Aatur D. Singhi

Comparison of human papillomavirus in situ hybridization and p16 immunohistochemistry in the detection of human papillomavirus-associated head and neck cancer based on a prospective clinical experience.

Human papillomavirus (HPV) is a causative agent in a subset of head and neck squamous cell carcinomas (HNSCCs). These HPV‐related cancers have a clinicopathologic profile that diverges from HPV‐negative HNSCCs. Accordingly, HPV testing may soon become integrated into standard pathologic assessment of HNSCCs.

Lymphoepithelial-like carcinoma of the oropharynx: a morphologic variant of HPV-related head and neck carcinoma.

Human papillomavirus-associated squamous cell cancer of the head and neck (HPV-HNSCC) represents an important subgroup of head and neck cancer that is characterized by distinct epidemiologic, clinical, and pathologic features including a relatively constant microscopic appearance. For those cancers that deviate from the morphologic prototype, an association with HPV may not be recognized and accurate tumor classification may not be achieved. We have identified 22 cases of HPV-HNSCC with well-developed lymphoepithelial features including tumor cells with syncytial cytoplasm, vesicular nuclei, and large central nucleoli dispersed in an inflammatory background as cell clusters or single cells. The pattern closely resembles Epstein-Barr virus (EBV)-induced undifferentiated carcinoma of the nasopharynx. Indeed, 3 of the carcinomas presenting as lymph node metastases were originally misdiagnosed as metastatic nasopharyngeal carcinoma. Unlike nasopharyngeal carcinoma, the cases were of oropharyngeal origin, p16 positive by immunohistochemistry (22 of 22, 100%), HPV-16 positive by in-situ hybridization (19 of 22, 86%), and EBV negative by in-situ hybridization (21 of 21, 100%). Like conventional HPV-related HNSCC, the cases tended to occur in patients below 60 years of age (77%), men (73%), and nonsmokers (59%). For carcinomas of the head and neck that exhibit lymphoepithelial features, one cannot assume an EBV-driven process by morphology alone. HPV testing has disclosed a previously unrecognized morphologic variant of HPV-HNSCC that is microscopically indistinguishable from EBV-related carcinoma. For lymphoepithelial carcinomas presenting as cervical lymph node metastases, testing for HPV and EBV is mandatory.

High-risk human papillomavirus in nasopharyngeal carcinoma.

Human papillomavirus (HPV), a cause of oropharyngeal carcinoma, has also been implicated as an etiologic agent in nasopharyngeal carcinomas.

Inflammatory fibroid polyps of the gastrointestinal tract: spectrum of clinical, morphologic, and immunohistochemistry features.

Inflammatory fibroid polyps (IFPs) are rare, benign tumors that can arise throughout the gastrointestinal tract. Although the molecular pathogenesis of these lesions has been well characterized, their morphologic features often vary. We report the clinicopathologic findings of the largest series of IFPs to date. A total of 83 IFPs seen at our institution were collected between 1999 and 2012. The specimens included 64 biopsies and 19 resections. A review of the clinical features identified a modest female predominance (47 women and 36 men) with patients ranging in age from 26 to 87 years (mean, 60 y). Involved sites included the esophagus (n=2), stomach (n=31; mainly antrum), small intestines (n=17), appendix (n=1), large intestines (n=31; majority within the rectosigmoid), and anal canal (n=1). Although most patients had a nonspecific presentation, those with small intestinal lesions frequently presented with intussusception. Grossly, the tumors ranged in size from 0.2 to 4.2 cm (mean, 1.7 cm). Histologically, IFPs were centered within the submucosa in all resection specimens, but mucosal extension was found in 74 of 83 (89%) cases. The tumors varied in both cellularity and degree of vascularity. However, the characteristic feature of perivascular onion skinning was present in only 54% (45/83) of the cases. In addition, a short fascicular growth pattern was also noted in 36% (30 of 83) of cases, whereas both features were present in 14 cases (17%). Eosinophils were present in 94% (78 of 83) of cases but varied widely in number from abundant (20/hpf) to sparse (1/hpf). Interestingly, in those cases with sparse eosinophils, prominent hyalinization was also present (11 of 78, 13%). In addition, although the majority of IFPs expressed CD34, 6 of 44 (14%) were negative. No associated dysplasia or malignancy was seen. IFPs represent a diverse set of submucosal-based lesions that commonly extend into the mucosa, making them amenable to endoscopic biopsy. Although their classic histologic features of perivascular onion skinning and predominance of eosinophils are well described, they may alternatively present with a short fascicular growth pattern, a sparse number of eosinophils, and prominent hyalinization.

Cystic pancreatic neuroendocrine tumors: a clinicopathologic study.

