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; Shaomin Hu, MD, PhD, staff pathologist, Cleveland Clinic; S. Emily Bachert, MD, breast pathology fellow, Brigham and Women’s Hospital, Boston; and Amarpreet Bhalla, MD, assistant professor of pathology, Albert Einstein College of Medicine, Montefiore Medical Center.
Prostatic metaplasia of the vagina and uterine cervix
March 2021—Prostatic-type differentiation in the lower female genital tract is rarely encountered and its causes and clinical associations are not well established. Reports have invariably described ectopic prostatic-type differentiation within the vagina as restricted to the lamina propria. The authors encountered a patient receiving testosterone for gender dysphoria whose vaginectomy specimen showed a prostatic glandular proliferation within the surface epithelium. To elucidate its potential association with androgen exposure, they sought similar lesions, resected during a 26-year period, from patients with exogenous or endogenous androgen excess. Thirteen cases, involving the vagina (n =12) and exocervix (n =1), were identified. The most common clinical context was gender dysphoria with long-term testosterone therapy, with the lesion present in seven of eight gender-dysphoric patients examined. Four other patients had congenital disorders of sexual development associated with endogenous androgen excess—congenital adrenal hyperplasia; 46, XY disorder of sexual development; and ovotesticular disorder of sexual development. Two had no known exposure to androgen excess. Immunohistochemistry was performed, and the most sensitive markers of glandular cells were found to be NKX3.1 and androgen receptor (both with 100 percent of cases positive), followed by CK7 (92 percent positive), while staining for prostate-specific antigen was generally weak (69 percent positive). Follow-up of one to 156 months showed no masses or neoplasia of the lower genital tract requiring biopsy or resection. The authors propose the designation androgen-associated prostatic metaplasia for this form of prostate tissue with distinctive clinical, histologic, and IHC features. It is novel and previously unrecognized within the vagina. It is also prevalent among patients undergoing gender-affirming surgery. Recognition is important to distinguish it from other potentially neoplastic glandular lesions and to generate more follow-up data to better understand its natural history.
Anderson WJ, Kolin DL, Neville G, et al. Prostatic metaplasia of the vagina and uterine cervix: an androgen-associated glandular lesion of surface squamous epithelium. Am J Surg Pathol. 2020;44(8):1040–1049.
Correspondence: Dr. S. O. Vargas at sara.vargas@childrens.harvard.edu
Role of PHOX2B immunostaining in diagnosis of Hirschsprung disease
Hirschsprung disease is a congenital disorder of the enteric nervous system that occurs in approximately one in 5,000 live births. It is characterized by the absence of ganglionic cells in the distal intestine. The diagnosis relies on thorough analysis of a rectal suction biopsy (RSB), which must show a complete absence of ganglionic cells after careful examination of at least 100 serial sections. Such a negative characteristic explains the difficulty of this diagnosis. Moreover, ganglionic cells may be immature in very young children or those born preterm, making them hard to recognize. Therefore, ancillary techniques, such as acetylcholinesterase histochemistry and calretinin immunostaining, have been developed to assist diagnosis. These techniques reveal only indirect clues, focusing primarily on the changes in nerve fibers and not on the ganglionic cells themselves. PHOX2B has been shown to be a specific transcription factor in ganglionic cells and progenitor enteric nerve cells. Therefore, the authors assessed PHOX2B immunostaining in immature enteric ganglia and the usefulness of PHOX2B immunostaining in RSBs performed for suspicion of Hirschsprung disease. They observed PHOX2B expression in all mature and immature ganglionic cells and noted its complete absence in Hirschsprung cases. The authors suggest that PHOX2B immunostaining is of great help in recognizing ganglionic cells in RSBs regardless of their differentiation and, therefore, in diagnosing Hirschsprung disease.
Drabent P, Bonnard A, Guimiot F, et al. PHOX2B immunostaining: a simple and helpful tool for the recognition of ganglionic cells and diagnosis of Hirschsprung disease. Am J Surg Pathol. 2020;44(10):1389–1397.
