalloproteinases and matrix metalloproteinases in several kinds of cartilaginous bone tumors at the messenger RNA level and immunohistochemical protein level and ascertained their relationships to the histologic degree of malignancy. Reverse transciptase-polymerase chain reaction and real-time quantitative reverse transciptase-polymerase chain reaction of the expression of the A disintegrin and metalloproteinase family in cartilaginous bone tumors demonstrated that A disintegrin and metalloproteinase 28 messenger RNA levels in grade I chondrosarcoma were significantly higher than those in enchondroma (P = .009). Moreover, positive immunoreactivity of A disintegrin and metalloproteinase 28 was observed in 12 (59%) of 22 patients with grade I chondrosarcoma and in 21 (91%) of 23 patients with grade II chondrosarcoma, respectively. In contrast, only 2 (9%) of 21 cases of enchondromas demonstrated positive staining for A disintegrin and metalloproteinase 28. On the other hand, the immunohistochemical expressions of matrix metalloproteinase 9 and matrix metalloproteinase 13 were significantly higher in enchondromas than in normal cartilage tissue; however, there is no statistically different expression between enchondromas and grade I chondrosarcomas. We detected that overexpression of A disintegrin and metalloproteinase 28 was increased according to its histologic grade in conventional chondrosarcoma and could be one of the helpful tools in distinguishing between low-grade chondrosarcoma and enchondroma.

Epstein-Barr virus–positive diffuse large B-cell lymphoma in elderly patients is rare in Western populations

2009-11-16

Summary: In the currently published World Health Organization-Classification, the new entity of Epstein-Barr virus–positive diffuse large B-cell lymphoma of the elderly was introduced largely based on findings from East-Asian populations. Little is known about its frequency or characteristics in the West, especially in European populations. Using a tissue microarray approach, we identified 8 out of 258 diffuse large B-cell lymphoma cases fulfilling the World Health Organization criteria of an Epstein-Barr virus–positive diffuse large B-cell lymphoma of the elderly, suggesting an incidence of 3.1% in a European population. The median patient age was 65 years. The highest diagnostic sensitivity was only achieved by EBER in situ hybridization. No correlation between Epstein-Barr virus status and outcome was noted except in latency type 3 lymphomas, which had a very poor survival. Sixty-seven percent of Epstein-Barr virus–positive cases showed the presence of necrosis and 50% expressed the activation marker CD30. However, no morphological or immunohistochemical features reliably distinguished all Epstein-Barr virus–positive diffuse large B-cell lymphoma cases. Thus, to identify these Epstein-Barr virus–positive diffuse large B-cell lymphoma in the elderly, EBER in situ hybridization of all de novo diffuse large B-cell lymphoma cases of patients older than 50 years should be considered. In summary, Epstein-Barr virus–positive diffuse large B-cell lymphoma of the elderly is rare in Europeans older than 50 years. It can only be diagnosed by EBER-ISH, and its precise prognostic role is unclear. Whether routine testing of all diffuse large B-cell lymphoma patients older than 50 years can be recommended depends essentially on its clinical relevance. Future studies are needed to address this question.

Overexpression of cell division cycle 7 homolog is associated with gene amplification frequency in breast cancer

2009-11-09

Summary: Cell division cycle 7 is a widely expressed protein kinase implicated in cell division, cell cycle checkpoint mechanisms, and cancer progression. To determine the relationship of cell division cycle 7 protein expression with tumor phenotype, molecular features and prognosis, 2197 highly characterized breast carcinomas were analyzed on a tissue microarray. Detectable cell division cycle 7 expression was found in 1088 (57%) of breast cancer specimens and 228 (11.9%) exhibited a moderate or strong expression. High levels of cell division cycle 7 expression were significantly related to medullary histotype (P < .0001); high tumor grade (P < .0001); negative estrogen receptor status (P < .0001); high Ki67 expression level (P < .0001); p53 and p16 overexpression (P < .0001); and amplification of HER2 (P < .0001), c-myc (P < .0001), MDM2 (P = .043), CCND1 (P = .0084), and ESR1 (P = .0012) as well as with the number of amplified genes (P < .0001). There was also a tendency towards worse prognosis in cell division cycle 7 positive as compared to negative breast cancers. The relationship between cell division cycle 7 and number of amplifications was independent from tumor proliferation raising the possibility of a direct influence of cell division cycle 7 expression for amplification development. In conclusion, cell division cycle 7 is a replication associated protein with relationships to gene amplification and genomic instability in breast carcinomas. These data support the potential utility of newly developed small molecule cell division cycle 7 inhibitors as a therapeutic alternative in at least a subset of breast carcinomas.

