Radiologic and histopathologic features of hydrogel sealant after lung resection in participants of a prospective randomized clinical trial.

PURPOSE: To summarize imaging and histopathologic characteristics of hydrogel sealant (plug) in lung parenchyma and assess their correlation with time since deployment of sealant. MATERIALS AND METHODS: Among a total of 208 participants randomized to the hydrogel sealant arm of a lung biopsy prospective randomized clinical trial, 51 underwent resection of the biopsied lesion. In 34 participants sealant material was present on histopathologic sections (n = 22), or they had cross-sectional imaging of chest between biopsy and resection (n = 23) or they had both imaging and histopathology (n = 11). Histopathologic and imaging findings were described. The association of these findings with time since sealant deployment was evaluated using the Wilcoxon rank sum test. RESULTS: The mean time since sealant deployment for histopathology was 45.7 days (median 36, range 14-181) and for imaging studies was 99 days (median 32, range 4-527). The sealant was infiltrated by inflammatory cells in 20 (91%) participants. The main general histopathologic pattern of sealant was foamy in 12 (57%) and mesh in 8 (38%) participants. Imaging appearance of sealant was serpiginous in 18 (60%), linear in 10 (33%) or lobulated in 2 (6.7%) participants. In 2 participants the sealant was hypermetabolic with no histopathologic evidence of tumor. No correlation was found between time since sealant deployment and imaging or histopathologic appearances. CONCLUSION: Hydrogel sealant appears as a serpiginous, linear, or lobulated opacity on cross-sectional imaging which can be metabolically active. It is associated with an inflammatory reaction with a foamy or mesh general pattern on histopathological assessment. No correlation was found between time since sealant deployment and imaging or histopathologic appearances.

Localized amyloidosis in usual-type vulvar intraepithelial neoplasia: High-risk HPV association and potential clinical significance. A series of 45 cases.

Localized cutaneous amyloidosis was reported recently in association with vulvar squamous intraepithelial neoplasia (VIN). High-risk human papillomavirus (hrHPV) type 16 is the most commonly reported subtype found in usual-type VIN. However, it is unknown whether any hrHPV subtype(s) is/are prevalent in simultaneous squamous intraepithelial lesions and localized amyloidosis in the same individual - the subject matter of this report. To observe the potential clinical significance, study cases were followed and compared to usual-type VINs without amyloid deposition. Of 45 patients of usual-type VINs associated with amyloidosis, 33 had detectable hrHPV, and 12 were negative. HPV 16 alone or in combination with HPV 31 accounted for 72%, HPV 51 alone accounted for 2% of the cases, and 26% were negative for hrHPV. Lack of demonstrable hrHPV in a significant proportion of cases (26%) raises the possibility of a novel or presently undetected hrHPV subtype. Five of the total 22 (23%) patients with amyloid had either Squamous cell carcinoma or high-grade VIN on follow-up. In contrast, 14 of 18 (78%) patients exhibiting lesions without amyloid had disease on follow-up. These findings may indicate that amyloid deposition may represent a feature of regression or a potential favorable prognostic indicator.

Primary cutaneous SMARCB1-deficient carcinoma.

BACKGROUND: SMARCB1-deficient malignancies can arise in various sites. We describe a novel primary SMARCB1-deficient carcinoma of skin (SDCS) and characterize SMARCB1 mutations in non-melanoma skin cancers (NMSC). METHODS: Cases underwent immunophenotyping and targeted exome sequencing (MSK-IMPACT) assay interrogating somatic mutations in 468 cancer-related genes. The MSK-IMPACT database from 2014 to 2020 encompassing 55, 000 cases was searched for NMSC with SMARCB1 mutations. RESULTS: SDCS arose on the scalp of an 18-year-old woman showing homozygous SMARCB1 deletion with a LATS2 G963E variant. Another case arose on the temple of a 76-year-old man harboring a SMARCB1 W206* mutation associated with loss of heterozygosity (LOH), 59 concurrent mutations, and a UV mutation signature (UV-MS). Both tumors exhibited INI1 loss, positive CK5/6, p40, p63, and claudin-4 with negative CD34. Of 378 NMSC cases, including 370 carcinomas, 7 SMARCB1-mutated tumors were identified: 3 squamous cell, 3 Merkel cell, and one basal cell carcinoma. Six showed UV-MS. Five INI1-interrogated cases retained protein expression suggesting they were SMARCB1-proficient. CONCLUSIONS: SDCS can be clinically aggressive, harbor SMARCB1 homozygous deletions or truncating SMARCB1 mutations associated with LOH, and can occur with or without UV-MS. Overall, SMARCB1 mutations in NMSC are rare with most being of undetermined significance and associated with retained INI1 and UV-MS.

