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.
Angiosarcoma of the liver: clinicopathologic features and morphologic patterns
November 2019—Angiosarcoma is a rare malignant neoplasm of the liver for which morphologic patterns have not been systematically studied. To provide more comprehensive data on morphologic patterns, the authors reviewed angiosarcomas that had been diagnosed between 1996 and 2016 at a large medical referral center. The major growth patterns were classified as sinusoidal (nonmass forming) or mass forming. The mass-forming cases were further subdivided into epithelioid, spindled, and vasoformative. The study identified 21 patients with primary hepatic angiosarcoma—13 men and eight women who ranged in age from 26 to 89 years. Seventeen angiosarcomas were mass-forming tumors, of which nine showed predominantly vasoformative growth. Six of these nine cases were composed of small vessels—two had slit-like vascular spaces and one showed a mixture of small and large vessels. There were seven mass-forming angiosarcomas without vasoformation—three had an epithelioid morphology and four were composed primarily of spindled cells. Another mass-forming tumor showed a mixture of vasoformative and nonvasoformative areas. Four of 21 cases were nonmass forming and showed diffuse sinusoidal infiltration (n = 2) or prominent peliotic changes (n = 2). Finally, three uncommon patterns were identified. The first case showed nodules of spindle cells arranged in prominent whorls in a background of loose connective tissue with abundant inflammation. The second arose in the setting of Blue Rubber Bleb Nevus Syndrome and showed numerous tumor nodules with an architectural pattern that resembled infantile hemangioma, some with areas of atypia consistent with malignant transformation to angiosarcoma. The third showed multiple nodules of thin-walled, large-caliber vascular proliferations, some of which showed atypia that reached the level of angiosarcoma. The results of this study indicate that the majority (two-thirds) of hepatic angiosarcomas are mass forming, a pattern that is recognizable on H&E when vasoformative but can mimic carcinoma or undifferentiated sarcomas when nonvasoformative (one-third of cases). The sinusoidal patterns are particularly challenging and frequently missed on initial review. The authors described several unusual patterns of angiosarcoma. Awareness of these classic and rare morphologic patterns can help in diagnosing this neoplasm.
Yasir S, Torbenson MS. Angiosarcoma of the liver: clinicopathologic features and morphologic patterns. Am J Surg Pathol. 2019;43(5):581–590.
Correspondence: Dr. Michael S. Torbenson at torbenson.michael@mayo.edu
Autoimmune pancreatitis type 2: diagnostic utility of PD-L1 immunohistochemistry
Autoimmune pancreatitis encompasses a heterogenous disease group that includes IgG4-related type 1 autoimmune pancreatitis (AIP) and non-iIgG4-related type 2 AIP. Clinically and on imaging, type 2 AIP mimics type 1 AIP, other forms of chronic pancreatitis, and pancreatic ductal adenocarcinoma (PDAC). Therefore, discriminatory markers may aid proper diagnosis. The authors conducted a study in which they examined the expression of PD-L1 and indoleamine 2,3-dioxygenase (IDO1) as a diagnostic tool to distinguish type 2 AIP from other forms of pancreatitis and PDAC. They evaluated 35 pancreatectomy specimens from patients diagnosed with type 2 AIP and potential mimics of this disease, including type 1 AIP (n =14); chronic pancreatitis, not otherwise specified (n =10); groove pancreatitis (n =14); and PDAC (n =278). They scored inflammatory infiltrates, fibrosis, and atrophy and performed IHC staining for PD-L1 and IDO1. The authors validated their findings on a series of endoscopic ultrasound-guided biopsies from patients with suspected type 2 AIP and inflammatory and neoplastic mimics of this disease (n = 37). The mean age of the patients with type 2 AIP was 50 years, with a F:M ratio of 1.2:1. Patients with type 2 AIP showed pancreatic ductal staining for PD-L1 and IDO1 in 69 percent (24 of 35) and 60 percent (15 of 25) of cases, respectively. PD-L1 reactivity was noted in three percent of patients with other forms of chronic pancreatitis and three percent of PDACs. Notably, peritumoral ducts and acini were negative. Eight of nine endoscopic ultrasound-guided biopsies with pancreatic ductal epithelium from patients with type 2 AIP were positive for PD-L1, while the inflammatory and neoplastic mimics were negative. Collectively, the sensitivity and specificity of PD-L1 as a marker of type 2 AIP were 70 percent and 99 percent, respectively. The authors concluded that ductal PD-L1 reactivity has the potential to distinguish type 2 AIP from other forms of pancreatitis and PDAC.
