Human Pathology

Masthead

2012-06-01

Editorial Board

2012-06-01

Information for Authors

2012-06-01

In This Issue - June 2012

2012-06-01

Advances in the pathology of penile carcinomas

Alcides Chaux, Antonio L. Cubilla — 2012-06-01

Summary: The incidence of penile cancer varies from country to country, with the highest figures reported for countries in Africa, South America, and Asia and lowest in the United States and Europe. Causes of this variation are not clear, but they are thought to be related to human papillomavirus infection, smoking, lack of circumcision, chronic inflammation, and poor genital hygiene. Most penile tumors are squamous cell carcinomas, and a variegated spectrum of distinct morphologies is currently recognized. Each one of these subtypes has distinctive pathologic and clinical features. About half of penile carcinomas are usual squamous cell carcinomas, and the rest corresponds to verrucous, warty, basaloid, warty-basaloid, papillary, pseudohyperplastic, pseudoglandular, adenosquamous, sarcomatoid, and cuniculatum carcinomas. Previous studies have found a consistent association of tumor cell morphology and human papillomavirus presence in penile carcinomas. Those tumors composed of small- to intermediate-sized, basaloid (“blue”) cells are often human papillomavirus positive, whereas human papillomavirus prevalence is lower in tumors showing large, keratinizing, maturing eosinophilic (“pink”) cells. Human papillomavirus–related tumors affect younger patients, whereas human papillomavirus–unrelated tumors are seen in older patients with phimosis, lichen sclerosus, or squamous hyperplasia. This morphologic distinctiveness is also observed in penile intraepithelial neoplasia. The specific aim of this review is to provide a detailed discussion on the macroscopic and microscopic features of all major subtypes of penile cancer. We also discuss the role of pathologic features in the prognosis of penile cancer, the characteristics of penile precursor lesions, and the use of immunohistochemistry for the diagnosis of invasive and precursor lesions.

Costaining for keratins 8/18 plus ubiquitin improves detection of hepatocyte injury in nonalcoholic fatty liver disease

2011-10-31

Summary: Nonalcoholic fatty liver disease is a global health dilemma. The gold standard for diagnosis is liver biopsy. Ballooned hepatocytes are histologic manifestations of hepatocellular injury and are characteristic of steatohepatitis, the more severe form of nonalcoholic fatty liver disease. Definitive histologic identification of ballooned hepatocytes on routine stains, however, can be difficult. Immunohistochemical evidence for loss of the normal hepatocytic keratin 8/18 can serve as an objective marker of ballooned hepatocytes. We sought to explore the utility of a keratin 8/18 plus ubiquitin double immunohistochemical stain for the histologic evaluation of adult nonalcoholic fatty liver disease. Double immunohistochemical staining for keratin 8/18 and ubiquitin was analyzed using 40 adult human nonalcoholic fatty liver disease core liver biopsies. Ballooned hepatocytes lack keratin 8/18 staining as previously shown by others, but normal-size hepatocytes with keratin loss are approximately 5 times greater in number than keratin-negative ballooned hepatocytes. Keratin-negative ballooned hepatocytes, normal-size hepatocytes with keratin loss, and ubiquitin deposits show a zonal distribution, are positively associated with each other, and are frequently found adjacent to or intermixed with fibrous matrix. All 3 lesions correlate with fibrosis stage and the hematoxylin and eosin diagnosis of steatohepatitis (all P < .05). Compared with hematoxylin and eosin staining, immunohistochemical staining improves the receiver operating characteristics curve for advanced fibrosis (0.77 versus 0.83, 0.89, and 0.89 for keratin-negative ballooned hepatocytes, normal-size hepatocytes with keratin loss, and ubiquitin, respectively) because immunohistochemistry is more sensitive and specific for fibrogenic hepatocellular injury than hematoxylin and eosin staining. Keratin 8/18 plus ubiquitin double immunohistochemical stain improves detection of hepatocyte injury in nonalcoholic fatty liver disease. Thus, it may help differentiate nonalcoholic steatohepatitis from nonalcoholic fatty liver.

c-kit gene mutation and CD117 expression in human anorectal melanomas

2011-12-12

Summary: c-kit and BRAF mutations play an important role during the pathogenesis of melanoma. The subtypes of melanomas arising from different parts of the body have variable c-kit or BRAF mutation frequencies. Few studies in the literature have examined c-kit and BRAF mutation status in melanomas that occur in the anus and rectum. In this study, we analyzed 40 cases of anorectal melanoma for c-kit and BRAF mutations by DNA sequencing using paraffin-embedded tissues. c-kit Mutations were detected in exons 9, 11, 13, and 17. CD117 expression in tumor cells was analyzed by immunohistochemistry. Our study showed that a c-kit mutation was found in 7 of the 40 cases of anorectal melanoma. CD117 expression was detected in 16 of the 40 cases, and 3 of these 16 cases also had c-kit mutations. Mutations in BRAF were also identified in 2 patients. These results indicate that a subset of anorectal melanomas have activating c-kit mutations, which suggests that kinase inhibitors such as imatinib may be used to treat this subset of melanoma patients. In addition, our results show that c-kit mutations do not correlate with CD117 expression.