Pancreatic neuroendocrine tumors (PanNETs) are typically solid neoplasms but in rare instances may present as cystic lesions. This unusual presentation can make clinical diagnosis challenging. In addition, the clinical and histopathologic characteristics of cystic PanNETs are poorly defined. We identified 53 cystic PanNETs in our single-institution experience of 491 surgically resected PanNETs. Similar to solid PanNETs, cystic PanNETs developed with an equal sex distribution and over a wide age range (23 to 91 y; mean, 52 y). The unusual cystic appearance made radiologic differentiation from other cystic pancreatic neoplasms difficult with a misdiagnosis in 23 of 53 (43%) cases. An association between cystic PanNETs and multiple endocrine neoplasia type 1 or multifocal disease [5 of 53 (9%) and 7 of 53 (13%), respectively] was not observed as compared with solid PanNETs (P=0.34 and P=0.31, respectively). Grossly, cystic PanNETs were predominantly located in the tail of the pancreas (n=28, 53%) and were similar in size (mean, 3.3 cm) to solid PanNETs (mean, 4.1 cm; P=0.12). All cysts were unilocular (n=53, 100%) and filled with clear to straw-colored fluid. Larger cysts were sometimes noted to be hemorrhagic. Histologically, the cysts were lined by a thin fibrous band that separated the cyst from the neoplastic cells. In comparison with their solid counterparts, cystic PanNETs were less likely to demonstrate tumor necrosis (6%; P=0.04), perineural invasion (8%; P<0.001), vascular invasion (4%; P<0.001), regional lymph node metastasis (13%; P<0.001), and synchronous distant metastasis (4%; P=0.015). The neoplastic cells of the cystic PanNETs were well differentiated (n=53, 100%) with a low mitotic rate and low Ki-67 proliferation index (range, 0.2% to 11%; mean, 1.8%). On the basis of both the American Joint Cancer Committee and European Neuroendocrine Tumor Society staging systems, the majority of cystic PanNETs presented at a lower pathologic stage as compared with solid PanNETs. In summary, cystic PanNETs are a distinctive subgroup of PanNETs with unique clinical, radiographic, and pathologic features.

Gastrointestinal tract langerhans cell histiocytosis: A clinicopathologic study of 12 patients.

Gastrointestinal (GI) tract involvement by Langerhans cell histiocytosis (LCH) is a rare condition. It is typically noted in male patients with systemic disease and is associated with both poor prognosis and high morbidity. The incidence peaks in childhood. However, a limited number of cases have been reported in adults. To further characterize this disease process, we collected 24 cases of GI tract LCH from 12 patients. The patients included 2 children (4 mo and 2.3 y) and 10 adults (40 to 77 y; mean, 58.4 y), with a female predominance (9 of 12, 75%). Both children presented with failure to thrive, bloody diarrhea, and anemia. In contrast, 5 of 10 (50%) adults were asymptomatic and the rest had unrelated symptoms. Endoscopically, the pediatric patients showed the involvement of the duodenum and multiple colonic sites. However, 8 of 10 (80%) adults presented with a solitary polyp, primarily involving the colorectum (7 of 8, 88%). The lesions ranged in size from 0.1 to 0.8 cm (mean, 0.4 cm), and were predominantly intramucosal (18 of 24, 75%) with either a marginated (14 of 24, 58%) or infiltrative (10 of 24, 42%) growth pattern. Microscopic features were similar to those of LCH found elsewhere, although some cases differed by showing prominent lymphocytes (12 of 24, 50%) rather than eosinophils and large nucleoli (2 of 24, 8%). Reactive overlying mucosal and entrapped epithelial changes (10 of 24, 42%), mucosal ulceration (3 of 24, 13%), focal necrosis (1 of 24), and multinucleated giant cells (1 of 24) were also identified. Mitotic figures were absent. On immunohistochemistry, all lesions expressed the S-100 protein and CD1a. Follow-up information was available for 11 (92%) patients ranging from 2 months to 5.3 years (mean, 1.8 y). One pediatric patient was lost to follow-up. However, the other patient developed multisystem disease and died 1 year after the initial diagnosis. Two adult patients developed cutaneous disease, 2 months and 2 years after the initial diagnosis, 1 of whom had multifocal colonic disease. On the basis of this study, GI tract LCH lesions present in both children and adults with a female predominance. Consistent with earlier reports, pediatric cases are associated with systemic disease and poor prognosis. However, in adults, LCH is typically encountered as an incidental, solitary polyp. Rare cases of systemic disease may occur and, therefore, close follow-up may be warranted.

MYC gene amplification is often acquired in lethal distant breast cancer metastases of unamplified primary tumors.