Lymphatic and blood vessels in scleroderma skin, a morphometric analysis

2009-12-11

Summary: Vascular involvement is frequent in systemic sclerosis, but the role of the lymphatic vasculature is poorly known. Our aim was to evaluate lymphatic vessels in systemic sclerosis skin lesions. We studied skin forearm biopsies of 9 patients with systemic sclerosis and 7 age-matched controls. Lymphatic vessels were labeled with the monoclonal antibody D2-40 and blood vessels with a polyclonal antibody to von Willebrand Factor. All blood and lymphatic vessels present in each section were counted and total area, inner luminal area, and shape factors were measured. The number of blood and lymphatic vessels in papillary dermis was greater and their diameter lower than in reticular dermis both in systemic sclerosis and controls. In the reticular dermis, the number of lymphatic vessels was markedly reduced in systemic sclerosis (4.9 ± 1.1 μm−2 versus 8.9 ± 1.2 μm−2 P = .03), and a similar trend was observed in papillary dermis (8.4 ± 3.7 μm−2 versus 8.1 ± 5.3 μm−2). Interestingly, the number of periglandular lymphatics in systemic sclerosis was not different from controls. The inner luminal area (possibly indicating compensatory dilation) of lymphatic vessels, particularly the periglandular ones, was greater in systemic sclerosis than in controls. No differences were observed in the number of blood vessels, but the percentage of blood vessel profiles (without lumen) was significantly less in systemic sclerosis both in papillary and in reticular dermis. In conclusion, our data show that skin lesions in systemic sclerosis are characterized by a selective rarefaction of lymphatic vasculature that spares periglandular vessels and that might have a pathogenic role in the evolution and in the clinical manifestations of the disease.

Quantitative expression of VEGF, VEGF-R1, VEGF-R2, and VEGF-R3 in melanoma tissue microarrays

2009-12-11

Summary: Angiogenesis is required for progression and metastasis of melanoma. Analysis of angiogenic molecules in benign and malignant tissues may allow identification of markers useful for prediction of sensitivity to antiangiogenic agents. We hypothesized that differential expression of vascular endothelial growth factor (VEGF) and its receptors VEGF-R1, VEGF-R2, and VEGF-R3 would be higher in melanomas than nevi and higher in advanced melanoma. Using automated quantitative analysis, we quantified VEGF, -R1, -R2 and -R3 expression in melanoma tissue microarrays composed of 540 nevi and 468 melanoma specimens (198 primaries, 270 metastases). VEGF, VEGF-R1, VEGF-R2, and VEGF-R3 expression was significantly higher in melanomas than nevi by unpaired t tests (P < .0001). VEGF-R2 expression was higher in metastatic specimens (P < .0001), but VEGF-R3 expression was higher in primaries (P < .0001). VEGF was coexpressed with all 3 receptors when assessed by Spearman's rank correlation. VEGF, VEGF-R1, VEGF-R2, and VEGF-R3 expression is higher in melanomas than nevi. Higher expression of VEGF-R2 was found in metastases versus primaries, supporting the idea that selection for an angiogenic phenotype in metastatic melanoma is conferred via up-regulation of VEGF-R2. However, higher expression of VEGF-R3 was seen on primary lesions, potentially implicating this receptor in initiation of lymphatic tumor spread. Clinical trials using antiangiogenic agents in melanoma should include correlative assays of VEGF, VEGF-R1, VEGF-R2, and VEGF-R3 as biomarkers of response to therapy, preferably using quantitative methods such as automated quantitative analysis. Such assessments could assist with evaluation of these molecules as therapeutic targets in melanoma, ultimately facilitating improved selection of patients for treatment.

