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.
Lymphocyte-predominant esophagitis: a distinct and likely immune-mediated disorder in adults
April 2020—Lymphocytic esophagitis is a well-known manifestation of Crohn disease among children but is not considered an immune-mediated mucositis in adults. The authors conducted a study for which they hypothesized that adult-onset lymphocyte-predominant esophagitis is also an immune-mediated inflammatory pattern, the nature of which has been masked by other conditions that feature esophageal lymphocytosis and occur in older adults. The intent of the study was to consolidate diagnostic criteria for lymphocyte-predominant esophagitis and determine its clinical significance. The authors identified 61 patients with lymphocyte-rich inflammation in the mid or proximal esophagus, none of whom had another explanation for esophageal lymphocytosis. Affected patients were usually older adults, and 72 percent were women. Fifty-six percent of patients presented with dysphagia, and 34 percent had eosinophilic esophagitis-like changes with circumferential rings, white exudates, or edematous mucosa and linear furrows. Intraepithelial lymphocytosis was accompanied by mucosal injury featuring edema, basal zone hyperplasia, and scattered dyskeratotic cells. Some cases displayed occasional neutrophils or even superficial microabscesses. Eosinophils were consistently infrequent. Sixty-seven percent of patients had at least one systemic immune-mediated disorder, in particular Crohn disease (30 percent) and connective tissue diseases (23 percent). Only one patient had mucocutaneous lichen planus. The authors concluded that mild mucosal lymphocytosis—that is, 20 or more lymphocytes per high-power field—alone is a frequent and nonspecific finding. Criteria for defining lymphocyte-predominant esophagitis should include evidence of mucosal injury and allow for more than the occasional neutrophil. When this diagnosis is limited to cases that feature lymphocytosis unattributed to acid reflux, motility disorders, or infection, lymphocyte-predominant esophagitis may represent an immune-mediated disorder with characteristic clinical manifestations and a higher frequency in middle-aged women.
Pittman ME, Hissong E, Katz PO, et al. Lymphocyte-predominant esophagitis: a distinct and likely immune-mediated disorder encompassing lymphocytic and lichenoid esophagitis. Am J Surg Pathol. 2020;44(2):198–205.
Correspondence: Dr. Rhonda K. Yantiss at rhy2001@med.cornell.edu
Value of tumor-infiltration depth and extranodal extension in TNM classification for OSCC
In the eighth edition of the American Joint Committee on Cancer’s AJCC Cancer Staging Manual, tumor-infiltration depth and extranodal extension are added to the pathological classification for oral squamous cell carcinoma. The authors conducted a study to determine the potential impact of these changes in the eighth edition pTNM classification on the prognosis and treatment strategy for oral squamous cell carcinoma in a well-defined series of pT1-T2 patients with long-term follow-up. They analyzed, retrospectively, 211 first primary pT1-T2 oral squamous cell carcinoma patients, with surgical resection as primary treatment. Of this group, 173 patients underwent neck dissection and 38 patients had frequent clinical neck assessments. Long-term follow-up (median, 64 months) and reassessed tumor-infiltration depth were available. Classification according to the eighth edition criteria resulted in 36 percent total upstaging with the T classification and 16 percent total upstaging with the N classification. T3-restaged patients (n = 30; 14 percent) had lower five-year disease-specific survival rates than T2-staged patients (81 versus 67 percent; P = .042). Postoperative chemoradiotherapy could have been considered in another seven (three percent) patients on the basis of the eighth edition criteria. The authors concluded that adding tumor-infiltration depth and extranodal extension to the eighth edition TNM classification improves the identification of oral squamous cell carcinoma patients with a worse prognosis who might benefit from an enhanced postoperative treatment strategy.
Boeve K, Melchers LJ, Schuuring E, et al. Addition of tumour infiltration depth and extranodal extension improves the prognostic value of the pathological TNM classification for early-stage oral squamous cell carcinoma. Histopathology. 2019;75(3):329–337.
Correspondence: Dr. K. Boeve at j.boeve@umcg.nl
Problems with reproducibility of small lung adenocarcinoma classification
The 2015 World Health Organization classification for lung adenocarcinoma provides criteria for adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma (INV), but differentiating these entities can be difficult. Because classification is inconsistent, the authors conducted a study in which they assessed agreement among an international panel of lung pathologists to identify factors contributing to this problem. For the study, six lung pathologists digitally reviewed 60 slides of small lung adenocarcinomas in three rounds, with consensus conferences and examination of elastic stains in round three. The panel independently reviewed each case to assess final diagnosis, invasive component size, and predominant pattern. The kappa value for AIS and MIA versus INV decreased from 0.44 (round one) to 0.30 and 0.34 (rounds two and three). Interobserver agreement for invasion (AIS versus other) decreased from 0.34 (round one) to 0.29 and 0.29 (rounds two and three). The range of the measured invasive component in a single case was up to 19.2 mm among the observers. Agreement was excellent in tumors with high-grade cytology and fair in those with low-grade cytology. Interobserver agreement in small lung adenocarcinomas was fair to moderate and improved minimally with elastic stains. Poor agreement was primarily attributed to subjectivity in pattern recognition, but high-grade cytology increased agreement. The authors concluded that more reliable methods for differentiating histological patterns, including refining the definition of each pattern and enhancing education, are necessary to improve interobserver agreement and, thereby, the classification of tumors and to provide appropriate patient care.