Gupta R, Neyaz A, Chougule A, et al. Autoimmune pancreatitis type 2: diagnostic utility of PD-L1 immunohistochemistry. Am J Surg Pathol. 2019;43(7):898–906.
Correspondence: Dr. Vikram Deshpande at vikramdirdeshpande@gmail.com
Evidence of a monoclonal origin for bilateral serous tubal intraepithelial neoplasia
Serous tubal intraepithelial carcinoma is found in 10 to 60 percent of cases of tuboovarian high-grade serous carcinoma (HGSC) and is presumed to be the site of origin, linking many HGSCs to the fallopian tube. Bilateral serous tubal intraepithelial carcinoma is present in approximately 20 percent of cases. Because clonal Tp53 mutations are a defining feature of HGSCs, including their associated serous tubal intraepithelial carcinomas, the authors analyzed four cases of bilateral serous tubal intraepithelial neoplasia (STIN), including serous tubal intraepithelial carcinoma and Tp53-mutated serous tubal intraepithelial lesions (STILs), associated with HGSC to determine whether they contained the same or different p53 mutations. Extracted DNA from STINs, concurrent HGSCs, and control tissues was analyzed for mutations in all exons of Tp53. Sequencing was successful in three of the four cases, and an identical Tp53 mutation was detected in the HGSC and bilateral STINs in two of these three cases. One STIN was morphologically a STIL. These findings confirm that a subset of bilateral STINs share the same Tp53 mutation, implying that at least one of the STINs is an intraepithelial metastasis from the contralateral STIN or HGSC. This study complements others that address the multiple origins of STIN in the setting of HGSC. It emphasizes that potential overlap in biologic behavior between STILs and serous tubal intraepithelial carcinomas, as well as timing and direction of metastatic spread, has yet to be resolved.
Meserve EE, Strickland KC, Miron A, et al. Evidence of a monoclonal origin for bilateral serous tubal intraepithelial neoplasia. Int J Gynecol Pathol. 2019;38(5):443–448.
Correspondence: Dr. Christopher P. Crum at cpcrum@bwh.harvard.edu
Breast cancer global tumor biomarkers: a QA study of intratumoral heterogeneity
Biomarker analysis of invasive breast carcinoma is useful for prognosis, as a surrogate for molecular subtypes of breast cancer, and for predicting response to adjuvant and neoadjuvant systemic therapies. The authors conducted a study to assess the heterogeneity of common biomarkers through comprehensive histological examination and biomarker analysis. Comprehensive biomarker analysis of estrogen receptor, progesterone receptor, HER2, and Ki67 labeling index was performed on each tissue block of 100 invasive breast carcinomas from 99 patients. Invasive carcinoma and in situ carcinoma were scored using semiquantitative histologic score (H-score) for estrogen receptor and progesterone receptor, HER2 expression from 0 to 3+, and percentage positive cells for Ki67. Core biopsy results were compared with surgical excision results; invasive carcinoma was compared with in situ carcinoma; and interblock tumoral heterogeneity was assessed using measures of dispersion (coefficient of variation and quartile coefficient of dispersion). Overall concordance between core biopsy and surgical excision was 99 percent for estrogen receptor and 95 percent for progesterone receptor. The mean histologic score for estrogen receptor was significantly lower in invasive carcinoma between core biopsy and surgical excision (P = .000796). Intratumoral heterogeneity was higher for progesterone receptor than for estrogen receptor. (Mean coefficient of variation for estrogen receptor was 0.08 [standard deviation, 0.13] versus 0.26 for progesterone receptor [standard deviation, 0.41]). Ki67 labeling index was significantly higher in invasive carcinoma compared with associated ductal carcinoma in situ on surgical resection specimen (P ≤ .0001). Ki67 hotspots were identified in 47 percent of cases. Of 52 HER2-negative cases on core biopsy, 10 were scored as equivocal on surgical resection. None of the 10 were amplified by HER2/neu FISH. Biomarkers on core biopsy showed concordance with the surgical excision specimen in the vast majority of cases. Biomarker expression of ductal carcinoma in situ closely approximates associated invasive carcinoma. Intratumoral heterogeneity of progesterone receptor is greater than for estrogen receptor. Biomarker expression on diagnostic core biopsy or single tumor block is representative of breast carcinoma as a whole, in most cases, and is appropriate for clinical decision-making.
