Editors: Rouzan Karabakhtsian, MD, PhD, professor of pathology and director of the Women’s Health Pathology Fellowship, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY; Nicole Panarelli, MD, associate professor of pathology, Albert Einstein College of Medicine, Montefiore Medical Center; Shaomin Hu, MD, PhD, gastrointestinal/liver pathology fellow, University of Chicago; and S. Emily Bachert, MD, pathology resident, Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington.
Distinct patterns of human liver regeneration following massive hepatic necrosis
January 2020—Massive hepatic necrosis is a rare and often fatal complication of various liver injuries. However, some patients survive by spontaneous hepatic regeneration. It is known that surviving hepatocytes or progenitor cells, or both, can participate in this process, but the mechanism of hepatic recovery is vague. The authors conducted a study in which they examined 13 explanted human livers removed due to acute liver failure. They applied a combination of IHC, digital image analysis, and three-dimensional reconstruction of serial sections. Two patterns of regeneration could be distinguished. In livers with centrilobular necrosis, the surviving injured periportal hepatocytes proliferated and arranged into acinar structures and expressed α-fetoprotein. If the injury wiped out almost all hepatocytes, large areas of parenchymal loss were invaded by an intense ductular reaction. The cells at the distal pole of the ductules differentiated into hepatocytes and formed foci organized by the branches of the portal vein. The expanding foci, often containing complete portal triads, were arranged around surviving central veins. Their fusion eventually could be an attempt to re-establish the hepatic lobules. The authors concluded that regeneration of human livers following massive hepatic necrosis can occur through proliferation of α-fetoprotein–positive acinary-arranged hepatocytes or through ductular progenitor cells, with the latter being less efficient. Additional investigation of these regenerative pathways may help identify biomarkers for the likelihood of complete regeneration and, therefore, have therapeutic implications.
Dezső K, Nagy P, Paku S. Human liver regeneration following massive hepatic necrosis: Two distinct patterns. J Gastroenterol Hepatol. 2019. doi:10.1111/jgh.14721.
Correspondence: Dr. S. Paku at [email protected]
Effect of progestin usage on interpretation of cervical HSIL
Progestin usage can alter the histologic and cytologic features of high-grade squamous intraepithelial lesion, which may potentially lead to underdiagnosis of this precancerous lesion. The authors conducted a study to assess the relationship between use of progesterone-based contraceptives and the cytologic features of high-grade squamous intraepithelial lesion (HSIL) of the cervix. For the case-control study, they assembled 46 cases of cervical HSIL (CIN 3), including samples from 26 patients with a known history of progestin usage (study group) and 20 samples from patients with no history of exogenous hormone usage (control group). Cell image analysis was performed on all samples using proprietary software. Immunohistochemical studies for Ki67, p16, estrogen receptor, and progesterone receptor were performed on all cases, as was RNA in situ hybridization for human papillomavirus (HPV) subtypes 16 and 18. Compared with the control group cases, the average nuclear size (21.5±1.80 μm) and the nuclear:cytoplasmic ratio (0.28 ± 0.015) of HSILs in the study group cases were significantly smaller (P = .026) and reduced (P = .005), respectively. In addition, the study group cases showed reduced nuclear atypia and pleomorphism and significantly reduced mitotic figures (1.74 ± 1.86/mm in the study group versus 5.94 ± 1.3/mm in the control group; P < .0001). The latter was likely a consequence of the significantly reduced mitotic figures in the superficial and middle epithelial layers of the study group cases compared with their control group counterparts (0.73 ± 0.88/mm versus 7.3 ± 2.6/mm; P < .0001). The authors concluded that progestin usage has no discernible effect on p16 immunoreactivity, Ki67 proliferative index, hormone receptor expression, or HPV RNA levels of HSIL lesions. Being aware of progestin-induced morphologic changes to those cervical precancerous lesions will improve the quality of patient care in daily practice.
Wang Y, Chen H, Jiang Q, et al. Effect of progestin usage on the interpretation of cervical high-grade squamous intraepithelial lesion. Am J Surg Pathol. 2019;43(8):1066–1073.
