The American Journal of Surgical Pathology最新文献

Secondary involvement of the uterine cervix by nongynecologic neoplasms is rare accounting for <2% of metastases to the gynecologic tract. This study aimed to analyze the clinicopathologic features of cervical involvement by nongynecologic malignancies. A total of 47 cases were identified including 39 (83%) carcinomas, 6 lymphomas (12.8%), and 2 (4.2%) cutaneous malignant melanomas. The most common primary site of origin among carcinomas was the gastrointestinal tract (27, 69.2%), followed by breast and urothelium (5 each, 12.8%), gallbladder, and lung (1 each, 2.6%). The gynecologic tract was involved at the presentation in 16 patients (34%), including 5 (10.6%) with the cervix being the first site, 7 (14.9%) with synchronous involvement of the cervix and other gynecologic sites, and 4 (8.5%) with the involvement of other gynecologic sites before the cervical presentation. Patients with lymphoma were younger compared with those with carcinoma (43.7 vs. >50.5) (P=0.01). Mean time to identification of cervical metastases was <1 year for gallbladder carcinoma, melanomas, and gastrointestinal signet ring cell carcinomas (P=0.03). Features that varied with different types of metastatic tumor included lymphovascular space invasion, depth of stromal invasion, growth pattern (glands lacking architectural complexity, cribriforming, solid), presence of goblet cells, and signet ring cells, degree of cytologic atypia, and overall findings mimicking a benign/noninvasive process (P≤0.027). Six tumors (12.8%) were initially misdiagnosed as cervical primary. Metastatic nongynecologic tumors can mimic primary in situ or invasive neoplasms in both ectocervix and endocervix. In patients with a known prior malignancy, the clinical history with ancillary studies and a high level of suspicion are crucial to ensure accurate diagnosis.

Identification of the primary site of cancer is essential for the treatment of patients with cancer. Numerous immunohistochemical markers have been developed to determine the differentiation of tumor cells and suggest possible primary sites, but markers of gastric and pancreatic adenocarcinomas are still lacking. Claudin-18 is a tight-junction protein uniquely expressed in gastric epithelial cells and has been shown to be expressed in gastric and pancreatic adenocarcinoma. Whether claudin-18 can be used as a marker for identifying the primary site of cancer is still unclear. In this study, we used the immunohistochemical method to stain claudin-18 in tissue arrays containing 575 carcinomas from different anatomic sites and representative sections of 157 metastatic adenocarcinomas. In the group of primary tumors, claudin-18 was frequently expressed in gastric, pancreatic, and pulmonary mucinous adenocarcinomas. Half of cholangiocarcinomas and ovarian mucinous carcinomas and some colorectal and pulmonary adenocarcinomas were also positive for claudin-18. In the metastatic cohort, 15 of 17 (88%) gastric adenocarcinomas, 18 of 23 (78%) pancreatic adenocarcinomas, and 4 of 7 (57%) cholangiocarcinomas and gallbladder adenocarcinomas were positive for claudin-18. Only 4 tumors that originated outside the stomach and pancreatobiliary tract were positive for claudin-18. After normalization to the tumor frequency, the sensitivity of claudin-18 for identifying the stomach and pancreatobiliary tract as primary tumor sites was 79%, and the specificity was 93%. The positive and negative predictive values were 76% and 94%, respectively. In conclusion, claudin-18 represents a sensitive and specific marker for stomach and pancreatobiliary adenocarcinoma that may be a useful diagnostic tool in routine surgical pathology.

