International Journal of Surgical Pathology

Following lung cancer, breast cancer is the second most common metastatic tumor to the brain, of which triple-negative breast cancer (TNBC) and human epidermal growth factor receptor 2+ (HER2+) breast cancer are the most common subtypes. TNBC does not have standard immunoprofiles and can be difficult to distinguish from other metastases. A tissue microarray was created from 47 patients with breast cancer metastases to the brain and 12 paired breast primaries. Of 47 breast cancer metastases, 24 were HER2+, 14 were TNBC, and 9 were luminal. Forty-five were cytokeratin 7 (CK7) positive, 36 were GATA-binding protein 3 (GATA3) positive, 7 were Sry-related HMg-Box gene 10 (SOX-10) positive, 20 were mammaglobin positive, and 19 were gross cystic disease fluid protein 15 positive. At least one of the CK7, GATA3, or SOX-10 was positive in all TNBC metastases. A panel of CK7, GATA3, and SOX-10 is complementary in the diagnosis of breast cancer brain metastasis. SOX-10 appears to be a specific but not particularly sensitive marker in this context.

Background. A higher Ki-67 labeling index is associated with a poorer prognosis in gastroenteropancreatic neuroendocrine neoplasms. It has also been proposed that the Ki-67 labeling index may increase during disease progression from the primary site to metastatic sites. Although biopsy specimens are used to measure the Ki-67 labeling index, heterogeneity in lesions is thought to affect the assessment of the Ki-67 labeling index. To overcome tumor heterogeneity, we evaluated the variability in the Ki-67 labeling index between primary lesions and hepatic metastases by analyzing only surgically resected specimens. Methods. We conducted a single-center retrospective study to analyze the variability in the Ki-67 labeling index and the change in tumor grade between the primary site and metastatic hepatic sites in 19 patients diagnosed with gastroenteropancreatic neuroendocrine neoplasms at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research from 1998 to 2018. Both the primary site and metastatic hepatic sites were surgically resected. Results. Among the 19 patients with gastroenteropancreatic neuroendocrine neoplasms, 12 patients (63%) showed higher levels of the Ki-67 labeling index at metastatic hepatic sites than at the primary site. The median Ki-67 labeling index levels for the primary lesion and metastatic hepatic lesions were 5% and 10%, respectively. The Ki-67 labeling index levels were significantly elevated in the metastatic hepatic lesions compared to the primary lesion (P = .002). Conclusions. This study addressed the heterogeneity of the Ki-67 labeling index by analyzing only surgically resected specimens. We observed a statistically significant increase in the Ki-67 labeling index in hepatic metastases compared to the primary lesion.

When more than one focus of stromal invasion is present in a superficially invasive cervical squamous cell carcinoma (SCC), determination of the tumoral lateral extent/horizontal extension, and hence tumor-nodes-metastases (TNM) staging, can be problematic. In recent years, a diagnostic approach to distinguish multifocal pT1a1 from pT1b cases has gained increased attention. These criteria call for classifying SCC as multifocal when invasive foci are separated by blocks of uninvolved cervical tissues, and/or are located on separated cervical lips in a tumor that is discontinuous, and/or are situated far apart (≥2 mm) from each other. In this study, we assess our experience with multifocal stage pT1a1 cervical SCC that was retrospectively classified as such using these criteria. Slides from the loop electrosurgical excision or conization specimens, comprising 212 pT1a1, 173 pT1a2, and 206 pT1b cases, were reviewed. Twenty-four (11%) of the 212 pT1a1 cases were classified as multifocal after review. The 24 multifocal pT1a1 cases were compared with the 188 unifocal pT1a1 cases regarding a variety of clinicopathologic parameters. Notably, these 2 groups showed no significant differences regarding all parameters that were evaluated, including patient age, recurrence rate, primary tumoral features in the primary excision specimen (rate of positive margins, median depth of stromal invasion, frequency of lymphovascular invasion), and frequency of residual disease in additional excisions. In summary, we demonstrate comparably favorable patient outcomes in both unifocal and multifocal cases of pT1a1 SCC of the cervix, and, accordingly, we conclusively affirm the validity of the aforementioned criteria for establishing multifocality.

Insulinoma-associated protein-1 (INSM1), a transcription factor encoded by the insulinoma associated-1 gene, is a second-generation biomarker of neuroendocrine differentiation. Its sensitivity and specificity in comparison with chromogranin-A and synaptophysin have been extensively validated in several organs, but evidence regarding its expression in mammary neoplasms is limited. In this study, INSM1 immunohistochemistry was validated in a cohort of 22 mammary neoplasms, enriched with special type breast carcinomas with known neuroendocrine differentiation as determined by immunohistochemistry for synaptophysin and chromogranin-A. Subsequently, INSM1 expression was evaluated in a consecutive series of 66 invasive breast cancer biopsies. In the validation cohort, 14 tumors were synaptophysin-positive, of which all but one showed INSM1 immunoreactivity. Eight tumors were synaptophysin-negative, of which 3 showed focal nuclear INSM1 expression. Six tumors were chromogranin-A-positive, of which one was INSM1-negative. When compared with synaptophysin, INSM1 seems more sensitive but less specific than chromogranin-A. In the biopsy cohort, only one invasive carcinoma of no special type showed substantial INSM1 immunoreactivity (ie, 25% of the tumor cells). Three more cases showed 1% nuclear INSM1 staining. We conclude that neuroendocrine differentiation in invasive breast carcinoma of no special type is a rare finding. Immunohistochemical biomarkers, comprising INSM1 as well as the first-generation biomarkers chromogranin-A and synaptophysin, are useful to distinguish neuroendocrine differentiation in breast neoplasms. The identification of neuroendocrine differentiation can be helpful to establish the diagnosis of special type breast carcinomas such as solid papillary carcinoma.