Correspondence: Dr. Wenxin Zheng at [email protected]
Incidence of succinate dehydrogenase and fumarate hydratase-deficient RCC based on IHC screening with SDHA/SDHB and FH/2SC
Mutations of the succinate dehydrogenase (SDH) enzyme subunits commonly lead to a loss of function of the holoenzyme complex, and germline SDHx mutations lead to a genetic predisposition to SDH-deficient neoplasms, including renal cell carcinomas (RCC). Similarly, loss-of-function alterations of fumarate hydratase (FH) lead to a genetic predisposition to hereditary leiomyomatosis and renal cell cancer-associated RCC. Loss of FH leads to an accumulation of fumarate and aberrantly high levels of S-(2-succino)-cysteine (2SC). The authors conducted a study of subtype-specific consecutively diagnosed renal cell neoplasms. Cases were not otherwise selected based on clinicopathologic features. Tissue microarrays were constructed from 1,009 renal cell neoplasms (papillary: 400, clear cell: 203, chromophobe: 87, oncocytomas [original diagnosis]: 273, unclassified: 46). These cases were immunostained for SDHA/SDHB to screen for SDH loss. A smaller subset (n = 730; oncocytomas, papillary, and unclassified RCC) were screened for FH deficiency using IHC for FH/2SC. Loss of SDHA/SDHB was seen in three of 273 (1.1 percent) tumors originally diagnosed as oncocytomas. Diffuse nuclear and cytoplasmic 2SC staining, with retained FH expression, was seen in one case, suggestive of dysfunctional FH protein. Two FH-deficient RCCs were identified in the papillary RCC cohort (0.5 percent; two of 400) and two additional cases were identified in the unclassified cohort (4.35 percent; two of 46). The authors concluded that these results can help guide IHC-based screening strategies for these rare tumors.
Gupta S, Swanson AA, Chen YB, et al. Incidence of succinate dehydrogenase and fumarate hydratase-deficient renal cell carcinoma based on immunohistochemical screening with SDHA/SDHB and FH/2SC. Hum Pathol. 2019;91:114–122.
Correspondence: Dr. R. E. Jimenez at [email protected]
Spinal cord high-grade infiltrating gliomas: clinicopathological and molecular evaluation
Primary high-grade infiltrating gliomas of the spinal cord are rare, with prior series including limited numbers of cases and reporting poor outcomes. Furthermore, the molecular profile of the tumors has not been well characterized. Therefore, the authors conducted a study in which they identified 13 adult patients with high-grade infiltrating gliomas of the spinal cord whose surgery had been performed at their institution during a 26-year period. Radiologically, nine cases harbored regions of post-contrast enhancement. Slides were reviewed, and when sufficient tissue was available, IHC stains—IDH1-R132H, H3K27M, H3K27-me3, ATRX, p53, and BRAF-V600E—and a targeted 150-gene neuro-oncology next-generation sequencing panel were performed. The 13 patients consisted of 11 men and two women who were a median age of 38 years (range, 18–69 years). Histologically, all cases were consistent with an infiltrating astrocytoma corresponding to 2016 World Health Organization grades III (n = 5) and IV (n = 8). By IHC, six cases were positive for H3K27M, all showing concomitant loss of H3K27-me3. Next-generation sequencing was performed successfully in 10 cases. Next-generation sequencing studies were performed successfully in four of the cases positive for H3K27M by IHC, and all were confirmed as H3F3A K27M mutant. Additional recurrent mutations identified included those of TERT promoter (n = 3), TP53 (n = 5), PPM1D (n = 3), NF1 (n = 3), ATRX (n = 2), and PIK3CA (n = 2). No HIST1H3B, HIST1H3C, IDH1, IDH2, FGFR1, or BRAF mutations were detected. Ten patients have died since their first surgeries, with a median survival of 13 months and one-year and two-year survival rates of 46 and 50 percent, respectively. The median survival was 48.5 months for H3K27M-positive cases, compared with one month for those with TERT promoter mutations and 77 months for those harboring neither (P = .019). The median survival for cases with TP53 mutations was 11.5 months and for those with PPM1D mutations was 84 months. The findings suggest that high-grade infiltrating gliomas of the spinal cord in adults represent a heterogeneous group of tumors, with variable outcomes possibly related to their molecular profiles.