E-cadherin nuclear staining is useful for the diagnosis of ovarian adult granulosa cell tumor

2011-11-14

Summary: We recently have demonstrated nuclear localization of E-cadherin in ovarian adult granulosa cell tumors (Histopathology 2011;58:423). The purpose of the present study is to investigate the diagnostic utility of E-cadherin nuclear staining for the differential diagnosis between ovarian adult granulosa cell tumor and its morphological mimics. Tissue samples taken from 81 ovarian tumors and 20 extraovarian tumors were immunohistochemically stained using monoclonal anti–E-cadherin antibody recognizing cytoplasmic domain (clone 36 supplied by BD Biosciences, San Jose, CA). The ovarian tumors consisted of 30 adult granulosa cell tumors, 3 Sertoli-stromal cell tumors, 14 fibrothecomas, 5 carcinoid tumors, 1 large cell neuroendocrine carcinoma, 18 endometrioid adenocarcinomas, and 10 poorly differentiated serous adenocarcinomas. Extraovarian tumors consisted of 16 uterine endometrial stromal neoplasms and 4 pulmonary small cell carcinomas. Only tumor cells with nuclear staining were considered positive in this study. Ninety percent of adult granulosa cell tumors, 67% of Sertoli-stromal cell tumors, 64% of fibrothecomas, 75% of endometrial stromal neoplasms, 75% of small cell carcinomas, and the one large cell neuroendocrine carcinoma showed E-cadherin nuclear expression, whereas all the ovarian carcinoid tumors, endometrioid adenocarcinomas, and poorly differentiated serous adenocarcinomas were negative. E-cadherin nuclear staining is useful in distinguishing between adult granulosa cell tumors and ovarian adenocarcinomas or carcinoid tumors. However, it is of limited use for distinguishing between adult granulosa cell tumors and endometrial stromal neoplasms or small cell carcinomas. E-cadherin should be included in the immunohistochemical panel for an accurate diagnosis of ovarian adult granulosa cell tumors.

Sarcoidosis does not belong to or overlap with immunoglobulin G4–related diseases based on an assessment of serum immunoglobulin G4 levels in cardiac and noncardiac sarcoidosis

2011-11-02

Summary: Although sarcoidosis may exhibit histopathologic features similar to those of a newly emerging clinical entity, immunoglobulin G4–related sclerosing disease, sarcoidosis is currently not considered to be associated with immunoglobulin G4–related immunoinflammation. Not many studies on this association have been reported. We investigated serum immunoglobulin G4 levels among patients with sarcoidosis with or without cardiac involvement (cardiac sarcoidosis and non–cardiac sarcoidosis patients). The mean serum immunoglobulin G4 level among the 65 patients with sarcoidosis was 56.8 ± 43.0 mg/dL, which did not significantly differ between patients with cardiac sarcoidosis (54 ± 48 mg/dL, n = 12) and patients without cardiac sarcoidosis (58 ± 42 mg/dL; n = 53). Serum level of soluble interleukin 2 receptor, a potent marker that may reflect sarcoidosis activity, was elevated in cardiac sarcoidosis (910 ± 683 U/L) and noncardiac sarcoidosis (689 ± 399 U/L) but did not significantly differ between the groups. Immunohistochemistry of cardiac or lymph node specimens from patients with cardiac sarcoidosis showed only sparse or no infiltration of immunoglobulin G4–positive lymphocytes, in contrast to the moderate to severe infiltration of CD68-positive macrophages and CD45-positive lymphocytes. Although the number of study subjects was small, these findings collectively suggest that regardless of the presence or absence of cardiac involvement, sarcoidosis does not belong to or overlap with immunoglobulin G4–related sclerosing disease.

Total parenteral nutrition therapy and liver injury: a histopathologic study with clinical correlation

Bita V. Naini, Charles R. Lassman — 2011-11-11

Summary: Total parenteral nutrition (TPN) therapy is a well-recognized cause of liver injury. The histologic changes attributed to TPN in the literature vary widely. In this study, we describe the histopathologic changes associated with TPN therapy and relate these changes to various clinical parameters. We conducted a retrospective study of 89 patients who underwent biopsy or liver transplantation while on TPN. We report that (1) ductopenia, a previously unreported finding, is seen in a significant number of patients on TPN. It is more frequently seen in patients with low stage of fibrosis and may have an inverse relationship with the length of therapy; (2) Perivenular fibrosis is a feature frequently seen in patients with high-stage portal fibrosis. In fact, we find the combination of portal and perivenular fibrosis to be a characteristic of TPN injury; (3) Infants are more susceptible to TPN–related hepatocellular injury, are more likely to develop fibrosis, and progress to high-stage fibrosis more rapidly than older children and adults; (4) Cholestasis, although more common in infants, is the most common pathologic finding in all age groups; (5) Steatosis is more commonly seen in older children and adults than in infants; (6) Progression to fibrosis in infants may be dependent on the length of therapy and the underlying disease for which TPN is administered; and (7) Clinical markers of liver injury (eg, elevated liver enzymes) do not predict the degree of hepatocellular injury or fibrosis, and therefore, serial biopsies may be indicated for patients on TPN therapy.