A Rare Perineurioma/Granular Cell Tumor Hybrid Peripheral Nerve Sheath Tumor.

Hybrid peripheral nerve sheath tumors (PNSTs) are rare benign composite neoplasms demonstrating features of multiple endogenous nerve sheath cell types. Hybrid PNSTs with granular cell components are exceedingly rare. Only a handful number of hybrid PNSTs composed of granular cell tumor and perineurioma have been described to date. We present a rare hybrid of perineurioma and granular cell tumor and review the literature.

Two Unusual Cases of Discoid Lupus Erythematosus Associated With Xanthomatized Macrophages.

We present 2 patients with chronic discoid lupus erythematosus (LE) associated with xanthomatized macrophages on light microscopic findings. Skin biopsies revealed hyperkeratotic and atrophic epidermis, vacuolar degeneration of the dermal-epidermal junction, thickened basement membrane, follicular plugging, and perivascular and perifollicular lymphohistiocytic infiltrate. Notably, large collections of lipid-laden histiocytes were observed within the subjacent dermis. The patients denied history of intralesional steroid treatment. The patients did not demonstrate any clinical or laboratory signs of hyperlipidemia, cholestasis, and diabetes mellitus and insipidus. Accumulation of lipid-laden foam cells in cutaneous LE is a rare phenomenon that has been reported in discoid LE and lupus panniculitis, each only once in the literature. It has also been described within lesions of various other dermatoses in patients without lipid, hepatic, or endocrine abnormalities. Its mechanism remains unclear, but it has been hypothesized that intracellular lipids released from degenerating cells contribute to lipidization of mononuclear scavengers. Xanthomatous infiltration in cutaneous LE is an unusual feature, and its presence may not necessarily signify an underlying metabolic disorder.

ColXα1 is a stromal component that colocalizes with elastin in the breast tumor extracellular matrix.

The tumor microenvironment regulates tissue development and homeostasis, and its dysregulation contributes to neoplastic progression. Increased expression of type X collagen α-1 (ColXα1) in tumor-associated stroma correlates with poor pathologic response to neoadjuvant chemotherapy in estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2)-positive breast cancers. Evaluation of ColXα1 expression patterns suggests a potential connection with elastin fibers. To investigate the possible interaction between ColXα1 and elastin, we evaluated the expression of ColXα1 in relation to elastin fibers in normal breast tissue, ductal carcinoma in situ, and invasive breast carcinomas at cellular and subcellular levels. Our findings demonstrate that ColXα1 colocalizes with elastin in invasive breast cancer-associated stroma by immunohistochemistry, immunofluorescence, and electron microscopy. In 212 invasive breast carcinomas, this complex was aberrantly and selectively expressed in tumor extracellular matrix in 79% of ER+/HER2-, 80% of ER+/HER2+, 76% of ER-/HER2+, and 58% of triple negative breast cancers. In contrast, ColXα1 was generally absent, while elastin was present perivascularly in normal breast tissue. ColXα1 and elastin were coexpressed in 58% of ductal carcinoma in situ (DCIS) in periductal areas. In mass-forming DCIS with desmoplastic stroma, the complex was intensely expressed in periductal areas as well as within the tumor-associated stroma in all cases. Our data suggest that the breast carcinoma neoplastic process may involve aberrant expression of ColXα1 and elastin in the tumor microenvironment emerging early at the DCIS stage. Enrichment of these complexes in tumor-associated stroma may represent a stromal signature indicative of intrinsic differences between breast cancers. These findings shed light on investigation into the role of aberrant collagen complex expression in tumorigenesis and tumor progression which may be leveraged in therapeutic and theranostic applications.

Temporal small arterial inflammation is common in patients with giant cell arteritis.