Abnormal expression of telomerase/apoptosis limits type II alveolar epithelial cell replication in the early remodeling of usual interstitial pneumonia/idiopathic pulmonary fibrosis

2009-12-02

Summary: Idiopathic pulmonary fibrosis is a distinctive, usually fatal, type of chronic fibrosing interstitial pneumonia of unknown cause that increases in prevalence with advanced age, characterized by failure of alveolar re-epithelization and progressive scar formation. Recently, limitation of the replicative capacity of tissues determined by telomerase/apoptosis balance has been implicated in pathogenesis of age-related diseases. In this study, we validated the importance of the expression of type 2 alveolar epithelial cells telomerase protein and studied the relationships between telomerase and apoptosis in early remodeling of usual interstitial pneumonia. We determined type 2 alveolar epithelial cells density, telomerase expression, and apoptosis in surgical lung biopsies from 24 patients with usual interstitial pneumonia, and in normal lung tissues from 18 subjects. We used immunohistochemistry, deoxynucleotidyl transferase method of end labeling, electron microscopy, and histomorphometry to evaluate the amount of type 2 alveolar epithelial cells staining for surfactant-A, telomerase, and in situ detection of apoptotic cells. Unaffected areas of usual interstitial pneumonia and normal lung tissue had similar densities of type 2 alveolar epithelial cells, but a significant minor subpopulation of type 2 alveolar epithelial cells was telomerase positive and a large population was telomerase negative. A significant inverse association was found between low type 2 alveolar epithelial cell telomerase expression and high apoptosis in unaffected areas of usual interstitial pneumonia. Although type 2 alveolar epithelial cell telomerase expression was higher than apoptosis in NLT group, no significant association was found between them. Electron microscopy confirmed epithelial apoptosis, alveolar collapse, and initial fibroplasia. We conclude that abnormal type 2 alveolar epithelial cells telomerase/apoptosis balance may reduce alveolar epithelial regenerative capacity, thus contributing to the early remodeling response in usual interstitial pneumonia.

Post-mortem pathologic and genetic studies in “dead in bed syndrome” cases in type 1 diabetes mellitus

2009-12-11

Summary: Dead in bed syndrome is a poorly understood cause of sudden death in young people with type 1 diabetes. The underlying cause remains unknown. One possible explanation may involve prolongation of the QT interval followed by a terminal malignant arrhythmia. Risk factors associated with QT interval prolongation include hypoglycemia and cardiac autonomic neuropathy. We sought to identify myocardial cellular changes and genetic influences that may contribute to the pathogenesis of dead in bed syndrome. Post-mortem reports between 1994 and 2006 from the 2 largest Departments of Forensic Medicine in Australia were reviewed for dead in bed syndrome cases. Post-mortem heart sections were immunohistochemically stained for collagen types I and III and connective tissue growth factor (CTGF). Genomic DNA was prepared from post-mortem samples, and genetic analysis was performed in the SCN5A, G6PC, PHOX2B, and CTGF genes. Twenty-two dead in bed syndrome cases were identified and staining of heart sections for collagen I and III, and CTGF showed no differences between dead in bed syndrome cases and controls. Genetic screening of SCN5A revealed 3 silent polymorphisms A29A, E1061E, and D1819D and 1 protein-changing variant H558R. No genetic variants were found in G6PC, PHOX2B, and CTGF, and dead in bed syndrome cases were not associated with the G-945C CTGF promoter polymorphism. In conclusion, this study is the first to investigate potential pathogenic mechanisms underlying the dead in bed syndrome in type 1 diabetes with the results substantially adding to knowledge of this condition. Understanding the causes and triggers of dead in bed syndrome will be critical in facilitating the identification of patients with type 1 diabetes at highest risk of developing sudden death.