Global histone modification of histone H3 in colorectal cancer and its precursor lesions

2011-09-14

Summary: Chromatin remodeling through histone modification is an important mechanism of epigenetic gene dysregulation in human cancers. However, little is known about global alteration of histone status during tumorigenesis and cancer progression. Histone H3 status was examined in benign and malignant colorectal tumors by immunohistochemistry and Western blotting. For immunohistochemical evaluation, 4 anti-histone H3 antibodies, specific to dimethylation at lysine 4 (H3K4me2), acetylation at lysine 9 (H3K9ac), dimethylation at lysine 9 (H3K9me2), and trimethylation at lysine 27 (H3K27me3), were used. On immunohistochemistry, H3K4me2, H3K9ac, and H3K27me3 showed no significant changes between normal and colorectal tumors. On the other hand, the global level of H3K9me2 was distinctly higher in neoplastic cells (adenoma and adenocarcinoma) than in normal glandular cells. In addition, it was significantly higher in adenocarcinoma than in adenoma. Correspondingly, Western blotting confirmed that H3K9me2 expression was significantly higher in adenocarcinomas than in normal colorectal mucosa. No alteration of H3K9me2 was observed with tumor differentiation and with the histological subtypes of colorectal cancers. These results suggest that aberration of the global H3K9me2 level is an important epigenetic event in colorectal tumorigenesis and carcinogenesis involved with gene regulation in neoplastic cells through chromatin remodeling.

Expression of endothelin 2 and localized clear cell renal cell carcinoma

2011-11-02

Summary: Despite the rising incidence of clear cell renal cell carcinoma, the molecular events that support its development and progression remain unclear. Herein, we evaluate the association of endothelin 2 expression with both clear cell renal cell carcinoma development and progression-free survival. We conducted real-time polymerase chain reaction to determine endothelin 2 expression levels on 238 patients who underwent nephrectomy for localized clear cell renal cell carcinoma, 161 of whom also had adjacent normal kidney samples available for analysis. To evaluate associations with clear cell renal cell carcinoma development, linear mixed models were used to compare differential expression between tumor and a normal kidney as well as to explore interactions with clinicopathologic features. To evaluate associations with prognosis, Cox proportional hazards models were used to assess the association of progression-free survival and endothelin 2 expression in tumor tissue. Overall, endothelin 2 expression was higher in tumor samples versus patient-matched normal kidney samples, with an average fold change of 1.99 (95% confidence interval, 1.48-2.60; P < .0001). This overexpression in tumor versus normal kidney samples was more pronounced in low- compared with high-grade tumors (interaction, P = .0002), in early- compared with late-stage tumors (interaction, P = .001), and in tumors without compared with those with necrosis (interaction, P = .001). Moreover, an increasing endothelin 2 expression in tumors was associated with a longer progression-free survival (hazard ratio, 0.89; 95% confidence interval, 0.80-0.99; P = .03); however, after controlling for known clinicopathologic factors, this association was attenuated (hazard ratio, 0.99; 95% confidence interval, 0.89-1.09; P = .7). Up-regulation of endothelin 2 is a common and early event in localized clear cell renal cell carcinoma. Higher tumor expression of endothelin 2 is associated with a longer progression-free survival but not after adjustment for well-known pathologic indices. Thus, although endothelin 2 does not appear to be an independent prognostic marker, there is evidence of a putative role in clear cell renal cell carcinoma progression. If supportive mechanistic data can be produced, endothelin 2 could represent a potential target for chemopreventive or neoadjuvant therapeutics for clear cell renal cell carcinoma.

Inhibin-α and synaptophysin immunoreactivity in synovial sarcoma with granular cell features

2011-11-07

Summary: We recognized immunoreactivity for the α subset of inhibin and synaptophysin in synovial sarcomas with granular cell features. Histologic findings of 90 cases of synovial sarcoma were reviewed. Two (2.2%) of the 90 cases had granular cell features, showing sheet or nested proliferation of characteristic epithelioid cells with abundant eosinophilic and granular cytoplasm, in addition to the typical spindle cell component. The 2 cases were both female (aged 86 and 76 years). The tumors were located in the foot and the retroperitoneum and measured 3.5 and 14 cm in maximum diameter. Reverse transcriptase polymerase chain reaction analysis revealed SS18-SSX1 transcripts in both cases. SS18 gene rearrangement was detected in granular cells as well as spindle cells by chromogenic in situ hybridization. Immunohistochemistry found the granular cells to be positive for inhibin-α in both cases and for synaptophysin in 1 case, whereas spindle cells were not. Thirty-six cases (20 monophasic fibrous, 11 biphasic, and 5 poorly differentiated synovial sarcomas) were additionally examined for comparison; they showed no immunoreactivity for inhibin-α or synaptophysin. This is the first report of immunoreactivity for inhibin-α and synaptophysin in synovial sarcoma. These immunohistochemical findings might be characteristic of synovial sarcomas with granular cell features.