To diagnose small cell lung carcinoma (SCLC), neuroendocrine (NE) phenotype markers such as chromogranin A, synaptophysin, and CD56 are helpful. However, because they are dispensable, SCLCs occur without apparent NE phenotypes. Insulinoma-associated protein 1 (INSM1) is a transcription factor for NE differentiation and has emerged as a single practical marker for SCLC. Using the surgical samples of 141 pulmonary NE tumors (78 SCLCs, 44 large cell NE carcinomas, and 19 carcinoids), and 246 non-NE carcinomas, we examined the immunohistochemical expression and prognostic relevance of INSM1 in association with NE phenotype markers. We evaluated its sensitivity and specificity for SCLC diagnosis, as well as its usefulness to diagnose SCLC without NE marker expression and to estimate the prognosis. INSM1 was expressed in SCLCs (92%, 72/78), large cell NE carcinomas (68%, 30/44), and carcinoids (95%, 18/19). In addition, among SCLCs with no expression of NE phenotype markers (n=12), 9 (75%) were positive for INSM1. These data suggest the superiority of INSM1 to the phenotype markers. Only 7% of adenocarcinomas (9/134) and 4% of squamous cell carcinomas (4/112) were positive for INSM1. SCLC with low-INSM1 expression (n=28) had a significantly better prognosis (P=0.040) than the high-INSM1 group (n=50). Our study revealed that INSM1 is highly sensitive and specific to detect SCLC and can estimate prognosis. INSM1 will be a promising marker for SCLC.

NK3 homeobox 1 (NKX3-1) is widely accepted as a highly sensitive and specific marker for prostatic adenocarcinoma. Prompted by published transcriptome data showing upregulation of NKX3-1 mRNA expression in EWSR1-NFATC2 sarcoma, we explored the utility of NKX3-1 immunohistochemistry in sarcoma diagnosis. We applied NKX3-1 immunohistochemistry to 11 EWSR1-NFATC2 sarcomas and 168 mimics using whole tissue sections. All EWSR1-NFATC2 sarcomas consisted of uniform small round or ovoid cells, all except 1 showing at least focally the typical growth pattern of nests, cords, or trabeculae within a fibrous/myxoid background. A variable eosinophilic infiltrate was common. NKX3-1 was expressed in 9 of 11 (82%) EWSR1-NFATC2 sarcomas, often diffuse and of moderate or strong intensity. All 12 mesenchymal chondrosarcomas tested were also positive for NKX3-1, with over half showing diffuse staining and moderate or strong intensity. The positive staining was seen only in the primitive small round cell component, whereas the cartilaginous component was mostly negative. Although 1 of 30 osteosarcomas showed focal NKX3-1 positivity, all the remaining 155 cases tested, including 20 Ewing sarcomas, 20 myoepithelial tumors, 11 ossifying fibromyxoid tumors, and 1 FUS-NFATC2 sarcoma were negative for NKX3-1. Our study provides the first evidence that EWSR1-NFATC2 sarcoma and Ewing sarcoma could be distinguished immunohistochemically, adding to the accumulating data that these tumors are phenotypically distinct. We suggest that NKX3-1 may have a diagnostic utility in the evaluation of sarcoma and we also call attention to potential pitfalls in the use of this well-known marker of prostatic adenocarcinoma.

Immunohistochemistry (IHC) for mismatch repair (MMR) proteins is recommended in endometrial carcinomas as a screening test for Lynch syndrome, and mismatch repair deficiency (MMRd) is reported in ∼30% of cases. However, few studies have evaluated the rate of MMR loss in uterine carcinosarcomas. A 5-year retrospective database search of uterine carcinosarcomas was performed at 3 academic institutions. The histologic diagnoses, type of carcinoma present, and MMR IHC interpretations were confirmed by a gynecologic pathologist. One hundred three cases of uterine carcinosarcomas with available MMR IHC results were identified. Ninety-nine cases (96%) showed intact expression and 4 cases (4%) showed loss of MLH1/PMS2. All MMRd carcinosarcomas identified in this series had an endometrioid carcinomatous component and wild-type p53 expression. In contrast, the majority of MMR intact carcinosarcomas had a serous morphology and aberrant p53 expression. Three additional cases initially diagnosed as carcinosarcoma also revealed MMRd; however, given the lack of clear mesenchymal differentiation, these cases were reclassified as dedifferentiated endometrial carcinomas and were subsequently excluded from the carcinosarcoma category. No cases of Lynch syndrome were identified among carcinosarcoma patients, as all 4 MMRd cases were due to somatic MLH1 hypermethylation. In summary, we found that the rate of MMRd is markedly lower in uterine carcinosarcoma when compared with endometrial carcinoma. In the setting of MMR loss, a diagnosis of dedifferentiated carcinoma should be considered as almost half of the MMRd tumors which were called carcinosarcomas initially were reclassified as dedifferentiated on review. However, given the interobserver variability in the classification of carcinosarcoma versus dedifferentiated carcinoma a universal screening approach that includes uterine carcinosarcoma is still recommended.