Elevated expression of phosphorylated c-Jun NH2-terminal kinase in basal-like and “triple-negative” breast cancers

Xiao Wang, Lan Chao, Xin Li, Guohui Ma, Liansheng Chen, Yixiu Zang, Gengyin Zhou — 2009-11-16

Summary: Basal-like carcinomas and human epidermal growth factor receptor 2 (HER-2/neu) overexpression carcinomas are the subgroups of breast cancers that have the most aggressive clinical behavior. Phosphorylation/activation of c-Jun NH2-terminal kinase is characterized as a stress-activated protein kinase, which regulates apoptosis after cellular stress. The aim of this study was to evaluate the association of phosphorylated c-Jun NH2-terminal kinase expression with phenotypes and clinicopathologic parameters of breast cancer. Phosphorylated c-Jun NH2-terminal kinase was immunohistochemically measured in a cohort of 160 patients with invasive breast cancer treated with therapeutic surgery followed by anthracycline or docetaxel-based chemotherapy. These results were further correlated with the phenotypes and clinicopathologic characteristics of breast cancers. Increased phosphorylated c-Jun NH2-terminal kinase expression was significantly associated with lack of estrogen receptor expression (P < .0001), positivity for cytokeratins 5/6 (P = .029), epidermal growth factor receptor (P = .035), basal-like phenotype (P = .015), and “triple-negative” phenotype (P = .01). Furthermore, the positive expression of phosphorylated c-Jun NH2-terminal kinase was positively correlated with p-glycoprotein (r = 0.54, P < .0001) and multidrug resistance–associated protein 1(r = 0.38, P < .0001) but not with lung resistance protein (r = −0.02, P = .78). Our results indicate that the activation of phosphorylated c-Jun NH2-terminal kinase may play a role in the carcinogenesis of basal-like and triple-negative breast carcinoma.

Autocrine and paracrine roles of VEGF/VEGFR-2 and VEGF-C/VEGFR-3 signaling in angiosarcomas of the scalp and face

Wataru Tokuyama, Tetuo Mikami, Mikio Masuzawa, Isao Okayasu — 2009-11-16

Summary: Angiosarcoma of the skin is an extremely rare malignant tumor of vascular origin that usually arises in the scalp and face of elderly persons. To clarify its characteristic features and cell cycle kinetics, we quantitatively evaluated the expression of cell cycle–related molecules and vascular endothelial growth factors using immunohistochemical staining, for comparison with 2 benign vascular tumors of the skin, the capillary hemangioma and the cavernous hemangioma. Cell proliferation, determined with reference to the Ki-67 labeling index, was highest in angiosarcomas and lowest in cavernous hemangiomas (angiosarcomas versus capillary hemangioma, P = .014; capillary hemangioma versus cavernous hemangiomas, P = 1.4 × 10−4). Similar differences were also found in cyclin A, cyclin E, and p21Waf1 expression. Expressions of cyclin D1 and p16INK4A were also significantly higher in angiosarcoma than in cavernous hemangioma. Expressions of these 5 proteins showed significant positive correlations with Ki-67 labeling indices (Spearman ρ = 0.91-0.43). Expression levels of vascular endothelial growth factor and its receptor, VEGFR-2, were highest in angiosarcomas. VEGF-C expression in angiosarcomas was significantly higher than in cavernous hemangiomas, and its receptor VEGFR-3 expression was highest in angiosarcomas. Furthermore, significant positive correlations of these protein expression with Ki-67 labeling indices were noted (Spearman ρ = 0.88-0.40). Among them, VEGFR-3 showed the highest correlation coefficient. These results suggest that not only VEGFR-2-mediated signal but also VEGFR-3-mediated signal may contribute to proliferation of vascular tumor cells as autocrine and paracrine signaling factors.

PBK/TOPK in the differential diagnosis of cholangiocarcinoma from hepatocellular carcinoma and its involvement in prognosis of human cholangiocarcinoma