Cyclin kinase subunit 1B nuclear expression predicts an adverse outcome for patients with relapsed/refractory multiple myeloma treated with bortezomib

Mei-Hsi Chen, Connie Qi, Donna Reece, Hong Chang — 2011-11-02

Summary: Amplification of cyclin kinase subunit 1B gene on chromosome 1q21 resulting in overexpression of cyclin kinase subunit 1B has been associated with disease progression in multiple myeloma. Bortezomib is a proteasome inhibitor that induces apoptosis in various cancer cells and has been shown to be effective as a salvage therapy for relapsed/refractory multiple myeloma. Our group has recently reported the adverse effect of 1q21 gains in relapsed and refractory multiple myeloma treated with bortezomib. However, whether nuclear cyclin kinase subunit 1B protein expression correlates with 1q21 gains and has prognostic value in patients with multiple myeloma receiving bortezomib regimen remains unclear. We, therefore, evaluated the nuclear expression of cyclin kinase subunit 1B protein in patients with relapsed/refractory multiple myeloma undergoing bortezomib therapy by immunohistochemistry. The 1q21 amplification status of the same cohort was examined by interphase cytoplasmic immunoglobulin fluorescence in situ hybridization. Of 60 cases, 19 (32%) were positive for cyclin kinase subunit 1B nuclear expression by immunohistochemistry. Seventeen (89%) of the immunohistochemistry-positive cases had 1q21 gain detected by cytoplasmic immunoglobulin fluorescence in situ hybridization, and 17 (77%) of the 22 cases with 1q21 gain showed increased cyclin kinase subunit 1B protein expression. cyclin kinase subunit 1B expression and 1q21 gain were strongly correlated (P < .0001). There was no significant difference in response rate between patients with and without cyclin kinase subunit 1B nuclear expression. However, patients with cyclin kinase subunit 1B expression had a significantly shorter progression-free survival (1.9 versus 5.6 months; P < .0001) and overall survival (4.9 versus 22.4 months; P = .012) compared with those without cyclin kinase subunit 1B expression. Our results indicated that cyclin kinase subunit 1B nuclear expression detected by immunohistochemistry is an adverse prognostic factor for patients with multiple myeloma treated with bortezomib therapy.

Total Survivin and acetylated Survivin correlate with distinct molecular subtypes of breast cancer

2011-11-07

Summary: Global gene expression profiling studies led to the recent classification of breast cancer into 4 distinct molecular subtypes including luminal, human epidermal growth factor receptor 2 enriched, basal like, and unclassified. Here, we used immunohistochemistry to evaluate expression of the antiapoptotic protein Survivin and its recently described acetylated form, Survivin acetyl129, in normal breast tissue and in 226 primary breast tumors of different molecular subtypes. Correlation of Survivin expression with molecular markers and its impact on patient outcomes were analyzed. Eighty-four percent of basal-like tumors expressed high levels of total Survivin, whereas 52% of luminal tumors expressed high levels of acetylated Survivin (P < .001). Overall survival (91%) for tumors expressing low levels of total Survivin was better than that for tumors expressing high levels of total Survivin (72%, P = .02), whereas the reverse was true for tumors expressing acetylated Survivin. In hierarchical cluster analysis, total Survivin clustered with basal marker expression, whereas acetylated Survivin clustered with luminal marker expression. In multivariate analysis, high total Survivin expression was an independent predictor of worse overall survival in patients with breast cancer (relative risk, 11; P < .01). These data indicate that high levels of total Survivin predict poor outcome in patients with grade 3 invasive ductal carcinoma and correlate directly with a basal-like phenotype. In contrast, high expression of the acetylated form of the protein associates with a favorable outcome and preferentially correlates with luminal-type tumors. Survivin likely has different functions in distinct breast cancer subtypes, and diagnostic strategies that incorporate immunohistochemical markers that detect both Survivin forms may help better strategize patient risk and direct therapy.

Anaplastic thymic carcinoma: a clinicopathologic and immunohistochemical study of 6 cases

Annikka Weissferdt, Cesar A. Moran — 2011-11-07

Summary: Primary thymic anaplastic (“undifferentiated”) carcinoma is an unusual thymic neoplasm that, to date, has not been properly characterized. We present 6 such cases in an attempt to better define this entity. The patients were 5 women and 1 man with an age range from 42 to 72 years (mean, 62 years). None of the patients had any history or radiologic evidence of tumor elsewhere. All patients presented with symptoms related to their anterior mediastinal masses: shortness of breath, chest pain, and cough. Histologically, the lesions were characterized by infiltrative tumors with marked cytologic atypia, bizarre tumor giant cells, and atypical mitoses. None of the neoplasms showed areas of other well-defined types of thymic carcinoma. Immunohistochemically, all tumors showed positive staining for pancytokeratin, 40% expressed Pax8, and none reacted with thyroid transcription factor 1 or β-human chorionic gonadotropin. Follow-up available for 4 patients showed that 3 patients had died 14, 22, and 63 months after diagnosis, whereas 1 patient is alive 4 months after diagnosis. Two patients were lost to follow-up. Anaplastic thymic carcinoma is a distinct morphological type of thymic carcinoma with an aggressive clinical course, which needs to be included in the differential diagnosis of tumors displaying giant cells in the anterior mediastinum.