DICER1 mutations (somatic or germline) are associated with a variety of uncommon neoplasms including cervical and genitourinary embryonal rhabdomyosarcoma (ERMS). We report a primary ovarian and 2 primary fallopian tube ERMS occurring in 60-, 13-, and 14-year-olds, respectively. The 3 neoplasms exhibited a similar morphologic appearance being polypoid and containing edematous hypocellular areas and hypercellular foci composed of small cells with scant cytoplasm exhibiting rhabdomyoblastic differentiation (desmin, myogenin, myoD1 positive). There was cellular cartilage in all cases and extensive foci of anaplasia, eosinophilic globules, and bone/osteoid in 1 case each. All 3 neoplasms exhibited DICER1 mutations; in 1 of the tubal cases, the patient had a germline mutation and in the other 2 cases, the DICER1 mutations were somatic. Accompanying DICER1 "second hits" were identified in all cases. In 2 of the neoplasms, SALL4-positive glandular structures were present which we speculate may represent an unusual primitive "metaplastic" phenomenon. Our study adds to the literature on ERMS at unusual sites associated with DICER1 mutations. ERMS arising at such sites, especially when they contain cartilage or bone/osteoid, are especially likely to be associated with DICER1 mutations. Pathologists should be aware of this as these may be the sentinel neoplasms in patients with DICER1 syndrome and confirming a germline mutation can facilitate the screening of the individual and affected family members for other neoplasms which occur in this syndrome.

Melanocytic tumors with inactivation of protein kinase A regulatory subunit-α (PRKAR1A) have large oval nuclei and intense pigmentation. Historically, these tumors have been categorized under various names, including epithelioid blue nevus, pigmented epithelioid melanocytoma (PEM) and animal-type melanoma. Although a subset of PEM harbor BRAF activating mutations and biallelic inactivation of PRKAR1A, there are only a few reports of melanomas, or of tumors with genomic alterations beyond those of PEMs. Herein, we describe the clinicopathologic and genetic features of 8 melanomas and tumors that lack PRKAR1α expression by immunohistochemistry but do not fit with conventional PRKAR1A-inactivated melanocytomas. These tumors tended to affect younger patients than conventional melanomas (median age=38 y) and presented as dark brown/black papules and nodules. Histopathologically, they demonstrated nodularity, sometimes in a background of conventional melanoma, and large vesicular nuclei with prominent nucleoli. With the exception of 1 case, the mitotic index was not significantly elevated. Immunohistochemically, all cases showed loss of PRKAR1α and of p16 expression. Seven tumors underwent massively parallel short read (next-generation) sequencing of a panel of 480 cancer-associated genes. Five tumors demonstrated truncating mutations of PRKAR1A and the 2 in which such mutations were not identified demonstrated loss of heterozygosity of the PRKAR1A locus. Four of the tumors harbored BRAF V600E mutations, and 1 harbored a FAM39B-BRAF gene fusion. Another harbored a GNA11 activating mutation. A MAP kinase activating mutation was not identified in the remaining case. Four tumors displayed TERT promoter mutations and chromosomal copy number changes supporting the diagnosis of melanoma. Two cases without these alterations and were classified as "high-grade PRKAR1A-inactivated melanocytomas". The 1 case with widespread metastases demonstrated mutations in TP53 and RB1. Overall, we provide the first genetic characterization of PRKAR1A-inactivated melanomas, discuss the differential diagnosis of heavily pigmented epithelioid melanocytic neoplasms, and propose a new nomenclature for such tumors.