2009-12-02

Summary: The increased expression of PDZ binding kinase/lymphokine-activated killer T-cell–originated protein kinase (PBK/TOPK) is associated with some human malignant tumors. In this study, we analyzed PBK/TOPK expression in hepatic primary tumor and explored its role in cholangiocarcinoma biology. Seventy-four cholangiocarcinomas, 33 hepatocellular carcinomas, and 10 normal liver tissues were prepared from paraffin-embedded specimens. PBK/TOPK protein was assessed by immunohistochemical staining, and the survival time was analyzed with the Kaplan-Meier method. The protein, mRNA of PBK/TOPK, and cell cycle of cholangiocarcinoma cell line after PBK/TOPK suppression with small interfere RNA were studied by Western blot, semiquantitative reverse transcriptase–polymerase chain reaction, and flow cytometry, respectively. PBK/TOPK was usually expressed in normal bile duct epithelial cells and much more frequently expressed in cholangiocarcinoma (68/74) but never expressed in hepatocytes and hepatocellular carcinomas (0/33). PBK/TOPK down-regulation was related to the poor prognosis of patients with cholangiocarcinoma (P = .013). Epidermal growth factor can enhance PBK/TOPK expression in cholangiocarcinoma QBC 939 cells, but suppression of PBK/TOPK in the cells did not affect their proliferation. PBK/TOPK protein could serve as a useful indicator for histopathologic differentiation between cholangiocarcinoma and hepatocellular carcinomas and the low expression of PBK/TOPK is predicative of poor survival in cholangiocarcinoma patients.

End-stage nonalcoholic fatty liver disease: evaluation of pathomorphologic features and relationship to cryptogenic cirrhosis from study of explant livers in a living donor liver transplant program

Nabeen C. Nayak, Nandini Vasdev, Sanjiv Saigal, Arvinder S. Soin — 2009-12-02

Summary: In a proportion of liver cirrhosis, the etiology continues to remain elusive. It is uncertain whether and to what extent cirrhosis evolving from nonalcoholic fatty liver disease contributes to this group of cryptogenic cirrhosis because the clinicopathologic features of nonalcoholic fatty liver disease cirrhosis are largely unknown. We explored these facets by examining the explant livers and clinical data in living donor liver transplant recipients. Among 103 adult liver transplant recipients with different types of chronic liver disease, 30 had a pre–liver transplant diagnosis of cryptogenic cirrhosis. A final categorization of the native liver disease was attempted in these cases on the basis of detail pathomorphological findings in adequately sampled explant liver correlated with careful review of pre–liver transplant clinical data. Of the 30 cryptogenic cirrhosis cases, 19 (63.3%) finally labeled as nonalcoholic fatty liver disease cirrhosis showed histologic features in several respects different from those reported for the early and established phases of nonalcoholic fatty liver disease. Steatosis was infrequent and focal or even absent, whereas variable grades of Mallory hyaline and inflammation were consistently present. Ductular proliferation and hydropic change of hepatocytes were also frequent. Only 9 (47%) of the 19 cases had nonalcoholic fatty liver disease associated risk factors like diabetes and obesity. It was concluded that appreciation of quantitative and qualitative differences in hepatic morphology between the cirrhotic and the early/established stage of nonalcoholic fatty liver disease will help in making a correct diagnosis of nonalcoholic fatty liver disease cirrhosis in the proper clinical setting. When appropriate criteria are used, nonalcoholic fatty liver disease appears to account for close to two thirds of cases currently labeled as cryptogenic cirrhosis.

The use of an immunohistochemical diagnostic panel to determine the primary site of cervical lymph node metastases of occult squamous cell carcinoma

2009-12-02

Summary: Cervical lymph node metastases from unknown primary sites account for approximately 3% to 9% of all head and neck malignant lesions. Squamous cell carcinoma is the most common type of cervical metastatic carcinoma. Our aim was to investigate the possibility of determining the site of primary tumors using an immunohistochemical diagnostic panel in metastatic cervical lymph nodes. Expression profiles of cytokeratins, 5/6; 8/18; 10; 13; 14; and 19, p16, and pRb were evaluated in 101 consecutive patients with cervical nodal metastasis who had undergone neck dissection to treat known head and neck squamous cell carcinoma (primary sites: 16, oral cavity; 38, oropharynx; 26, hypopharynx; 21, larynx). Cytokeratin 10 was more frequently expressed in oral cavity primary tumors, whereas cytokeratin 19 staining was more frequently observed in tumors originated from the pharynx and larynx. The expression of p16 and altered pRb status (0% or >50%) were more frequently observed in oropharynx primary tumors. To select the best subset among the 8 antibodies tested, classification and regression tree analysis was performed. The analysis correctly classified the four primary sites (25.0% of oral cavity, 89.5% of oropharynx, 30.8% of hypopharynx, and 57.1% of larynx) using 5 variables (histologic subtype, p16, cytokeratins 10 and 19, and pRb). The p16 was the single best predictor. The classification tree method using immunostaining profiles of p16, cytokeratins 10 and 19, or pRb may be helpful in the identification of the primary site of metastatic squamous cell carcinoma with occult primary.

