One of the major immune checkpoints responsible for immune evasion in cancer cells is the interaction between programmed cell death-1 (PD-1) and its ligand (PD-L1). As human trophoblastic cells ...display many of the features of malignant cells such as the ability to invade normal tissue including blood vessels and are apparently not eradicated by the host immune system, we undertook the present study to determine whether PD-L1 was upregulated in different types of trophoblastic cells during normal pregnancy and in gestational trophoblastic diseases. Immunohistochemistry using an anti-PD-L1-specific antibody demonstrated that in early and term normal placentas, PD-L1 was highly expressed in syncytiotrophoblast and to a much lower extent in intermediate trophoblastic cells located in the chorion laeve and implantation site. PD-L1 immunoreactivity was undetectable in cytotrophoblastic cells. This staining pattern in normal placenta was recapitulated in various types of gestational trophoblastic disease. PD-L1 was highly expressed by syncytiotrophoblast in complete moles and choriocarcinomas. The intermediate trophoblastic neoplasms, placental site trophoblastic tumors, and epithelioid trophoblastic tumors showed variable PD-L1 immunoreactivity but at a lower intensity than in the neoplastic syncytiotrophoblast in choriocarcinoma. In addition, we observed PD-1-positive lymphocytes located within the implantation site and in trophoblastic tumors. In summary, this study describes a novel mechanism for trophoblastic cells to create a tolerogenic feto-maternal interface by upregulating PD-L1 in syncytiotrophoblast and in intermediate trophoblast. Trophoblastic tumors may also use PD-L1 expression to evade the host immune response thereby promoting their survival.
Gastric-type cervical adenocarcinoma (GCA) is an aggressive type of endocervical adenocarcinoma characterized by mucinous morphology, gastric-type mucin, lack of association with human papillomavirus ...(HPV) and resistance to chemo/radiotherapy. We characterized the landscape of genetic alterations in a large cohort of GCAs, and compared it with that of usual-type HPV-associated endocervical adenocarcinomas (UEAs), pancreatic adenocarcinomas (PAs) and intestinal-type gastric adenocarcinomas (IGAs). GCAs (n = 68) were subjected to massively parallel sequencing targeting 410–468 cancer-related genes. Somatic mutations and copy number alterations (CNAs) were determined using validated bioinformatics methods. Mutational data for UEAs (n = 21), PAs (n = 178), and IGAs (n = 148) from The Cancer Genome Atlas (TCGA) were obtained from cBioPortal. GCAs most frequently harbored somatic mutations in TP53 (41%), CDKN2A (18%), KRAS (18%), and STK11 (10%). Potentially targetable mutations were identified in ERBB3 (10%), ERBB2 (8%), and BRAF (4%). GCAs displayed low levels of CNAs with no recurrent amplifications or homozygous deletions. In contrast to UEAs, GCAs harbored more frequent mutations affecting cell cycle-related genes including TP53 (41% vs 5%, p < 0.01) and CDKN2A (18% vs 0%, p = 0.01), and fewer PIK3CA mutations (7% vs 33%, p = 0.01). TP53 mutations were less prevalent in GCAs compared to PAs (41% vs 56%, p < 0.05) and IGAs (41% vs 57%, p < 0.05). GCAs showed a higher frequency of STK11 mutations than PAs (10% vs 2%, p < 0.05) and IGAs (10% vs 1%, p < 0.05). GCAs harbored more frequent mutations in ERBB2 and ERBB3 (9% vs 1%, and 10% vs 0.5%, both p < 0.01) compared to PAs, and in CDKN2A (18% vs 1%, p < 0.05) and KRAS (18% vs 6%, p < 0.05) compared to IGAs. GCAs harbor recurrent somatic mutations in cell cycle-related genes and in potentially targetable genes, including ERBB2/3. Mutations in genes such as STK11 may be used as supportive evidence to help distinguish GCAs from other adenocarcinomas with similar morphology in metastatic sites.