Alvi MA, Ida CM, Paolini MA, et al. Spinal cord high-grade infiltrating gliomas in adults: clinico-pathological and molecular evaluation. Mod Pathol. 2019;32(9):1236–1243.
Correspondence: Dr. Aditya Raghunathan at [email protected]
Loss of SATB2 expression as a biomarker of IBD-associated colorectal dysplasia and adenocarcinoma
SATB2 is a sensitive immunohistochemistry marker of colorectal carcinoma and non-neoplastic colorectal epithelium that is complementary to CDX2. However, its expression is affected by molecular alterations. Inflammatory bowel disease (IBD)-associated neoplasia demonstrates molecular alterations that differ from those in sporadic colorectal neoplasia. To assess SATB2 immunohistochemistry as a biomarker of IBD-associated neoplasia, the authors examined SATB2 expression in 73 cases of IBD-associated neoplasia (37 dysplasia cases and 36 carcinomas) and compared the expression patterns with 50 cases of nondysplastic colorectal mucosa in patients with active IBD, 40 sporadic colonic polyps (20 conventional adenomas and 20 sessile serrated lesions/polyps), and 343 sporadic colorectal adenocarcinomas. Loss of SATB2 expression was identified in colorectal dysplasia arising in IBD (15 of 37; 41 percent) but was not seen in nondysplastic colorectal mucosa with active IBD or sporadic colonic polyps (P < .001). It was also identified in endoscopically visible dysplasia (11 of 28; 39 percent) and invisible dysplasia (four of nine; 44 percent). In addition, loss of SATB2 expression was identified in 67 percent (24 of 36) of IBD-associated carcinomas and was significantly more frequent than in sporadic colorectal carcinomas (47 of 343; 14 percent; P < .001). There was no difference in positive CDX2 expression between IBD-associated colorectal carcinoma and sporadic colorectal carcinoma (89 versus 85 percent; P = 1.0). The authors concluded that loss of SATB2 expression is common in IBD-associated colorectal dysplasia and adenocarcinoma and may be a helpful ancillary biomarker when evaluating for IBD-associated dysplasia.
Ma C, Henn P, Miller C, et al. Loss of SATB2 expression is a biomarker of inflammatory bowel disease-associated colorectal dysplasia and adenocarcinoma. Am J Surg Pathol. 2019;43(10):1314–1322.
Correspondence: Dr. Reetesh K. Pai at [email protected]
Diagnostic upgrade of atypical ductal hyperplasia based on histologic features and CNB
Atypical ductal hyperplasia of the breast is increasingly diagnosed using core needle biopsy. Because higher-grade lesions have been found in the excision in a substantial proportion of atypical ductal hyperplasias (ADH) on core needle biopsy, factors predicting risk of subsequent upgrade are clinically significant. The authors conducted a study to investigate relevant histopathological factors in core needle biopsy that could predict diagnostic upgrade at excision. They evaluated 143 cases of core needle biopsy with paired subsequent excision for multiple clinicopathological parameters related to core needle biopsy sampling, ADH morphology, calcification, and other coexisting histological features. They also determined which of these parameters were associated with diagnostic upgrade at subsequent excisions. Forty-eight (34.3 percent) cases were upgraded to malignancy—15 invasive cancers and 33 ductal carcinomas in situ. An increased tissue area occupied by ADH (P = .026), higher number of ADH foci (P = .004), presence of solid pattern (P = .037), and older age (P = .012) were positively associated with upgrade. Negative associations were found with the presence of micropapillary pattern (P = .025), coexisting columnar cell lesions (P = .001), and presence of calcifications (P = .009). Multivariate logistic regression analysis showed that the number of ADH foci (hazard ratio [HR], 2.810; P = .013) was an independent positive predictor for upgrade, while coexisting columnar cell lesions (HR, .391; P = .013) were an independent negative predictor. Patients with ADH in core needle biopsy showing the presence of coexisting columnar cell lesions and a lower number of ADH foci have a lower risk of disease upgrade at excision and are potential candidates for observation-only management.
Chen LY, Hu J, Tsang JYS, et al. Diagnostic upgrade of atypical ductal hyperplasia of the breast based on evaluation of histopathological features and calcification on core needle biopsy. Histopathology. 2019;75(3):320–328.
Correspondence: Dr. G. M. K. Tse at [email protected]