Pseudo-signet ring parietal cell vacuolation has been described as a mimic of invasive signet ring cell carcinoma. Moreover, signet ring cell carcinoma has been described in a fundic gland polyp. This case demonstrates parietal cell vacuolation in a fundic gland polyp in a patient on a long-term proton pump inhibitor.

Atypical cells in peritoneal clefts are usually either reactive mesothelial cells or pT4 colonic adenocarcinoma in colon specimen removed for primary colon cancer. However, rarely if ever are these atypical cells metastasis from other primary visceral malignancy due to “sac-like” anatomic structure of this area. We present a case where these atypical cells were determined to be metastasis of gynecological origin by judicious use of immunohistochemical stains. A final diagnosis of serous tubal intraepithelial carcinoma of right fallopian tube was diagnosed only after total abdominal hysterectomy bilateral salpingo-oophorectomy. To our knowledge, this is the first report of a serous tubal intraepithelial carcinoma presenting as stage 4 colonic adenocarcinoma. The importance of this interesting case is 2-fold. It highlights the peritoneal cleft as an anatomic region not often recognized or discussed as well as tumor presentation in this region. In addition, this example stresses the need for additional mesothelial markers in addition to WT-1 workup of atypical mesothelial proliferation.

Tubulosquamous polyp (TSP) of the vagina is a rare and benign lesion, best considered along the spectrum of lesions derived from Skene’s glands, the female counterpart of male prostatic glands. It is likely underdiagnosed and represents a challenging diagnosis if one is unfamiliar with this entity. We present an illustrative case of TSP occurring as an upper vaginal wall nodule of a 75-year-old woman, with characteristic morphology and broad immunophenotype. It should be suspected in postmenopausal women with a polyp that demonstrates biphasic squamous and glandular components, which show a prostatic immunophenotype.

Ciliated muconodular papillary tumors (CMPTs) are rare peripheral lung lesions, characterized by papillary architecture and ciliated columnar cells admixed with mucous cells and basal cells. Only about 50 cases have been reported to date and is categorized as a benign neoplasm. In this article, we report an extremely rare case of 79-year-old man with a CMPT that developed in his right upper lobe. The central region of the tumor showed features of classic CMPT, while marginal area of the tumor showed the characteristics of invasive lung cancer. In central classic CMPT region, the ciliated, basal, and mucous cells were positive for thyroid transcription factor-1, cytokeratin 7 (CK7), and NapsinA. Basal cells were positive for CK5/6 and p40. Mucous cells were weakly positive for MUC2 and MUC5AC. However, CK5/6 and p40 were negative in the peripheral malignant area. Both of the benign and malignant regions had an EGFR driver mutation in exon 21. We concluded that this tumor was an extremely rare malignant case of CMPT.

Epithelial-myoepithelial carcinoma (EMCA) is a rare low-grade carcinoma of the salivary glands with multiple morphological variants. One such variant, sebaceous EMCA (SEMCA), has been reported in the literature. Distinguishing it from other tumors such as sebaceous carcinoma is crucial, as SEMCA typically behaves more indolently. We present a case of a SEMCA in the right parotid of a 71-year-old man that shows features of aggressive behavior such as facial nerve invasion and extraparenchymal extension. Also, we report evidence of preexisting pleomorphic adenoma within this tumor.

Hereditary pancreatitis is a rare form of recurrent acute pancreatitis that typically has an onset in early adulthood. We report a rare case of hereditary pancreatitis in an individual with a serine protease inhibitor Kazal type 1 (SPINK1) mutation. Histologically the pancreas showed features of chronic pancreatitis with variable fibrosis, acinar destruction, and prominent inspissated secretions within the pancreatic ducts. Additionally, focal areas of low-grade pancreatic intraepithelial neoplasia (PanIN) were present. Although the histopathology of common gene mutations resulting in hereditary pancreatitis have been well described, the histopathology of pancreatitis secondary to SPINK1 mutation has been described in only one previous study.