Relationship between alpha-methylacyl–coenzyme A racemase expression and mucin phenotype in gastric cancer

Yujiro Nozawa, Ken Nishikura, Yoichi Ajioka, Yutaka Aoyagi — 2011-11-14

Summary: Alpha-methylacyl–coenzyme A racemase controls β-oxidation of branched-chain fatty acid and their derivatives. Many investigators have described alpha-methylacyl–coenzyme A racemase expression in various neoplasias and their precursor lesions. Although there have been a few reports regarding alpha-methylacyl–coenzyme A racemase expression in gastric neoplasia, these reports did not discuss the relationship between alpha-methylacyl–coenzyme A racemase expression and mucin phenotype. This study analyzed alpha-methylacyl–coenzyme A racemase expression of gastric carcinomas with regard to mucin phenotype. Alpha-methylacyl–coenzyme A racemase expression was evaluated in 85 cases of gastric biopsies including gastric epithelial neoplasia and nonneoplasia and in 108 cases of surgically resected early gastric cancer. In biopsy cases, alpha-methylacyl–coenzyme A racemase was more highly expressed in neoplasia (69.7%, 23/33) than in nonneoplasia (0%, 0/42) (P = .001). Alpha-methylacyl–coenzyme A racemase was overexpressed in 20.0% (2/10) of cases that were indefinite for neoplasia, and the 2 positive cases were ultimately diagnosed as adenocarcinoma. In resected cases of early gastric adenocarcinoma, alpha-methylacyl–coenzyme A racemase expression significantly correlated with mucin phenotype (P = .003), but not with tumor progression, histologic classification, or clinicopathologic features. Alpha-methylacyl–coenzyme A racemase expression was significantly higher in intestinal-phenotype carcinoma (90.2%, 37/40) than in gastric-phenotype carcinoma (56.3%, 18/31) (P = .006) and also correlated with an increase in CDX2 expression (P = .018) and a decrease in MUC5AC expression (P = .048). This tendency was observed in all histologic types. Our results indicate that alpha-methylacyl–coenzyme A racemase is a useful marker for distinguishing gastric neoplasia from nonneoplasia even at an early stage. Alpha-methylacyl–coenzyme A racemase expression is associated with mucin phenotypes of gastric neoplasia, particularly with the expression of CDX2 and MUC5AC.

High density of tryptase-positive mast cells in patients with renal cell carcinoma on hemodialysis: correlation with expression of stem cell factor and protease activated receptor-2

2011-12-28

Summary: Patients on hemodialysis are at higher risk of renal cell carcinoma probably because of inflammatory and immune system disorders. The aim of this study was to clarify the pathologic roles of 2 phenotypes of mast cells, mast cell tryptase and mast cell chymase, and their correlation with stem cell factor and protease-activated receptor 2 in patients with renal cell carcinoma on hemodialysis. The densities of mast cell tryptase and mast cell chymase and expressions of stem cell factor and protease-activated receptor 2 were examined in 35 patients with hemodialysis-renal cell carcinoma and 39 with non–hemodialysis-renal cell carcinoma who were diagnosed and treated in our hospital. Protein expression was examined by immunohistochemistry. The proliferation index represented the number of Ki-67–positive cells. There were no significant differences in clinicopathologic features between the 2 groups. Mast cell tryptase densities in intratumoral (8.3 per high-power field) and peritumoral areas (8.7 per high-power field) were higher in hemodialysis-renal cell carcinoma than non–hemodialysis-renal cell carcinoma (2.7 and 5.3 per high-power field). No such significant correlations were detected in mast cell chymase. In hemodialysis-renal cell carcinoma, intratumoral mast cell tryptase density correlated with the proliferation index (P = .039 and P = .008, respectively) and also with stem cell factor and protease-activated receptor 2 expression. Our results emphasize the important roles of mast cell tryptase in cancer cell proliferation and recurrence in hemodialysis-renal cell carcinoma. Stem cell factor and protease-activated receptor 2 seem to up-regulate mast cell tryptase functions in these patients. The results suggest collaborative effects of stem cell factor, mast cell tryptase, and protease-activated receptor 2 on the malignant potential of hemodialysis-renal cell carcinoma.

Evaluation of the detection of melanin by the Fontana-Masson silver stain in tissue with a wide range of organisms including Cryptococcus