Correspondence: Dr. Dominique Berrebi at dominique.berrebi2@aphp.fr
Genomic profiling of primary and recurrent aGCT of the ovary
Adult-type granulosa cell tumor (aGCT) is a rare malignant ovarian sex cord-stromal tumor harboring recurrent FOXL2 c.C402G/p.C134W hotspot mutations in 97 percent or more of cases. These tumors have a favorable prognosis. However, recurrence occurs in 10 to 30 percent, and the tumors exhibit long latency periods. The authors conducted a study to determine the genetic alterations associated with aGCT disease progression. They subjected primary nonrecurrent aGCTs (n = 7), primary aGCTs that subsequently recurred (n = 9) and their matched recurrences (n = 9), and aGCT recurrences without matched primary tumors (n =10) to targeted massively parallel sequencing of 410 or more cancer-related genes. In addition, they subjected three primary nonrecurrent aGCTs and nine aGCT recurrences to FOXL2 and TERT promoter Sanger sequencing analysis. All aGCTs harbored the FOXL2 C134W hotspot mutation. The authors found that TERT promoter mutations were significantly more frequent in recurrent (18 of 28, 64 percent) than primary aGCTs (five of 19, 26 percent; P = .017). Mutations affecting TP53, MED12, and TET2 were restricted to aGCT recurrences. Pathway annotation of altered genes demonstrated that aGCT recurrences were enriched for genetic alterations affecting cell cycle pathway-related genes. Analysis of paired primary and recurrent aGCTs revealed that TERT promoter mutations were present in primary tumors and matched recurrences or restricted to the recurrence and absent in the respective primary aGCT. Clonal composition analysis of these paired samples further revealed that aGCTs display intratumor genetic heterogeneity and harbor multiple clones at diagnosis and relapse. The authors observed that in a subset of cases, recurrences acquired additional genetic alterations not present in primary aGCTs, including TERT, MED12, and TP53 mutations and CDKN2A/B homozygous deletions. These data provide evidence to suggest that aGCTs are genetically heterogeneous tumors and that TERT promoter mutations or genetic alterations affecting other cell cycle-related genes, or both, may be associated with disease progression and recurrence.
Paula ADC, da Silva EM, Segura SE, et al. Genomic profiling of primary and recurrent adult granulosa cell tumors of the ovary. Mod Pathol. 2020;33(8):1606–1617.
Correspondence: Dr. Deborah F. DeLair at deborah.delair@nyulangone.org or Dr. Britta Weigelt at weigeltb@mskcc.org
Microscopic size measurements in post-neoadjuvant therapy resections of PDAC
Pancreatic ductal adenocarcinomas are increasingly being treated with neoadjuvant therapy. However, American Joint Committee on Cancer (AJCC) eighth edition T staging based on tumor size does not reflect treatment effect, which often results in multiple small foci of residual tumor in a background of mass-forming fibrosis. The authors evaluated the performance of AJCC eighth edition T staging in predicting patient outcomes using a microscopic tumor size measurement method. They reviewed 106 post-neoadjuvant therapy pancreatectomies and measured all individual tumor foci. T stages based on gross size with microscopic adjustment (GS) and the largest single microscopic focus size (MFS) were examined in association with clinicopathological variables and patient outcomes. Sixty-three of 106 (59 percent) tumors were locally advanced; 78 percent received Folfirinox treatment. The average GS and MFS were 25 mm and 11 mm, respectively. Based on GS and MFS, respectively, nine cases each were classified as T0, 35 and 85 cases as T1, 42 and 12 cases as T2, and 20 and zero cases as T3. Higher GS- and MFS-based T stages were significantly associated with higher tumor regression grade, lymphovascular and perineural invasion, and higher N stage. Furthermore, higher MFS-based T stage was significantly associated with shorter disease-free survival (P< .001) and shorter overall survival (P= .002). GS was significantly associated with overall survival (P= .046) but not with disease-free survival. The authors concluded that in post-neoadjuvant therapy PDAC resections, MFS-based T staging is superior to GS-based T staging for predicting patient outcomes, suggesting that microscopic measurements have clinical utility beyond the conventional use of GS measurements alone.
Zhang ML, Kem M, Rodrigues C, et al. Microscopic size measurements in post-neoadjuvant therapy resections of pancreatic ductal adenocarcinoma (PDAC) predict patient outcomes. Histopathol. 2020;77(1):144–155.
Correspondence: Dr. Mari Mino-Kenudson at mminokenudson@partners.org
Morphologic and genetic heterogeneity in breast fibroepithelial lesions
Breast fibroepithelial lesions encompass the common fibroadenoma and relatively rare phyllodes tumor. The latter is usually classified as benign, borderline, or malignant. Intratumoral heterogeneity is a notable feature of phyllodes tumors, making accurate histologic evaluation challenging. Despite their rarity, phyllodes tumors are a significant clinical problem due to their propensity for recurrence and, in the case of malignant phyllodes tumor, metastasis. Surgical excision is the mainstay for managing them. Recent research has uncovered myriad genetic alterations in breast fibroepithelial lesions (FELs). The authors conducted a study in which exome sequencing was performed on seven cases of morphologically heterogeneous breast FELs, including fibroadenomas, phyllodes tumors of all grades, and a metaplastic spindle cell carcinoma arising in a phyllodes tumor, to elucidate their intratumoral genetic repertoire. The gene mutations identified encompassed cell signaling, tumor suppressor, DNA repair, and cell cycle regulating pathways. Mutations common to multiple tumor regions generally showed higher variant allele frequency. Mutations commonly recurred in MED12, TP53, RARA, and PIK3CA. Histological observations of increased cellular density and pleomorphism correlated with mutational burden. Phylogenetic analyses revealed disparate pathways of possible tumor progression. The authors concluded that histological heterogeneity correlates with genetic changes in breast FELs.