Desmoplastic small round cell tumor of the submandibular gland—a rare but distinctive primary salivary gland neoplasm

Wei-Hua Yin, Shuang-Ping Guo, Hong-Yu Yang, John K.C. Chan — 2009-11-16

Summary: Desmoplastic small round cell tumor is a highly aggressive neoplasm that generally involves the peritoneum and pelvis of young patients. Only rare cases occur outside the abdomen. We report a case presenting as a primary submandibular gland tumor in a 24-year-old man. Histologically, although there were irregular tumor islands lying in an abundant desmoplastic stroma, there were also areas comprising large cellular islands with scanty stroma in between, raising the differential diagnosis of various salivary gland carcinomas. The tumor cells were medium sized, with hyperchromatic nuclei and moderate amounts of cytoplasm. The diagnosis of desmoplastic small round cell tumor was confirmed by the presence of a polyphenotypic immunoprofile (positive for cytokeratin, desmin, and neuron-specific enolase) and the characteristic EWS-WT1 gene fusion. Although rare, desmoplastic small round cell tumor has to be considered in the differential diagnosis of poorly differentiated neoplasms of the salivary gland, especially in young patients.

Glioblastoma with signet-ring morphology: a case report and review of the literature

Sarah E. Martin, Jose M. Bonnin, David C. Hall, Eyas M. Hattab — 2009-12-02

Summary: Primary central nervous system tumors with signet-ring morphology are exceedingly rare. We report an unusual case of glioblastoma with signet-ring cell features in an 81-year-old woman. Microscopic examination revealed a highly anaplastic tumor, with a prominent proportion of tumor cells exhibiting signet-ring appearance characterized by classic round cytoplasmic inclusions and eccentrically positioned nuclei. The tumor cells were immunoreactive for glial fibrillary acidic protein and S100, and negative for cytokeratins, confirming their glial origin. Ultrastructurally, the tumor cells were noted to contain intermediate filaments, and by fluorescence in-situ hybridization analysis, they demonstrated intact 1p/19q. The presence of signet-ring cells in the central nervous system should immediately raise the suspicion of metastatic carcinoma, particularly from the upper gastrointestinal tract. In the present case, however, the morphological and immunohistochemical features were diagnostic of a malignant primary glial neoplasm (glioblastoma). This case highlights the diagnostic difficulties that can arise in such instances, given the rarity of signet-ring morphology in primary central nervous system tumors.

Case report: focal nesidioblastosis (“nesidioblastoma”) in an adult

Michele K. McElroy, Andrew M. Lowy, Noel Weidner — 2009-12-11

Summary: Adult nesidioblastosis is an uncommon cause of hyperinsulinemic hypoglycemia characterized by diffuse islet hyperplasia with β-cell hypertrophy and atypia. The cause of nesidioblastosis in adults is unclear but may be different from nesidioblastosis in infants. In contrast to infants, a focal form of adult nesidioblastosis (ie, “nesidioblastoma”) has not been documented, although proposed. We report a 44-year-old man with symptomatic hypoglycemia and localized nesidioblastosis treated with surgical enucleation resulting in normalization of blood glucose. Postoperative euglycemia has persisted in this patient to date (4 months at the time of manuscript submission).