Intraductal papilloma of the breast is a benign, mass-forming, proliferative lesion with a papillary architecture confined within a duct. Lobular neoplasia can rarely arise from an intraductal papilloma of the breast. In this article, we report the morphologic features of a rare case of classical LCIS (lobular carcinoma in situ) arising from an intraductal papilloma in a 76-year-old woman. The monomorphic dyscohesive cells were present between the myoepithelial and luminal epithelial layer in the periphery of the papilloma. These cells partially obliterated the spaces between the papillae forming solid sheets. The monomorphic dyscohesive cells showed lack of E-cadherin expression and uniform staining for estrogen receptor. We review the histologic differential diagnosis and stress the importance of correct classification to ensure optimal care for patients. We also propose a new criterion for the distinction of lobular neoplasia within a papilloma.

Adenomyoepithelioma (AME) of the male breast is a rare tumor characterized by biphasic proliferation of gland epithelial cells and myoepithelial cells. Though pleomorphic adenoma (PA) is also known to be an epithelial-myoepithelial tumor in the breast, and these tumors are considered to exist on the same spectrum by some authors, to the best of our knowledge, there have been no reports of a clear transition from AME to PA in the male breast. Therefore, the case of an 85-year-old man with AME with PA-like components is presented.

ALK-positive histiocytosis was first described in 2008 as a systemic histiocytic disorder involving young infants and neonates. Subsequently, cases of local ALK-positive histiocytosis as well as clinical presentation in adult patients have been increasingly reported in the literature. The current case documented the hitherto largest local ALK-positive histiocytosis lesion involving the mesentery of a 20-year-old female patient, a clinical presentation that has not been previously reported in the medical literature. Of note was the presence of numerous lymphocytes, plasma cells, and eosinophils as well as the formation of lymphoid follicles in the lesion, mimicking an inflammatory myofibroblastic tumor. Other unique histologic aspects of the current case included the nested arrangement of the histiocytes, intravascular extension of the histiocytic proliferation into a large vein, and tumor necrosis. Notably, molecular studies revealed a novel TRIM33 (exon 12)-ALK (exon 20) gene fusion. Therefore, ALK-positive histiocytosis with TRIM33-ALK gene fusion expands the clinical, histologic, and molecular spectrum of local ALK-positive histiocytosis. Since ALK-positive histiocytosis associated with a significant inflammatory component can pose considerable diagnostic challenges, increased awareness of this peculiar variant of ALK-positive histiocytosis is essential to minimize the risk of misdiagnosis.

Langerhans cell histiocytosis (LCH) with primary involvement of the upper gastrointestinal (GI) tract is rare. We report 2 adult cases of localized LCH in the upper-GI tract, including the second reported adult case of esophageal LCH and review 11 previously reported cases. Case 1 involved the esophagus of a 61-year-old man; histiocytosis was detected when endoscopy was performed for an examination of epigastric pain. Case 2 involved the stomach of a 56-year-old woman wherein the lesion was detected during a follow-up endoscopy after Helicobacter pylori infection. Both biopsy specimens exhibited diffuse proliferation of mononuclear cells with nuclear convolution and a background of eosinophilic infiltrate. The cells were immunohistochemically positive for CD1a and langerin, and BRAF V600E mutation was detected in Case 2. Follow-up endoscopy for both cases revealed that the lesions disappeared without any treatment. It is important to avoid misdiagnosing LCH of the upper-GI tract as a malignant neoplasm.

Some gastric epithelial neoplasms show predominant chief cell differentiation (oxyntic gland neoplasms), in which the entity of “gastric adenocarcinoma of fundic gland type” was firstly designated, whereas a possible more aggressive subgroup “gastric adenocarcinoma of fundic gland mucosa type” (GA-FGM) was subsequently proposed. However, the histopathologic progression mode of these neoplasms has not been sufficiently reported. In this article, we describe a case of GA-FGM in which we could observe its progression during 5 years. The tumor was removed by endoscopic submucosal dissection 5 years after the first biopsy, which had already shown a feature of oxyntic gland neoplasm. During the follow-up period, the endoscopy revealed little change in the tumor appearance. However, the histology of endoscopic submucosal dissection showed submucosal extension with its histological progression. Besides, other oxyntic gland neoplasms of the stomach were observed metachronously or synchronously, giving an implication about a common pathogenetic basis of these lesions.

Sclerosing epithelioid fibrosarcoma (SEF) is a rare, aggressive soft-tissue tumor, commonly occurring in upper and lower extremities, the limb girdle, and the head and neck, which shows morphologic and molecular overlap with low-grade fibromyxoid sarcoma. For SEF in soft tissues, 100 case reports have been published. To our knowledge, the present case is the first to be reported in English literature for a primary SEF of the stomach with a rare FUS-CREM fusion. We report a case of gastric SEF in a 35-year-old female who presented with nonspecific symptoms, including night sweat, cough, and iron deficiency anemia for the past few months. Further workup showed, on computed tomography, a large, heterogeneously enhancing and centrally necrotic left upper quadrant mass, which measured approximately 8.4 cm. A laparoscopic partial gastrectomy with distal pancreatectomy and splenectomy was performed. Histological examination and immunohistochemical staining suggested the diagnosis of primary gastric SEF, which was later confirmed by sarcoma fusion panel showing FUS-CREM fusion. In this article, we report this first case of SEF in the stomach with a rare FUS-CREM fusion, which has been previously reported only once in SEFs of soft tissue.