Tan BY, Md Nasir ND, Chang HY, et al. Morphologic and genetic heterogeneity in breast fibroepithelial lesions—a comprehensive mapping study. Mod Pathol. 2020;33:1732–1745.
Correspondence: Dr. Puay Hoon Tan at tan.puay.hoon@singhealth.com.sg
Clinicopathologic and molecular characteristics of FAP-associated TSA
Colorectal carcinogenesis in familial adenomatous polyposis follows a conventional adenoma-carcinoma sequence. However, previous studies have also reported the occurrence of traditional serrated adenomas (TSAs) in patients with familial adenomatous polyposis (FAP). The authors conducted a study in which they analyzed the clinicopathologic and molecular features of 37 TSAs from 21 people with FAP. The majority of FAP-associated TSAs showed typical cytology and slit-like serration, but ectopic crypt formation was infrequent. Next-generation sequencing and Sanger sequencing identified KRAS and BRAF V600E mutations in 18 (49 percent) and 14 (38 percent) TSAs, respectively. Somatic adenomatous polyposis coli (APC) mutations were detected in 26 lesions (84 percent of analyzed cases). Three lesions had BRAF non-V600E mutations, and two of them had a concurrent KRAS mutation. Seven TSAs were associated with a precursor polyp, six with a hyperplastic polyp, and one with a sessile serrated lesion, and all of them had the BRAF V600E mutation. Additional sequencing of four TSAs with a precursor polyp showed that the BRAF V600E mutation was shared between the TSA and precursor components. However, APC mutations were exclusive to the TSA component in all of the lesions analyzed. None of the lesions showed the high CpG island methylation phenotype. These results indicate that FAP-associated TSAs frequently have KRAS or BRAF mutations, similar to sporadic cases. Second-hit somatic APC mutations are commonly involved in the tumorigenesis of FAP-associated TSAs, as in other FAP-associated tumors. Although progression to adenocarcinoma is likely rare, tumorigenesis via the serrated pathway occurs in people with FAP.
Okamura T, Hashimoto T, Tomoaki N, et al. Clinicopathologic and molecular characteristics of familial adenomatous polyposis–associated traditional serrated adenoma. Am J Surg Pathol. 2020;44(9):1282–1289.
Correspondence: Dr. S. Sekine at ssekine@ncc.go.jp
Analysis of SRCC in patients with hereditary diffuse gastric cancer
Hereditary diffuse gastric cancer is a rare autosomal dominant syndrome associated with an increased risk of developing Laurén’s diffuse-type gastric carcinoma and lobular breast carcinoma. Although signet ring cell carcinoma in situ (SRCC-pTis) has been identified as a characteristic lesion in HDGC cases with CDH1 germline mutations (CDH1 pathogenic variant) and as a precursor of conventional intramucosal SRCC (SRCC-pT1a), its histopathologic features and specificity have not been clarified sufficiently. The authors examined gastrectomy samples from six Japanese hereditary diffuse gastric cancer (HDGC) patients with CDH1 germline mutations who belonged to four families and analyzed their SRCC lesions histologically and immunohistochemically. Of the 274 foci found in the six samples, SRCC-pT1a accounted for 225 lesions (range, eight to 107; mean, 45.7 lesions per patient), and 46 foci were of SRCC-pTis (range, one to 15; mean, 7.67 foci per patient). All SRCC-pTis foci were observed in the fundic gland area and on the superficial side of the mucosa. In the histologic assessment, tumor cells of SRCC-pTis were found between normal foveolar epithelial cells and the basement membrane, following a typical pagetoid spread pattern. In immunohistochemical evaluation, E-cadherin expression was lost in SRCC-pTis (27 of 28, 96.4 percent) more frequently than in SRCC-pT1a (95 of 197, 48.2 percent; P < .001). To elucidate the specificity of SRCC-pTis in HDGC, 60 samples (range, 0.12 to 1.49 m; total, 28.8 m of mucosal length) from gastric cancer cases, in which no SRCC-pTis was identified, were analyzed as controls. The results of the analysis indicate that SRCC-pTis is a distinct histologic feature with high specificity for HDGC cases with CDH1 germline mutations.
Tsugeno Y, Nakano K, Nakajima T, et al. Histopathologic analysis of signet-ring cell carcinoma in situ in patients with hereditary diffuse gastric cancer. Am J Surg Pathol. 2020;44(9):1204–1212.
Correspondence: Dr. Hiroshi Kawachi at hkawachi-path@umin.ac.jp