In breast cancer, amplification of MYC is consistently observed in aggressive forms of disease and correlates with poor prognosis and distant metastases. However, to date, a systematic analysis of MYC amplification in metastatic breast cancers has not been reported. Specifically, whether the MYC amplification status may change in metastases in comparison to the corresponding primary breast tumor, and potential variability among different metastases within the same patient have also not been assessed. We generated single patient tissue microarrays consisting of both primary breast carcinomas and multiple matched systemic metastases from 15 patients through our previously described rapid autopsy program. In total, the 15 tissue microarrays contained 145 primary tumor spots and 778 spots derived from 180 different metastases. In addition, two separate tissue microarrays were constructed composed of 10 matched primary breast cancers and corresponding solitary metastases sampled not at autopsy but rather in routine surgical resections. These two tissue microarrays totaled 50 primary tumor spots and 86 metastatic tumor spots. For each case, hormone receptor status, HER2/neu, EGFR and CK5/6 expression were assessed, and the cases were characterized as luminal, basal-like or HER2 based on published criteria. Both fluorescence in situ hybridization and immunohistochemistry for MYC was performed on all cases. Of the 25 cases, 24 were evaluable. While 4 of 24 primary tumors (16%) demonstrated MYC amplification, an additional 6 (25% of total evaluable cases) acquired MYC amplification in their systemic metastases. Of note, there was remarkably little heterogeneity in MYC copy number among different metastases from the same patient. MYC immunoreactivity was increased in metastases relative to matched primaries in the surgical cohort, although there was no perfect correlation with MYC amplification. In conclusion, amplification of MYC is a frequent event in breast cancer, but occurs more frequently as a diffuse, acquired event in metastatic disease than in the corresponding primary. These observations underscore the importance of MYC in breast cancer progression/metastasis, as well as its relevance as a potential therapeutic target in otherwise incurable metastatic disease.

Pancreatic Neuroendocrine Tumor With Cystlike Changes: Evaluation With MDCT

OBJECTIVEnThe objective of our study was to determine the prevalence and CT appearance of cystlike changes of pancreatic neuroendocrine tumor (NET), particularly of small (≤ 3 cm) tumors.nnnMATERIALS AND METHODSnThe clinical records, images, and pathologic reports of 74 consecutive patients (average age, 55.5 years) with surgically resected pancreatic NETs who underwent preoperative CT were retrospectively reviewed. The size and location of the pancreatic NETs were recorded. The tumors were classified on the basis of CT appearance as small (≤ 3 cm) or large (> 3 cm) and as solid, partially (≤ 50% or > 50%) cystic, or purely (≈ 100%) cystic. Peripheral contrast enhancement on CT was characterized, and lymph node and liver metastases found by pathologic examination were recorded.nnnRESULTSnA total of 78 pancreatic NETs were reviewed. Five were not visualized on CT, leaving 73 pancreatic NETs in 69 patients (multiple tumors were visualized on CT of three patients) for analysis. The mean size of the 73 tumors was 3.0 ± 2.6 (SD) cm (range, 0.7-13.1 cm); 52 tumors were 3 cm or smaller and 21 tumors were larger than 3 cm. Gross pathologic results confirmed that 13 of the 73 (17.8%) tumors were predominantly (> 50% or ≈ 100%) cystic: 10 of the 52 (19.2%) tumors 3 cm or smaller and three of the 21 (14.3%) tumors larger than 3 cm. Peripheral contrast enhancement was seen in 11 of the 13 (85%) predominantly cystic pancreatic NETs. Compared with solid pancreatic NETs, predominantly cystic pancreatic NETs were less commonly associated with lymph node and liver metastases.nnnCONCLUSIONnCystic pancreatic NETs are not rare and should be included in the differential diagnosis of a cystic pancreatic mass, particularly if the cystic mass is associated with peripheral contrast enhancement. A minority of cystic pancreatic NETs can present with no peripheral enhancement.

Gastric adenocarcinoma with chief cell differentiation: a proposal for reclassification as oxyntic gland polyp/adenoma.