Giant cell arteritis (GCA) primarily involves medium-to-large arteries. Small-vessel inflammation is a recognized phenomenon occurring in association with GCA. However, its significance is poorly elucidated. Histologic sections and medical records of105 temporal artery specimens were retrospectively reviewed between 2008 and 2017 to examine associated clinical manifestations and laboratory data including antinuclear antibody and p-antineutrophilic cytoplasmic antibody titers. Immunohistochemical staining for CD4 and CD8 was performed in select cases to assess the nature of the inflammatory response. Seventy-eight patients meeting the diagnostic criteria of temporal arteritis were included in the analysis. Twenty-eight specimens demonstrated temporal arteritis with small arterial inflammation (SAI), and 50 specimens showed temporal arteritis without SAI. Eight (28.6%) of 28 patients with SAI presented with jaw claudication, whereas 5 (17.9%) were febrile at presentation. In contrast, in 50 patients without SAI, jaw claudication and fever were seen in 11 and 2 cases, respectively (P = .01 and P = .0047, respectively). No statistically significant difference was noted between other symptoms and laboratory indices between the 2 groups. Elevated p-antineutrophilic cytoplasmic antibody titers in GCA may be associated with concomitant polymyalgia rheumatica or treatment-resistant disease. We also identified a higher count of CD4 and CD8 T cells in SAI cases, although the ratio of CD4/CD8 T lymphocytes was within normal limits. In conclusion, simultaneous involvement of arterioles and medium- to large-sized arteries is common in GCA and may be associated with treatment-refractory disease. Documentation of small arterial involvement in GCA will help the clinicians to manage the disease more effectively.

Alanine-glyoxylate aminotransferase 1 (AGXT1) is a novel marker for hepatocellular carcinomas.

Arginase-1 has been demonstrated as a marker for hepatocellular carcinoma (HCC) with higher sensitivity and specificity than HepPar-1 and glypican-3. However, its sensitivity is diminished in moderately and poorly differentiated HCCs. In the current study, we evaluated the utility of AGXT1 as a diagnostic marker. Immunostains for AGXT1 and arginase-1 were performed in tissue microarrays of 139 HCCs and 374 gastrointestinal and nongastrointestinal carcinomas. AGXT1 exhibited granular cytoplasmic immunoreactivity in contrast to the diffuse cytoplasmic staining characteristic of arginase-1 in nonneoplastic and neoplastic hepatocytes. Sensitivities of AGXT1 for all HCCs were 90.0% compared to 87.8% for arginase-1. A small number of tumors expressed only 1 of the 2 markers. Sensitivity increased to 92.1% when the presence of either marker was considered positive. Excepting 5 cases of cholangiocarcinoma, both AGXT1 and arginase-1 were negative in all non-HCC tumors with specificities of 98.7%. Our data support the consideration of AGXT1 as a novel hepatocellular marker with equally high specificity and slightly higher sensitivity as compared to arginase-1. AGXT1 may aid in diagnostic workup especially in conjunction with arginase-1 for HCCs that may otherwise defy conventional immunostaining patterns.

TGR5 expression in normal kidney and renal neoplasms.

BACKGROUND: The G protein-coupled bile acid receptor (TGR5) is a cell surface receptor which induces the production of intracellular cAMP and promotes epithelial-mesenchymal transition in gastric cancer cell lines. TGR5 is found in a wide variety of tissues including the kidney. However, the patterns of TGR5 expression have not been well characterized in physiologic kidney or renal neoplasms. We explore the expression of TGR5 in benign renal tissue and renal neoplasms and assess its utility as a diagnostic marker. METHODS: Sixty-one renal cortical neoplasms from 2000 to 2014 were retrieved. TGR5 protein expression was examined by immunohistochemistry. TGR5 mRNA was also measured by real-time PCR. RESULTS: In normal renal tissue, TGR5 was strongly positive in collecting ducts, distal convoluted tubules and thin loop of Henle. Proximal convoluted tubules showed absent or focal weak staining. In clear cell renal cell carcinomas (RCCs), 25 of 27 cases (92%) were negative for TGR5 (p < 0.001). TGR5 mRNA was also significantly decreased in clear cell RCCs, suggesting that decreased TGR5 protein expression may be attributable to the downregulation of TGR5 mRNA in these tumors. All 11 papillary RCCs expressed TGR5 with 45% (5/11) exhibiting moderate to strong staining. All chromophobe RCCs and oncocytomas were positive for TGR5 with weak to moderate staining. TGR5 mRNA expression in these tumors was similar to normal kidney. All urothelial carcinomas of the renal pelvis strongly expressed TGR5 including a poorly differentiated urothelial carcinoma with sarcomatoid features. CONCLUSION: TGR5 is strongly expressed in collecting ducts, distal convoluted tubules and thin loop of Henle. TGR5 protein and mRNA expression were notably decreased in clear cell RCCs and may be helpful in differentiating these tumors from other RCCs.