Shih AR, Uruga H, Bozkurtlar E, et al. Problems in the reproducibility of classification of small lung adenocarcinoma: an international interobserver study. Histopathology. 2019;75(5):649–659.
Correspondence: Dr. Mari Mino-Kenudson at mminokenudson@partners.org
Appraisal of yolk sac tumor-like phenotypes in endometrial tumors
The authors conducted a study in which they performed a multi-faceted examination of yolk sac tumor-like phenotypes in endometrial tumors based on an analysis of three groups of uterine tumors. In group one, nine endometrial tumors that had been classified as yolk sac tumors or as having a yolk sac tumor component were assessed with a 35-marker IHC panel to define their immunophenotypic spectrum. In group two, 70 endometrial carcinomas of various histotypes were analyzed for their expression of SALL4, glypican-3, and AFP to assess the specificity of these markers for yolk sac tumors relative to endometrial carcinomas. In group three, 626 archived cases of endometrial carcinoma/carcinosarcoma were reviewed to define the frequency of yolk sac tumor-like morphology therein. The authors found that yolk sac tumor areas in the group one cases were consistently immunoreactive for SALL4 and glypican-3 and variably positive for AFP (89 percent), villin (89 percent), PLAP (78 percent), 34βE12 (67 percent), CAM 5.2 (62.5 percent), EMA (56 percent), CD117 (50 percent), p16 (50 percent), CDX2 (44 percent), p53 (44 percent aberrant), MOC31 (37.5 percent), CK7 (33 percent), GATA3 (33 percent), CK5 (25 percent), and PAX8 (11 percent). They were negative for CD30, napsin A, OCT4, estrogen, androgen, and progesterone receptors. Twenty-nine of the 70 (41 percent) group two cases expressed at least one of the three markers, and 96 percent of the positive cases were a high-grade histotype. Glypican-3, SALL4, and AFP were positive in 30 percent, 20 percent, and 2.8 percent of group two cases, respectively. However, co-expression of any two markers, or all three, was uncommon (fewer than nine percent of cases and 1.4 percent of cases, respectively). Potential yolk sac tumor-like morphology was identified in five of 626 (0.8 percent) group three cases, and three were determined to be true yolk sac tumor phenotypes based on their morphologic and immunophenotypic similarity to the group one cases. These findings highlight the broad immunophenotypic spectrum of uterine yolk sac tumors, potential pitfalls associated with using immunophenotypes alone to define yolk sac tumor differentiation in endometrial carcinoma, and utility and limitations of morphologic assessment to identify yolk sac tumors at this site.
Fadare O, Shaker N, Alghamdi A, et al. Endometrial tumors with yolk sac tumor-like morphologic patterns or immunophenotypes: an expanded appraisal. Mod Pathol. 2019;32:1847–1860.
Correspondence: Dr. Oluwole Fadare at oluwole.fadare@gmail.com
Regional metastasis unrelated to histologic grade in mucoepidermoid carcinoma of the oropharynx
The designation mucoepidermoid tumor is a historic one used in reference to a form of mucoepidermoid carcinoma (MEC) that was believed to be benign. This conclusion of benignancy was based on the observation that the vast majority of MECs arising from the intraoral minor salivary glands behave in a benign fashion, particularly when they do not exhibit high-grade features. There has been a move to partition the oral vault into the oral cavity proper and oropharynx because these compartments are distinct and because similar tumor types arising from these compartments may behave in dramatically different ways—for example, oral cavity squamous cell carcinoma versus oropharyngeal squamous cell carcinoma. The pathology databases from three large academic medical centers were searched for cases of MEC arising in the oropharynx. Relevant clinical and pathological information was collected from the medical records, and 25 MECs from the oropharynx were identified. They were from 18 females (72 percent) and seven males (28 percent) who ranged in age from 31 to 88 years (median, 61 years). Twenty-two (88 percent) of the MECs were classified as low (n =12) or intermediate (n =10) grade, and three (12 percent) as high grade. Most arose from the base of the tongue (n = 24), but one arose from the lateral pharyngeal wall. The median tumor size was 2 cm. Nineteen patients underwent neck node dissections. Thirteen (68 percent) of them had histologically documented lymph node metastases. MECs that lacked high-grade features were almost as likely to metastasize as those with high-grade features (50 versus 66 percent; Fisher exact =1). Of three metastases tested, two harbored the MAML2 gene fusion. MECs arising from the base of the tongue are associated with an alarmingly high rate of nodal metastases. This behavior cannot be predicted by histologic grading or MAML2 status. The propensity to metastasize may, to some degree, reflect the unique microenvironment of the oropharynx.