Ovarian clear cell carcinoma (CCC) is one of the most malignant types of ovarian carcinomas, particularly at advanced stages. Unlike the more common type of ovarian cancer, high-grade serous ...carcinoma, ovarian CCC is often resistant to platinum-based chemotherapy, and therefore an effective treatment for this tumor type at advanced stages is urgently needed. In this study, we analyzed 97 ovarian CCCs for sequence mutations in KRAS , BRAF , PIK3CA , TP53 , PTEN , and CTNNB1 as these mutations frequently occur in other major types of ovarian carcinomas. The samples included 18 CCCs for which affinity-purified tumor cells from fresh specimens were available, 69 microdissected tumors from paraffin tissues, and 10 tumor cell lines. Sequence mutations of PIK3CA , TP53 , KRAS , PTEN, CTNNB1 , and BRAF occurred in 33%, 15%, 7%, 5%, 3%, and 1% of CCC cases, respectively. Sequence analysis of PIK3CA in 28 affinity-purified CCCs and CCC cell lines showed a mutation frequency of 46%. Samples with PIK3CA mutations showed intense phosphorylated AKT immunoreactivity. These findings demonstrate that ovarian CCCs have a high frequency of activating PIK3CA mutations. We therefore suggest that the use of PIK3CA-targeting drugs may offer a more effective therapeutic approach compared with current chemotherapeutic agents for patients with advanced-stage and recurrent CCC.
The assessment of an accurate mitotic index (MI) is one of the major parameters in the proper classification of uterine smooth muscle tumors. This assessment can be hampered by the presence of ...increased number of apoptotic bodies or piknotic nuclei, which frequently mimic mitoses. Phospho-histone H3 (PHH3) is a recently described immunomarker specific for cells undergoing mitoses. In this study, we evaluated the MI of 2 subsets of uterine smooth muscle tumors--6 leiomyosarcomas (LMS) and 6 smooth muscle tumors of undetermined malignant potential (STUMP)--using PHH3-labeled sections and hematoxylin and eosin (H&E)-stained slides. In the STUMP group, the MI on H&E ranged from 0 to 9 mitoses/10 high-power fields (HPFs) (mean, 3.2), and in the LMS group, it ranged from 0 to 37 mitoses/10 HPFs (mean, 19). PHH3 showed 0 to 16 mitoses/10 HPFs (mean, 3.8) in the STUMP group and 0 to 61 mitoses/10 HPFs (mean, 26) in the LMS group. In 7 cases, the MI difference (MID) between H&E-stained and PHH3-stained slides varied from 0 to 3 mitoses (mean, 1.6). In only one LMS, the PHH3 MI was lower than on H&E-stained slides (MID 7). The MI on H&E-stained and PHH3-stained slides were comparable in 7 cases, 5 of which were STUMPs. In 4 other cases, 3 of which were LMS, the PHH3 MI was significantly higher than the one obtained on H&E. The higher MI obtained with PHH3-labeled sections in some cases is most likely due to the recognition of true mitoses by the antibody, which were initially misinterpreted as apoptotic bodies and/or piknotic nuclei on H&E and not included in the formal count, and the fact that the phosphorilation of histone H3 starts just before the prophase and at this stage mitoses cannot be identified by H&E.
Although pancreatic acinar metaplasia in the gastric mucosa is well recognized in chronic gastritis, gastric carcinoma with acinar differentiation is very rare. We encountered a case of gastric ...adenocarcinoma with prominent histologic and immunohistochemical features of pancreatic acinar differentiation in the absence of identifiable heterotopic pancreatic tissue. Distinct glandular and diffuse patterns of adenocarcinoma were also present, and there was focal mucin production. The tumor strongly expressed pancreatic exocrine enzymes trypsin and chymotrypsin, and focal neuroendocrine staining was also present. To investigate the prevalence of acinar differentiation in histologically typical gastric cancers, we performed immunohistochemical staining for trypsin and chymotrypsin on a tissue microarray containing 111 conventional gastric adenocarcinomas (60 intestinal, 28 mixed, 22 diffuse type, and 1 undifferentiated). No obvious morphologic evidence of acinar differentiation was identified in any of the 111 cases. Although some cases showed equivocal staining for at least 1 pancreatic exocrine enzyme on the initial tissue microarray sections, repeat immunohistochemical staining on representative whole-tissue sections failed to reproduce positive staining. Thus, acinar differentiation is rare in gastric adenocarcinomas, other than in histologically unusual cases such as the one we report, and in others from the literature, which are reviewed.
Background
The variable incidence of gallbladder cancer (GBCA) suggests regional pathogenetic differences. This study compares cell cycle-regulatory, angiogenesis-related, and PI3K pathway protein ...expression in GBCAs from three continents.
Methods
Immunohistochemical expression of several proteins was assessed, correlated with clinicopathologic variables, and compared among centers from Chile (Fundación Arturo López Pérez FALP), Japan (Yokohama City University YCU), and the United States (Memorial Sloan-Kettering Cancer Center MSKCC). Hierarchical clustering was used to partition the data based on protein-expression and treatment center.