Differentiating breast carcinoma with signet ring features from gastrointestinal signet ring carcinoma: assessment of immunohistochemical markers.

Signet ring morphology is recognized throughout the gastrointestinal tract. However, this pattern may be observed in other primary sites giving rise to diagnostic challenges in the work-up of metastases. Relatively newer immunohistochemical markers have not been evaluated in this context. We assessed expression patterns of several common immunohistochemical markers in tumors with Signet ring morphology to delineate a pragmatic approach to this differential diagnosis. Primary breast and gastrointestinal carcinomas showing Signet ring features were reviewed. Non-mammary and non-gastrointestinal tumors with this morphology were included for comparison. Estrogen receptor (ER), progesterone receptor (PR), E-cadherin, CK7, CK20, GCDFP-15, mammaglobin, CDX2, GATA-3, and HepPar-1 immunohistochemistry was performed. Expression patterns were compared between breast and gastrointestinal tumors as well as lobular breast and gastric tumors. Ninety-three cases were identified: 33 breast carcinomas including 13 lobular, 50 gastrointestinal tumors including 23 gastric, and 10 from other sites. ER (sensitivity=81.8%, specificity=100%, positive predictive value (PPV)=100%, negative predictive value (NPV)=89.3%) and GATA-3 (sensitivity=100%, specificity=98%, PPV=96.8%, NPV=100%) expression were associated with breast origin. CK20 (sensitivity=66.7%, specificity=93.3%, PPV=94.1%, NPV=63.6%) and CDX2 (sensitivity=72%, specificity=100%, PPV=100%, NPV=68.9%) demonstrated the strongest discriminatory value for gastrointestinal origin. These markers exhibited similar discriminatory characteristics when comparing lobular and gastric signet ring carcinomas. In a limited trial on metastatic breast and gastric cases, these markers successfully discriminated between breast and gastric primary sites in 15 of 16 cases. ER and GATA-3 are most supportive of mammary origin and constitute an effective panel for distinguishing primary breast from primary gastrointestinal Signet ring tumors when combined with CK20 and CDX2 immunohistochemistry.

Cell Polarity Reversal Distinguishes True Micropapillary Growth From Retraction Artifact in Invasive Urothelial Carcinoma.

Focal micropapillary features in invasive urothelial carcinoma is sometimes difficult to distinguish from retraction artifact morphologically. Cell polarity reversal has been demonstrated in micropapillary tumors by epithelial membrane antigen (EMA) immunostaining. We have previously described the use of E-cadherin as a cell polarity marker in ovarian micropapillary serous borderline tumors. The aim of this study was to evaluate the utility of immunohistochemistry for EMA and E-cadherin in differentiating micropapillary urothelial carcinoma from retraction artifact. We identified 29 invasive urothelial carcinomas with micropapillary features and 30 invasive urothelial carcinomas without reported micropapillary features but with areas of retraction artifact. Cell polarity reversal was considered present if E-cadherin showed membranous apical cup-like staining or if EMA demonstrated a well-defined basal staining towards the stroma. Twenty-seven of 29 cases (93%) of urothelial carcinoma with micropapillary features demonstrated EMA or E-cadherin staining patterns consistent with cell polarity reversal. Staining consistent with micropapillary architecture was identified with both markers in 20 of these 27 cases (74%). Six cases showed reversal of polarity by E-cadherin alone, whereas 1 case showed polarity reversal by EMA alone. Retraction artifacts showed circumferential staining by E-cadherin and lacked well-defined basal staining by EMA. Three cases originally classified as with retraction artifact showed reversal of cell polarity by both EMA and E-cadherin and were reclassified as micropapillary. Our data show that pathologists can reliably make this distinction in most cases. However, in some cases with ambiguous features, EMA and E-cadherin immunostaining may aid in resolving this diagnostic dilemma.