Gastric adenocarcinoma with chief cell differentiation (GA-CCD) has been reported as a new, rare variant of gastric adenocarcinoma. Only 12 cases in Japanese patients have been described to date, but they demonstrate distinct clinicopathologic features. To further characterize these lesions, we have collected 10 additional cases. Patients ranged in age from 44 to 79 years (mean, 64.2 y) with a relatively equal sex distribution (6 women and 4 men). Stratified by race, 4 patients were Hispanic, 2 were White, 2 were African American, 1 was Asian (Chinese), and the race was unknown for 1 patient. All patients presented with gastroesophageal reflux that prompted an endoscopic examination. The majority of GA-CCDs were identified in the fundus (7 of 10, 70%) and the remaining in the cardia (n=3). Grossly, they were solitary and polypoid, ranging in size from 0.2 to 0.8 cm (mean, 0.4 cm). Histologically, all cases were centered in the deep mucosa, with focal involvement of surface foveolar epithelium in 3 (30%) cases but not the submucosa. The tumors consisted of clustered glands and irregular branching cords of oxyntic epithelium. Thin wisps of radiating smooth muscle separated the epithelium, but desmoplasia was distinctly absent in all cases. The oxyntic mucosa was 1 to 2 cells thick and composed of a mixture of mucous neck, parietal, and chief cells. In 7 of 10 (70%) cases, chief cells were the predominant cell type, whereas the remaining 3 cases consisted primarily of mucous neck cells. The nuclei were mildly enlarged with slight nuclear pleomorphism, but no mitotic figures were identified. In addition, necrosis, lymphovascular invasion, and perineural invasion were absent. Immunohistochemically, GA-CCDs were diffusely positive for MUC6 (10 of 10, 100%) and negative for MUC5AC (0%) and MUC2 (0%). Ki-67 immunolabeling demonstrated variable expression, with the highest areas ranging from 0.2% to 10%. Clinical follow-up was available for 9 of 10 (90%) patients and ranged from 6 to 39 months. One patient had persistence of lesion at 6 months because of incomplete removal, whereas the other 8 were disease free. In summary, GA-CCDs are solitary, mucosal lesions of the gastric cardia/fundus that arise in patients from multiple ethnic backgrounds. Considering that patients within this study and those reported previously have had neither true recurrence nor progression of disease, these lesions are best regarded as benign. Consequently, the term GA-CCD is contradictory and we prefer the descriptive term “oxyntic gland polyp/adenoma” until further studies can clarify the pathogenesis of these lesions and their natural history.

Reticulin loss in benign fatty liver: An important diagnostic pitfall when considering a diagnosis of hepatocellular carcinoma

Reticulin stains are commonly used in surgical pathology to assess mass lesions for the possibility of hepatocellular carcinoma. The loss of normal reticulin staining can help support a diagnosis of hepatocellular carcinoma, and this stain has proven to be particularly helpful on limited biopsies and fine-needle aspirates. However, an underappreciated diagnostic pitfall is that non-neoplastic liver tissue can also show reticulin loss when there is fatty change. To further characterize this important diagnostic pitfall, reticulin staining was studied in cases of nonalcoholic steatosis, nonalcoholic steatohepatitis, and hepatic adenomas with fatty change. A total of 112 cases with varying degrees of steatosis were collected from 4 academic centers, including 49 cases of steatosis, 49 cases of steatohepatitis, and 14 hepatic adenomas with fatty change. Steatosis was graded as mild (5% to 30% macrovesicular steatosis), moderate (31% to 60%), and marked (>60%). Reticulin stains were scored as the number of foci with diminished reticulin staining in 10 hpf. A focus of diminished reticulin was scored when the extent of reticulin loss was similar to that seen in hepatocellular carcinomas. In the total study set, 28 cases showed mild steatosis, 40 cases showed moderate steatosis, and 44 cases showed marked steatosis. Interestingly, increasing amounts of fat were associated with decreased reticulin staining. For mild steatosis, reticulin loss was rare, with the number of foci of reticulin loss per 10 hpf averaging 0.8 (range, 0 to 3); however, this increased for moderate steatosis, which showed a mean of 3.0 foci per 10 hpf (range, 0 to 5), and was most prominent with marked steatosis, which showed an average of 5.8 foci of reticulin loss per 10 hpf (range, 5 to 8). An almost identical pattern was seen in cases of nonalcoholic steatohepatitis. Overall, reticulin loss was not associated with the degree of inflammation or with the presence or absence of balloon cell change. Reticulin loss also did not correlate with fibrosis stage. In hepatic adenomas, reticulin loss was seen only in areas of fatty change, and decreased reticulin again paralleled the amount of steatosis, with more prominent reticulin loss in those cases with marked steatosis. In conclusion, reticulin loss that reaches levels seen in hepatocellular carcinoma can be seen focally in benign liver tissues with fatty change. Overall, loss of reticulin is more common and more extensive with marked fatty change and does not seem to be linked to inflammation or fibrosis stage. Loss of reticulin can also be seen in hepatic adenomas with fatty change. Increased awareness of this important diagnostic pitfall will help prevent overcalling of reticulin loss when evaluating biopsies and resections of hepatic neoplasms with fatty change.