Factitial soft tissue pseudotumor due to injection of anabolic steroids: a report of 3 cases in 2 patients

Ilan Weinreb, John R. Goldblum, Brian P. Rubin — 2009-12-30

Summary: Traumatically induced inflammation or reactive processes are a relatively well-known phenomenon in both skin and soft tissue. These include panniculitides, fat necrosis, nodular fasciitis, and nonspecific fibrosis. Occasionally, traumatic reactions can be associated with factitial injury due to self-induced blunt trauma or injection of chemical agents. Factitial pseudotumors of soft tissue mimicking neoplasms and occurring in deep-seated locations are rare and not well recognized. We have had the opportunity to review a handful of cases over the years of soft tissue pseudotumors caused by self injection of steroids for the purposes of bodybuilding. Three of these cases in 2 patients are presented here. One patient developed a deep lateral thigh mass that was radiologically suspicious for sarcoma but upon core biopsy was found to be a lipogranulomatous reaction. The second patient had 2 masses occurring in the upper and lower extremity with an interval of 1 year between the two. This patient had both masses resected. The first had the appearance of a giant cell tumor with no immediately discernible foreign material. The second mass was initially presumed to be a metastasis from the upper extremity tumor and showed similar areas to the first specimen; however, it also had areas of obvious reactive features with foreign material. These features were found in the first tumor as well upon retrospective review. Both patients admitted to self injection of anabolic steroids after further history was sought by the clinicians. Deep soft tissue pseudosarcomas caused by injection of steroids are not well documented, and patient's reluctance to provide this information leads to difficulty in arriving at a correct diagnosis. Recognition of this possibility is important in avoiding incorrect diagnoses and unnecessary treatments.

Priti Lal — 2010-01-22

Silva's Diagnostic Renal Pathology is a unique—and quite successful—attempt to present the vast subject of renal pathology in encyclopedic fashion in a single volume. Beginning with a detailed explanation of basic renal anatomy and physiology, its 17 chapters proceed in a logical fashion to encompass medical renal disease, cystic and developmental diseases, transplant pathology, and even the spectrum of renal tumors. The chapter on renal tumors, by Drs Tickoo, Argani, and Amin, and the one on renal disease from the nephrologists' perspective help make this book unusually comprehensive.

Virtual 3D microscopy in pathology education

Ralf Zwönitzer, Harald Hofmann, Albert Roessner, Thomas Kalinski — 2010-01-08

In the August issue of Human Pathology, Fred R. Dee provided a detailed overview of virtual microscopy in pathology education . As requested by the author, we would like to supplement his contribution by findings on the current speed and efficiency of virtual 3-dimensional (3D) microscopy, and by further trends in image distribution using common standards.

Re-evaluation of IgG4 in systemic fibroinflammatory disease with intracardiac involvement

Mikiko Takikita-Suzuki, Mitsuaki Ishida, Hidetoshi Okabe — 2010-03-01

We previously published a case report in Human Pathology entitled “A case of multifocal fibrosclerosis with intracardiac solid masses” . Briefly, a 70-year-old woman had fibrosclerotic intracardiac solid masses contiguous to thickened pericardium and fibrosclerosis in the pericardium, mediastinum, abdominal cavity, and retroperitoneum. Because the areas of fibrosis were observed in multiple lesions, her disease was diagnosed as multifocal fibrosclerosis accompanied with peculiar intracardiac masses. This systemic disease overlaps recently established clinicopathologic entity of IgG4-related systemic disease. However, the concept was not completely developed when the report was published, and we did not evaluate IgG4 expression in the plasma cells in this case.

Grading of skin sebaceous carcinoma

Teresa Pusiol, Maria Grazia Zorzi, Francesco Piscioli — 2010-03-01

Tumor grade is a system used to classify cancer cells in terms of how abnormal they look under a microscope and how quickly the tumor is likely to grow and spread. Many factors are considered when determining tumor grade, including structure and growth pattern of the cells. The specific factors used to determine tumor grade vary with each type of cancer. Tumor grade may be used to plan treatment and to estimate the future course and the outcome of disease (prognosis) with certain types of cancers such as breast and prostate. Recently, we have observed a case of sebaceous carcinoma (SC) of the vulva and have examined Word Health Organization (WHO) Classification of Skin Tumours and fascicle of AFIP regarding nonmelanocytic tumour of the skin.

Human Pathology

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Grading of skin sebaceous carcinoma