Thyroid gland teratomas are rare tumors that span a wide clinicopathologic spectrum. Although benign and immature teratomas arise in infants and young children and generally have good outcomes, malignant teratomas affect adults and follow an aggressive course. This divergent behavior raises the possibility that benign/immature and malignant teratomas are separate entities rather than different grades of a single tumor. However, the histogenesis and molecular underpinnings of thyroid gland teratomas are poorly understood regardless of grade. In this study, we performed next-generation sequencing on 8 thyroid gland teratomas, including 4 malignant, 3 benign, and 1 immature. We identified DICER1 hotspot mutations in all 4 malignant cases (100%) but not in any benign/immature cases (0%). No clinically significant mutations in other genes were found in either group. We also performed immunohistochemistry to characterize the primitive components of malignant teratomas. Not only did all cases consistently contain immature neural elements (synaptophysin and INSM1 positive), but also spindled cells with rhabdomyoblastic differentiation (desmin and myogenin positive) and bland epithelial proliferations of thyroid follicular origin (TTF-1 and PAX8 positive). Although DICER1 mutations have previously been implicated in multinodular hyperplasia and well-differentiated thyroid carcinomas, these findings demonstrate the first recurrent role for DICER1 in primitive thyroid tumors. The combined neural, rhabdomyoblastic, and homologous epithelial elements highlighted in this series of malignant thyroid gland teratomas parallel the components of DICER1-mutated tumors in other organs. Overall, these molecular findings further expand the differences between benign/immature teratomas and malignant teratomas, supporting the classification of these tumors as separate entities.

In patients with multiple myeloma, plasmablastic transformation in the bone marrow is rare and associated with poor outcomes. The significance of discordant extramedullary plasmablastic transformation in patients with small, mature clonal plasma cells in the bone marrow has not been well studied. Here, we report the clinicopathologic, cytogenetic, and molecular features of 10 such patients (male/female: 6/4, median age: 65 y, range: 48 to 76 y) with an established diagnosis of multiple myeloma in the bone marrow composed of small, mature plasma cells in parallel with a concurrent or subsequent extramedullary plasmablastic transformation. Eight patients with available survival data showed an overall aggressive clinical course with a median survival of 4.5 months after the diagnosis of extramedullary plasmablastic transformation, despite aggressive treatment and even in patients with low-level bone marrow involvement. Pathologically, the extramedullary plasmablastic myeloma were clonally related to the corresponding bone marrow plasma cells, showed high levels of CMYC and/or P53 expression with a high Ki-67 proliferation index by immunohistochemistry and harbored more complex genomic aberrations including frequent mutations in the RAS pathway and MYC rearrangements compared with their bone marrow counterparts. In summary, although genetic and immunohistochemical studies were not uniformly performed on all cases due to the retrospective nature of this study, our data suggest that discordant extramedullary plasmablastic transformation of multiple myeloma has an aggressive clinical course and is characterized by frequent mutations in the RAS pathway and more complex genomic abnormalities.

Giant cell tumor of bone (GCT) is a benign locally aggressive neoplasm composed of mononuclear cells admixed with innumerable osteoclast-type giant cells. H3F3A gene mutations producing mutant histone protein product H3.3 have been identified in 96% of GCT; mutant H3.3 is reliably demonstrated by immunohistochemistry. GCT may contain woven bone and rarely, neoplastic cartilage nodules which causes diagnostic challenges with aggressive neoplasms such as osteosarcoma. We describe the features of GCT with cartilage matrix and report the next-generation sequencing findings in a subset of tumors. Seventeen cases of GCT with cartilage matrix form the cohort: 7 males and 10 females, 13 to 55 (mean: 25) years old. Tumors involved the fibula (6), femur (6), and patella, tibia, humerus, S1, and scapula (1 case each). Tumors were radiolucent, circumscribed, lytic, and expansile. All contained classic GCT, foci of cartilage matrix, and trabeculae of woven bone. Immunohistochemistry showed diffuse staining for H3.3 in 9/9 cases and 1 case was positive for S100 and SOX9 in the cartilage areas. Next-generation sequencing showed a mutation in the H3F3A gene in 6/6 cases. On follow-up, 2 patients who underwent resection showed no disease after 12, and 7 months, respectively. Three patients had recurrences 10, 12, and 27 months after curettage; there were no metastases. GCT with cartilage matrix is uncommon. The cartilage matrix is associated with woven bone suggesting the neoplastic cells may differentiate into chondrocyte-like and osteoblast-like cells. Recognition of this neoplasm is important to prevent misdiagnosis and overtreatment of affected patients.