Clark BZ, Onisko A, Assylbekova B, et al. Breast cancer global tumor biomarkers: a quality assurance study of intratumoral heterogeneity. Mod Pathol. 2019;32:354–366.
Correspondence: Dr. Beth Z. Clark at clarkbz@upmc.edu
Specificity and sensitivity of TFE3 IHC in diagnosis of TFE3-rearranged neoplasms
TFE3 rearrangements are characteristic of alveolar soft part sarcomas, Xp11.2 translocation renal cell carcinomas, and other rare tumors. Whether immunohistochemistry for TFE3 protein is a reliable surrogate for TFE3 molecular studies is the subject of debate. The authors compared two methods for TFE3 IHC to determine if technical differences account for differing results. Ninety-eight archival cases of mixed type, 19 alveolar soft part sarcomas (ASPS), and eight Xp11-renal cell carcinomas (Xp11-RCC) were stained for TFE3 at laboratory A and laboratory B using routine protocols. Positive controls were normal human testis (laboratory A) and Xp11-RCC (laboratory B). Nuclear staining was scored as negative, 1+ (less than 10 percent), 2+ (10 to 50 percent), and 3+ (more than 50 percent). Intensity was scored as negative, weak, moderate, or strong. Only moderate-strong 2+ or 3+ staining was considered positive. The results for laboratory A were 43 percent (42 of 98) for archival cases, 84 percent (16 of 19) for ASPS, and 88 percent (seven of eight) for Xp11-RCC. The results for laboratory B were five percent (five of 98) for archival cases, 74 percent (14 of 19) for ASPS, and 63 percent (five of eight) for Xp11-RCC. TFE3 FISH was positive in all tested ASPS and Xp11-RCC. The overall sensitivity and specificity of TFE3 IHC for TFE3-rearranged neoplasms were 85 percent (23 of 27) and 57 percent (56 of 98), respectively, at laboratory A, and 70 percent (19 of 27) and 95 percent (93 of 98), respectively, at laboratory B. Technical differences, particularly the type of control tissue, likely account for the difference in results. The findings of this study and prior studies suggest that TFE3 IHC should play a minor role, or no role, in the diagnosis of TFE3-rearranged tumors, with FISH as the preferred method.
Sharain RF, Gown AM, Greipp PT, et al. Immunohistochemistry for TFE3 lacks specificity and sensitivity in the diagnosis of TFE3-rearranged neoplasms: a comparative, 2-laboratory study. Hum Pathol. 2019;87:65–74.