Diffuse dermal angiomatosis mimicking inflammatory breast carcinoma.

Diffuse dermal angiomatosis (DDA) is a rare pathologically distinct subtype of reactive angioendotheliomatosis. In the literature, few biopsy-proven cases involving breast skin have been reported. We present a case of a 49-year-old female who presented with an indurated, erythematous, weeping, puckered and tender lesion with focal ulceration. Mammography demonstrated diffuse cutaneous and trabecular thickening concerning for inflammatory breast carcinoma. A punch biopsy demonstrated findings consistent with DDA. To our knowledge, this is the first reported case of DDA mimicking inflammatory carcinoma of the breast by clinical and radiologic examination.

T-complex-associated-testis-expressed 3 (TCTE3) is a novel marker for pancreatobiliary carcinomas.

Several markers of pancreatobiliary lineage have been described in the literature. However, none have demonstrated sufficient specificity and sensitivity to warrant diagnostic use. We evaluated the utility of T-complex-associated-testis-expressed 3 (TCTE3) as a pancreatobiliary marker. A set of 247 adenocarcinomas from the gastrointestinal (GI) tract was identified including 18 from the gastroesophageal junction (GEJ), 29 stomach, 17 ampullary, 62 pancreatic, and 16 common bile duct and gallbladder (CBD/GB), 13 non-ampullary small intestine, 32 colon, and 24 rectum. The remainder consisted of 16 cholangiocarcinomas and 20 hepatocellular carcinomas (HCC). Additionally, 163 adenocarcinomas from the breast, gynecologic tract, prostate, urothelium, kidney, and lung were stained for comparison. Immunohistochemistry for TCTE3 and other gastrointestinal markers was performed. Positive expression of TCTE3 was characterized by a strong, well-defined membranous pattern with or without weak cytoplasmic staining. Expression was identified in the normal epithelial cells of pancreatobiliary tree, but staining was absent in normal epithelial cells of esophagus, stomach, and intestine. Hepatocytes, pancreatic acini and islets and other non-epithelial cells were also negative for staining. TCTE3 was expressed in 93.5% of pancreatic ductal adenocarcinomas, 37.5% of CBD/GB adenocarcinomas, 50% of cholangiocarcinomas, 76.4% of ampullary adenocarcinomas, and 33.3% of GEJ adenocarcinomas. Only 3.5% of the gastric, 7.7% of non-ampullary small intestinal and 6.25% of colonic tumors exhibited positive staining. Expression was absent in rectal carcinomas and HCCs. These results suggest that TCTE3 is a useful marker of pancreatobiliary differentiation and may aid in distinguishing these tumors from gastric and intestinal primary tumors.

ALOX15 Immunohistochemistry Aids in the Diagnosis of Eosinophilic Esophagitis on Pauci-eosinophilic Biopsies in Children.

Histologically, esophageal biopsies should have ≥15 intraepithelial eosinophils (IEEs) per high power field (HPF) to support a clinicopathologic diagnosis of eosinophilic esophagitis (EoE). Children with clinically apparent EoE may show pauci-eosinophilic biopsies due to patchy involvement. Immunostaining (Immunohistochemistry) for arachidonate-15 lipooxygenase (ALOX15) has been demonstrated to be a sensitive marker for EoE. We retrospectively assessed the expression of ALOX15 in 48 biopsies from 21 patients with established diagnosis of EoE and with tissue fragments below the threshold of 15 IEEs/HPF. Fragments were classified into pauci-eosinophilic and non-pauci-eosinophilic groups using cutoffs of 10 and 15 IEEs/HPF. Controls included patients with reflux and normal biopsies. Sixty-five (43.9%) fragments showed <10 IEEs/HPF and 83 (56.1%) showed ≥10 IEEs/HPF. Using a cutoff of 15 IEEs/HPF, 87 (58.7%) fragments showed <15 IEEs/HPF while 61 fragments (41.2%) had ≥15 IEEs/HPF. ALOX15 was positive in 53/65 (81.5%) of fragments with <10 IEEs/HPF versus 82/83 (98.8%) of fragments with ≥10 IEEs/HPF ( P < .001). For a cutoff of 15 IEEs/HPF, 75/87 (86.2%) of pauci-eosinophilic fragments were ALOX15-positive, while 60/61(98.4%) of biopsies meeting the threshold were positive ( P < .001). In 3/21 (14.3%) patients with EoE, all of the fragments (n = 7) were pauci-eosinophilic and all of them were positive for ALOX15. Two of 24 patients with reflux (one with 9 and one with 14 IEEs/HPF) were also positive. Fragments from normal controls (0 IEEs/HPF) were negative. Our results support the utility of ALOX15 immunohistochemistry in supporting the diagnosis of EoE in rare situations with strong clinical suspicion where no fragments reach 15 IEEs/HPF.