Navale P, Rooper LM, Bishop JA, et al. Mucoepidermoid carcinoma of the oropharynx: a tumor type with a propensity for regional metastasis unrelated to histologic grade. Hum Pathol. 2019;93. https://doi.org/10.1016/j.humpath.2019.08.014.
Correspondence: Dr. William H. Westra at william.westra@mountsinai.org
Morphologic and IHC characterization of myomectomy and hysterectomy specimens from women with HLRCC
Hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC), caused by a germline mutation in the fumarate hydratase gene, predisposes women to uterine and cutaneous smooth muscle tumors and an aggressive type of renal cell carcinoma. Almost all women with HLRCC develop symptomatic uterine leiomyomas, resulting in surgery at young ages and necessitating early detection and the implementation of surveillance measures for renal cell carcinoma. Fumarate hydrastase-deficient uterine leiomyomas can show characteristic morphologic features (FH-d morphology), which have been described in the literature. IHC for FH can also be helpful in detecting FH deficiency in leiomyomas, which manifests as complete loss of staining for FH. However, the distribution and topography of FH-d morphology and FH loss by IHC in the context of multiple leiomyomas in patients with HLRCC has not been evaluated. The authors conducted a study to describe in detail the clinical and pathologic characteristics of uterine leiomyomas from women with HLRCC. The study included six patients with proven FH germline mutations. All available slides were reviewed, and FH IHC staining was performed on multiple blocks when possible. Clinical data were extracted from online medical records. All six patients (ages 24–36 years) presented with symptomatic uterine fibroids and underwent myomectomy, followed by hysterectomy in two patients (ages 31 and 40 years). The specimens showed conventional leiomyomas, cellular leiomyomas, and leiomyomas with bizarre nuclei. FH-d morphology was present in leiomyomas from all patients and was typically observed as a diffuse finding in the majority of slides across different leiomyoma types. FH-d morphology was absent in some leiomyoma sections from one patient, and the morphologic features were focal and subtle in leiomyomas from two patients. Both hysterectomy specimens were also notable for showing scattered irregular tongues and nodules of smooth muscle proliferation (leiomyomatosis-like) in the background myometrium. IHC staining of multiple slides per patient for FH showed retained staining in all sections (two of six cases), loss of staining in all sections (one case), or variable staining across different leiomyomas (three cases). The authors concluded that patients with HLRCC undergo surgery at young ages for highly symptomatic uterine leiomyomas. FH-d morphology is usually a diffuse and well-developed finding across different leiomyomas but may be absent or focal and subtle. FH IHC can show variable results, and the presence of retained FH staining should not be used to exclude the possibility of HLRCC. Referral for genetic counseling and testing should be considered in a young patient with uterine leiomyomas showing FH-d morphology, even if IHC staining for FH is retained.
Chan E, Rabban JT, Mak J, et al. Detailed morphologic and immunohistochemical characterization of myomectomy and hysterectomy specimens from women with hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC). Am J Surg Pathol. 2019;43(9):1170–1179.
Correspondence: Dr. Karuna Garg at karuna.garg@ucsf.edu
CDX2 loss with microsatellite stable phenotype as a predictor of outcome in colorectal carcinoma
Risk factors in stage II colorectal carcinoma are insufficient to guide treatment decisions. Loss of CDX2 has been associated with poor clinical outcome and the ability to predict the benefit of adjuvant chemotherapy in stages II and III colorectal carcinomas. However, the prognostic relevance of CDX2 in stage II disease has not been sufficiently validated, especially in relation to such clinical risk factors as microsatellite instability (MSI) status, BRAF mutation status, and tumor budding. The authors conducted a study in which they evaluated the protein expression of CDX2 in the tumor center and front areas in tissue microarray material from stage II colorectal carcinoma patients (n = 232). CDX2 expression showed a partial or total loss in respective areas in 8.6 and 10.9 percent of patient cases. Kaplan-Meier plots demonstrated that patients with loss of CDX2 had shorter disease-specific survival when measured in the tumor center or tumor front area cores (log rank, P = .012; P = .012). Loss of CDX2 predicted survival independently of other stage II risk factors, such as MSI status and BRAF mutation status, pT class, and tumor budding. It should be noted that CDX2 loss predicted inferior survival only in patients with a microsatellite-stable phenotype. Interestingly, CDX2 loss was associated with low E-cadherin expression, tight junction disruption, and high expression of ezrin protein. The study demonstrates that loss of CDX2 is an independent risk factor for poor disease-specific survival in stage II colorectal carcinoma. Furthermore, it suggests that CDX2 loss could functionally associate with epithelial-to-mesenchymal transition but independently of tumor budding.
Slik K, Turkki R, Carpén O, et al. CDX2 loss with microsatellite stable phenotype predicts poor clinical outcome in stage II colorectal carcinoma. Am J Surg Pathol. 2019;43:1473–1482.
Correspondence: Dr. Teijo Pellinen at teijo.pellinen@helsinki.fi