2011-12-12

Summary: It is not uncommon for surgical pathologists to encounter yeast and yeast-like organisms in tissue sections, and correct identification is imperative for guiding therapy. The Fontana-Masson silver stain for detecting melanin has been accepted as a relatively specific stain for diagnosing cryptococcosis in tissue based on few studies with limited numbers of organisms. This study was designed to test the value of the Fontana-Masson silver by investigating a large collection of tissues with infections that may mimic cryptococcosis. Cases of cryptococcosis and other infections that can morphologically mimic it were identified in the pathology archives of The Johns Hopkins Hospital and The Armed Forces Institute of Pathology. Overall, Fontana-Masson silver was positive in 25 (56%) of 45 cases, including infections caused by Cryptococcus neoformans (9/9), Coccidioides immitis (7/7), Blastomyces dermatitidis (4/10), Paracoccidioides brasiliensis (2/2), Lacazia loboi (1/1), and Rhinosporidium seeberi (1/1). The percentage of organisms staining varied widely, from less than 1% to 100%. Fontana-Masson silver was negative in all infections caused by Histoplasma capsulatum (n = 10), Histoplasma duboisii (n = 1), Sporothrix schenckii (n = 1), and the alga genus Prototheca (n = 2). Fontana-Masson silver was 100% sensitive for cryptococcosis. The specificity was low, however, with 5 of 9 noncryptococcal species being positive in some cases. These results need to be confirmed and extended to other isolates and species but it is clear that many organisms in the morphological differential diagnosis of cryptococcosis can be Fontana-Masson silver stain positive. Accordingly, results of the Fontana-Masson silver stain, especially a positive, should be interpreted cautiously and only in the context of the organism's morphological features and host factors.

Expression of CXCR4 indicates poor prognosis in patients with clear cell carcinoma of the ovary

2011-12-14

Summary: Recent reports have shown that CXCR4 is expressed in various solid tumors and is involved in tumor development and metastasis. We examined the distribution and expression of this molecule in clear cell carcinoma of the ovary to elucidate its clinical significance. Paraffin sections from clear cell carcinoma of the ovary tissues (n = 42) were immunostained with CXCR4 antibody, and the staining intensities were evaluated. The clinicopathologic factors examined were age, FIGO (International Federation of Gynecology and Obstetrics) staging, preoperative value of cancer antigen 125 test, and residual tumor after cytoreductive surgery. Overall survival and progression-free survival were evaluated using the Kaplan-Meier method, and multivariate analysis was completed using Cox proportional hazards analysis. Of the 42 carcinomas, lower level CXCR4 immunoexpression was observed in 21 cases (50.0%) (CXCR4low group); and higher level immunoexpression, in 21 cases (50.0%) (CXCR4high group). Five-year overall survival was significantly poorer in the CXCR4high group than in the CXCR4low group (overall survival, CXCR4low group [90.2%], CXCR4high group [50.3%]; P = .0002). In addition, CXCR4high immunoexpression significantly predicted a poorer progression-free survival when compared with lower expression (5-year progression-free survival, CXCR4low group [90.5%], CXCR4high group [36.2%]; P < .0001). Furthermore, multivariate analyses including the age, preoperative cancer antigen 125 test value, FIGO stage, and CXCR4 expressions revealed that CXCR4high expression was an independent prognostic factor for poorer overall survival and progression-free survival of patients with clear cell carcinoma of the ovary (overall survival, P = .0011; progression-free survival, P = .0008, respectively). Our current study suggested that the assessment of CXCR4 immunoreactivity may be a useful prognostic indicator and that CXCR4 may play a critical role in the progression of clear cell carcinoma of the ovary.

Pancreatic acinar-like adenocarcinoma of the proximal stomach invading the esophagus

2011-11-07

Summary: The aim of this study was to systematically investigate clinicopathologic features of the recently described pancreatic acinar-like adenocarcinoma of the proximal stomach invading the esophagus (n = 43). Patient median age was 66 years (range, 51-90 years). The male-to-female ratio was 7.6. Grossly, pancreatic acinar-like adenocarcinoma tumors were nonencapsulated with the median size of 5.5 cm (range, 2-10.5). Bormann's types 1 to 4 tumors were in 7%, 9%, 67%, and 16% cases, respectively. Frank necrosis, hemorrhage, and cysts were rare or absent. Lymphovascular (81%), perineural (74%), and lymph node (81%) invasions were more common in the pancreatic acinar-like adenocarcinoma than in the non–pancreatic acinar-like adenocarcinoma (n = 94) groups. Microscopically, pancreatic acinar-like adenocarcinoma tumors showed acinar (78%), micropapillary (12%), microcystic, solid, trabecular, and mixed neuroendocrine or signet ring (33%) patterns of growth. No adenosquamous differentiation was noted in the pancreatic acinar-like adenocarcinoma group. Nuclei were round to oval with thickened nuclear membrane, stippled chromatin, and single prominent nucleoli. Mitotic figures were variable. The cytoplasm was moderate, eosinophilic, finely granular, and diffusely immunoreactive to the α1-chymotrypsin antibody in all cases to various degrees. Tumor stroma was nondesmoplastic, delicate, and fibrovascular. Pancreatic acinar-like adenocarcinoma tumors staged pI, pII, pIII, and pIV were in 2%, 21%, 70%, and 7% of cases, respectively. The median number of follow-up months after surgery was 29. The 2-year survival rate was 67%, lower than that (73%) in the non–pancreatic acinar-like adenocarcinoma group. A worse overall survival trend was found for patients in the pancreatic acinar-like adenocarcinoma than in non–pancreatic acinar-like adenocarcinoma groups, but the difference was not statistically significant. Age older than 75 years and overall pathology stage were independent risk factors.