Human Papillomavirus Genotyping of Incidental Malignant and Premalignant Lesions on Hemorrhoidectomy Specimens.

Routine histopathologic examination of hemorrhoidectomy specimens is controversial having been described as not useful and expensive with few of these common cases demonstrating incidental lesions. However, unexpected premalignant and malignant lesions have been detected on excised hemorrhoids. The high-risk human papillomavirus (HR-HPV) types associated with these incidentally identified high-grade lesions are presently unknown. We aimed to identify cases of incidental high-grade anal intraepithelial neoplasia (HG-AIN) and anal squamous cell carcinoma incidentally discovered on hemorrhoidectomy specimens, genotype HR-HPVs from these lesions, and assess p53 and p16 expression by immunohistochemistry to identify risk factors for their development. With institutional approval, cases with associated demographics from 1995 to 2015 were reviewed to identify and confirm incidental HG-AIN or squamous cell carcinoma in hemorrhoidectomy specimens. Genotyping for HR-HPV types and immunohistochemical staining for p53 and p16 was performed. Statistical analysis comparing HPV genotypes, p53 and p16 staining, and potential risk factors by the Fisher exact test was performed. In the largest series of incidental high-grade lesions on hemorrhoidectomy, HPV 16 was the most common HR-HPV detected though multiple-type infections were common including some HPV 16/18-negative cases. By genotyping, HPV 39 was significantly associated with IV-drug abuse history (P=0.0015) and HIV-positive status (P=0.037), whereas HPV 58 detection correlated with chemotherapy-induced immunosuppression (P=0.029). There was frequent overlap between p53 staining and HPV positivity, particularly when HPV 31 was detected. We also identified several mimickers of HG-AIN that may present diagnostic challenges in these specimens. Our data support continued routine examination of hemorrhoidectomy specimens and suggest that adjunctive studies such as immunohistochemistry for challenging cases may be useful.

Relevance of the Pap Test: A Report of HPV-DNA Test-Negative High-Grade Squamous Intraepithelial Lesions of the Female Lower Genital Tract.

OBJECTIVE: A vast majority of cervicovaginal intraepithelial lesions are caused by high-risk human papillomaviruses (HPVs). The Pap test has been the sole method used for the screening of cervicovaginal squamous intraepithelial lesions (SIL). Recently, the FDA approved an HPV-DNA assay as a method of primary screening. We report on a series of FDA-approved HPV-DNA test-negative SIL with HPV genotyping, using an alternative method on the corresponding surgical biopsy specimens. STUDY DESIGN: A retrospective review identified cytology-positive HPV-negative cases over a 15-month period at a tertiary care gynecologic oncology institution. Corresponding biopsies were reviewed and genotyped for high-risk HPVs. RESULTS: Of the 18,200 total cases, 17 patients meeting the study criteria were selected with 27 surgical specimens corresponding to their cytologic diagnoses. Four patients with high-grade lesions were identified, 3 of whom (75%) were positive for HPV. One of these 4 patients (25%) showed high-grade SIL on biopsies from 4 separate sites in the cervix and vagina. Multiviral HPV infections were frequent. CONCLUSIONS: We discuss the relevance of cotesting for screening cervical SILs and emphasize that false-negative results are possible with the FDA-approved HPV screening assay, also in patients with high-grade SIL. These cases may be detectable by cytologic examination and this suggests that the Pap test remains an important diagnostic tool.