Correspondence: Dr. A. L. Folpe at folpe.andrew@mayo.edu
Surgical staging in stage I clear cell and endometrioid ovarian carcinomas
The authors conducted a study to evaluate occult metastasis after comprehensive surgical staging of clear cell ovarian carcinoma and endometrioid ovarian carcinoma that appeared to be confined to the ovary at the time of surgery. Between 1998 and 2016, 85 patients with clear cell ovarian carcinoma (CCC) and endometrioid ovarian carcinoma (EMCA) were identified who were comprehensively staged and considered to be stage I intraoperatively. Of these 85 patients, four (4.7 percent) had omental and dense pelvic side-wall tumor adhesions. On final pathology, 67 (79 percent) patients were diagnosed as stage IA, of whom 29 (43 percent) were upstaged to IC1 due to intraoperative rupture. The remaining 18 (21 percent) patients were staged as IC2/IC3. The one- and five-year disease-free survival for pathology stage IA tumors were 94 percent and 76 percent, respectively, and for IC2/IC3 tumors were 100 percent and 75 percent, respectively. Among patients who received adjuvant chemotherapy, the five-year disease-free survival was nearly the same for the pathology stage IA and IC2/IC3 groups (73 versus 74 percent), with a lower five-year disease-free survival for CCC compared with EMCA (72 versus 78 percent). There were 16 (19 percent) recurrences, and 12 were pathology stage IA. Of these 12 patients, nine (75 percent) had CCC, of whom two received adjuvant chemotherapy. Even in the presence of dense adhesions (4.7 percent), the likelihood of extraovarian disease in CCC and EMCA confined to the ovary was very low. The findings of this study indicate that comprehensive surgical staging for what appears to be stage I CCC and EMCA may provide no benefit in detecting occult disease that would upstage the tumor.
Padhy RR, Savage J, Kurman RJ. Comprehensive surgical staging in stage 1 clear cell and endometrioid ovarian carcinomas: Is it necessary? Int J Gynecol Pathol. 2019;38(3):241–246.
Correspondence: Dr. R. R. Padhy at rani_padhy@hotmail.com
Value of desmoplastic reaction categorization in stage II colorectal cancer
Highly accurate risk assessment of recurrence may improve adjuvant treatment practice in stage II colorectal cancer, which lacks definite prognostic factors. Recent studies indicate the importance of stroma in determining cancer behavior, although there are few histopathologic criteria for evaluating it. The authors conducted a pathology review of 679 stage II colorectal cancer patients who had undergone R0 surgery at one institution between 1980 and 2005. Desmoplastic reaction results were classified as mature, intermediate, or immature depending on the presence of hyalinized collagen bundles and myxoid stroma observed at the extramural desmoplastic front on hematoxylin-and-eosin–stained slides. A total of 430, 180, and 69 tumors were classified as mature, intermediate, and immature, respectively. On the basis of desmoplastic reaction results, five-year recurrence rates ranged from 9.1 to 30.7 percent. Five-year relapse-free survival (RFS) rates were highest in the mature group (85.2 percent), followed by the intermediate (77.1 percent) and immature (60.9 percent) groups. Multivariate analyses revealed an independent effect of desmoplastic reaction pattern on RFS. In addition, 446 patients treated at four independent institutions in 2007 and 2008 were examined as a second cohort for result validation, revealing an adverse prognostic impact of unfavorable desmoplastic reaction and identifying desmoplastic reaction categorization as an independent prognostic factor. In both cohorts, Harrell’s concordance index for RFS was higher than the other conventional factors in the desmoplastic reaction, including T stage. Categorizing desmoplastic reaction pattern based on the histologic products of fibroblasts at the desmoplastic front helps elucidate their important biological role in cancer development, which provides clinically useful prognostic information regarding stage II colorectal cancer.
Ueno H, Kanemitsu Y, Sekine S, et al. A multicenter study of the prognostic value of desmoplastic reaction categorization in stage II colorectal cancer. Am J Surg Pathol. 2019;43(8):1015–1022.
Correspondence: Dr. Hideki Ueno at ueno_surg1@ndmc.ac.jp