EGFR, HER2, survivin, and loss of pSTAT3 characterize high-grade malignancy in salivary gland cancer with impact on prognosis

2011-12-12

Summary: Increased gene copy number (high polysomy or amplification) of EGFR and HER2 has evolved as a predictor for response to targeted therapy. STAT3 and the apoptosis inhibitor survivin represent distinct oncogenes in various human neoplasms. The purpose of this study was to evaluate protein and gene status of these biomarkers by immunohistochemistry and dual color fluorescence in situ hybridization on tissue microarrays of 286 salivary gland carcinomas in the context of clinical and histopathologic characteristics. Diverse tumor types showed overexpression and increased gene copy number of EGFR and HER2. Amplification of HER2 was found in 35.5% of salivary duct carcinomas. Protein overexpression was strongly associated with high gene copy number for both EGFR and HER2 (P < .001). Overexpression and increased gene copy number of EGFR and HER2 were correlated to high-grade malignancy (P < .001) and unfavorable prognosis (P < .001). Strong nuclear staining of survivin was found in 18.9% of tumors and was associated with high-grade malignancy (P < .001), overexpression, and high gene copy number of EGFR and HER2 (P ≤ .05) as well as unfavorable prognosis (P < .001). Overexpression of nuclear pSTAT3 was found in 28.3% of tumors and correlated with well tumor differentiation (P < .001) and favorable prognosis (P = .001). Loss or weak expression of pSTAT3 was inversely associated with overexpression of survivin (P < .001) as well as overexpression and high gene copy number of EGFR and HER2 (P < .05). Overall, overexpression and increased gene copy number of EGFR and HER2 characterize high-grade malignancy with unfavorable prognosis in salivary gland cancer. Nuclear survivin typifies aggressive tumors with worse prognosis, whereas nuclear pSTAT3 might play a role as a tumor suppressor in absence of EGFR, HER2, and survivin.

Unusual thyroid carcinoma with excessive extracellular hyaline globules: a case of “hyalinizing papillary carcinoma”

2011-12-16

Summary: We present an unusual case of papillary thyroid carcinoma in a 47-year-old Japanese woman. The tumor, 0.8 cm in diameter, was located in the upper left lobe of the thyroid. Histologically, we observed a microfollicular-like and trabecular arrangement of the tumor cells with marked hyalinized stroma and hyaline globules. Immunohistochemically, tumor cells were positive for thyroglobulin and thyroid transcription factor 1. Hyaline stroma and globular bodies were immunopositive for laminin and type IV collagen. MIB-1 index was approximately 1% without membranous immunoreactivity. Under the electron microscope, hyaline stroma and globules showed electron-dense, complex meshwork structures composed of granular and fibrous elements similar to the structure of the lamina densa. Genetic analysis demonstrated a BRAFV600E mutation. Based on these findings, we diagnosed the present tumor as a rare morphological variation of papillary thyroid carcinoma with excessive hyaline globules consisting of basal membrane materials.

Oral extragonadal yolk sac tumor in a patient with Aicardi syndrome: putative origin and differential diagnosis

2012-01-06

Summary: We report, for the first time, a primary oral presentation of a germ cell yolk sac tumor in a 4-year-old girl with Aicardi syndrome. The diagnosis, differential diagnosis, and histogenesis are discussed.

Diffuse reticuloendothelial system involvement in type IV glycogen storage disease with a novel GBE1 mutation: a case report and review

2012-02-10

Summary: Glycogen storage disease type IV is a rare autosomal recessive disorder of glycogen metabolism caused by mutations in the GBE1 gene that encodes the 1,4-alpha-glucan-branching enzyme 1. Its clinical presentation is variable, with the most common form presenting in early childhood with primary hepatic involvement. Histologic manifestations in glycogen storage disease type IV typically consist of intracytoplasmic non–membrane-bound inclusions containing abnormally branched glycogen (polyglucosan bodies) within hepatocytes and myocytes. We report a female infant with classic hepatic form of glycogen storage disease type IV who demonstrated diffuse reticuloendothelial system involvement with the spleen, bone marrow, and lymph nodes infiltrated by foamy histiocytes with intracytoplasmic polyglucosan deposits. Sequence analysis of the GBE1 gene revealed compound heterozygosity for a previously described frameshift mutation (c.1239delT) and a novel missense mutation (c.1279G>A) that is predicted to alter a conserved glycine residue. GBE enzyme analysis revealed no detectable activity. A review of the literature for glycogen storage disease type IV patients with characterized molecular defects and deficient enzyme activity reveals most GBE1 mutations to be missense mutations clustering in the catalytic enzyme domain. Individuals with the classic hepatic form of glycogen storage disease type IV tend to be compound heterozygotes for null and missense mutations. Although the extensive reticuloendothelial system involvement that was observed in our patient is not typical of glycogen storage disease type IV, it may be associated with severe enzymatic deficiency and a poor outcome.

A novel t(6;13)(q15;q34) translocation in a giant cell reparative granuloma (solid aneurysmal bone cyst)

2012-01-27

Abstract: Aneurysmal bone cyst is a rapidly growing and locally aggressive lesion that commonly affects children and young adults. Initially regarded as a reactive process, primary aneurysmal bone cyst is now widely accepted as a neoplasm owing to recent findings of recurrent clonal chromosomal alterations, mostly t(16;17)(q22;p13). However, other infrequent chromosomal rearrangements have also been reported. Giant cell reparative granuloma, previously regarded as a nonneoplastic process and histologically indistinguishable from the solid variant of aneurysmal bone cyst, is frequently seen in the gnathic bones and the short tubular bones of the hands and feet. Here we present such a case of giant cell reparative granuloma (solid aneurysmal bone cyst) in the finger of a 63-year-old white man. Cytogenetic analysis revealed a novel alteration involving a reciprocal translocation between 6q and 13q, with a karyotype of 46,XY,t(6;13)(q15;q34),del(20)(q13.1).

Ectopic hepatic tissue presenting as right atrial mass

Lauren Xu, Jean Jeudy, Allen P. Burke — 2012-01-25

Summary: A 52-year-old woman had a well-circumscribed, mobile mass (1.8 × 1.7 cm) in the right atrium detected by echocardiography and confirmed by magnetic resonance imaging. Subsequent histologic evaluation of the mass revealed benign, ectopic hepatic tissue. Ectopic liver is a rare occurrence, and most frequent anatomical distribution of ectopic hepatic tissue is the region around the gallbladder. In exceptional cases, ectopic liver can be found within the thorax. The reported case demonstrates that ectopic liver should be included in the differential diagnosis of right atrial masses removed surgically.

Ultraviolet radiation resistance-associated polyadenine deletions in human gastric cancer

Giovanni Corso, Valeria Pascale, Daniele Marrelli, Franco Roviello — 2012-06-01

We read with great interest the results published in Human Pathology by Kim et al . The Authors first described 3 ultraviolet radiation resistance–associated gene (UVRAG) somatic mutations in gastric cancer (GC) with microsatellite instability (MSI) phenotype; UVRAG is a tumor suppressor gene activating autophagic cell death . These novel mutations were identified at the polyadenine (poly-A) tract of exon 8; these somatic alterations disrupt the gene activity, with consequent inactivation of function in cancer cells; in particular, this evidence has been observed in MSI colon carcinoma . In this study, the authors reported that 9.4% of gastric tumors were associated with UVRAG poly-A frameshift mutations, only in gastric tumors showing the MSI pattern.

Maria Martinez-Lage — 2011-09-14

As the “master gland” of all endocrine function, there is no doubt that the pituitary requires an exquisite team of worldwide experts to abridge the information available from basic science and clinical practice into a comprehensive and comprehensible text. This is what Shlomo Melmed continues to accomplish in this third edition of The Pituitary.

Human Pathology

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Editorial Board

Table of Contents

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In This Issue - June 2012

Advances in the pathology of penile carcinomas

Costaining for keratins 8/18 plus ubiquitin improves detection of hepatocyte injury in nonalcoholic fatty liver disease

c-kit gene mutation and CD117 expression in human anorectal melanomas

E-cadherin nuclear staining is useful for the diagnosis of ovarian adult granulosa cell tumor

Sarcoidosis does not belong to or overlap with immunoglobulin G4–related diseases based on an assessment of serum immunoglobulin G4 levels in cardiac and noncardiac sarcoidosis

Total parenteral nutrition therapy and liver injury: a histopathologic study with clinical correlation

Global histone modification of histone H3 in colorectal cancer and its precursor lesions

Expression of endothelin 2 and localized clear cell renal cell carcinoma

Inhibin-α and synaptophysin immunoreactivity in synovial sarcoma with granular cell features

Cyclin kinase subunit 1B nuclear expression predicts an adverse outcome for patients with relapsed/refractory multiple myeloma treated with bortezomib

Total Survivin and acetylated Survivin correlate with distinct molecular subtypes of breast cancer

Anaplastic thymic carcinoma: a clinicopathologic and immunohistochemical study of 6 cases

Relationship between alpha-methylacyl–coenzyme A racemase expression and mucin phenotype in gastric cancer

High density of tryptase-positive mast cells in patients with renal cell carcinoma on hemodialysis: correlation with expression of stem cell factor and protease activated receptor-2

Evaluation of the detection of melanin by the Fontana-Masson silver stain in tissue with a wide range of organisms including Cryptococcus

Expression of CXCR4 indicates poor prognosis in patients with clear cell carcinoma of the ovary

Pancreatic acinar-like adenocarcinoma of the proximal stomach invading the esophagus

EGFR, HER2, survivin, and loss of pSTAT3 characterize high-grade malignancy in salivary gland cancer with impact on prognosis

Unusual thyroid carcinoma with excessive extracellular hyaline globules: a case of “hyalinizing papillary carcinoma”

Oral extragonadal yolk sac tumor in a patient with Aicardi syndrome: putative origin and differential diagnosis

Diffuse reticuloendothelial system involvement in type IV glycogen storage disease with a novel GBE1 mutation: a case report and review

A novel t(6;13)(q15;q34) translocation in a giant cell reparative granuloma (solid aneurysmal bone cyst)

Ectopic hepatic tissue presenting as right atrial mass

Ultraviolet radiation resistance-associated polyadenine deletions in human gastric cancer