Results
Tissue from 117 patients (MSKCC = 76; FALP = 22; YCU = 19) was analyzed. Mdm2 overexpression was seen only at MSKCC (
p
< 0.0001). Absence of p21 (
p
= 0.03) and VEGFR2 (
p
= 0.018) were more common and p27 expression was less frequent (
p
= 0.047) in tumors from YCU. Ki-67 labeling index in YCU tumors (median = 10) was two-thirds lower than at other centers. On hierarchical clustering analysis, all YCU patients (
p
= 0.017) and those with early tumors (
p
= 0.017) clustered separately from MSKCC. Median disease-specific survival after curative intent (R0) resection was 27 months and was similar among centers (
p
= 0.9). Median disease-specific survival of patients with early tumors was 28.4 months and was higher at YCU (not reached,
p
= 0.06).
Conclusions
Cell cycle-regulatory protein expression patterns of YCU tumors differed from those treated at FALP and MSKCC. The differential clustering of protein expression and survival in patients with early tumors suggest regional differences in pathogenesis and disease biology.
Abstract Mucoepidermoid carcinoma (MEC) comprises approximately 30% of all salivary gland malignancies, making it the most common malignant tumor of the salivary glands. Multiple histologic variants ...with a wide range of differentiation have been described. Sclerosing MEC (SMEC) is a rare subtype that may be misdiagnosed as a benign reactive condition or low-grade non-SMEC malignancy. We report 4 cases of SMEC and evaluated them with Her-2/neu and MIB-1 to determine whether an association exists between the histologic grade and immunohistochemical findings. In 3 cases, histologic examination demonstrated relatively well-circumscribed, nonencapsulated tumors composed of extensive central sclerosis with keloid-like stroma and scattered epithelial islands of low-grade MEC. In the fourth case, the tumor showed similar sclerotic stroma; but the epithelial component was of intermediate grade. In all 4 cases, eosinophils and neutrophils were part of the inflammatory infiltrate; and the edges were surrounded by lymphoid tissue, with germinal center formation and residual epithelial islands. A Mayer mucicarmine stain revealed abundant intracytoplasmic mucin. We found MIB-1 labeling indices of 5% or less in cases 1, 2, and 3 and 12% in case 4, suggesting an association between MIB-1 index and tumor grade. The tumors were negative for Her-2/neu in all 4 cases. The latter seems to bear no relationship to tumor grade.
Sinonasal chondromyxoid fibroma Veras, Emanuela F.T., MD; Santamaria, Inmaculada Barredo, MD; Luna, Mario A., MD
Annals of diagnostic pathology,
02/2009, Volume:
13, Issue:
1
Journal Article
Peer reviewed
Abstract Chondromyxoid fibroma (CMF) is a rare benign cartilaginous tumor that usually arises from the metaphysis of long bones. In rare cases, however, CMF presents in unusual locations, such as the ...facial bones and sinonasal tract. We present a case of a 60-year-old woman with a CMF of the nasal septum. The initial radiographic findings were suggestive of a vascular tumor or a malignancy, but microscopic examination revealed the typical pathologic features of CMF, and SOX9 immunostaining confirmed its cartilaginous origin. The tumor was successfully excised, and the patient was free of disease at 12-month follow-up. Recognizing CMF is important when it presents in unexpected locations, especially because of its histologic resemblance to chondrosarcoma. We believe that the use of SOX9 in our case assisted in the recognition of the chondroid nature of the lesion and facilitated the diagnosis of CMF.
Choriocarcinoma is an uncommon malignant neoplasm, which can be either gestational or nongestational in origin. Distinction of these subtypes has prognostic and therapeutic implications. Twenty-two ...tumors were genotyped using polymerase chain reaction amplification of 15 short tandem repeat loci and the amelogenin locus (XY determination). DNA patterns from tumor and maternal tissue, as well as villous tissue from any available prior or concurrent gestation, were compared, to determine gestational versus nongestational nature (containing vs. lacking a paternal chromosome complement, respectively) and the relationship between the tumor and any prior or concurrent gestation. Nineteen tumors were gestational. Of these, 14 were purely androgenetic/homozygous XX6 uterine tumors with a concurrent or prior genetically related complete hydatidiform mole (CHM), 4 uterine tumors without an accompanying villous component, 1 uterine cornual tumor separate from a genetically distinct second trimester intrauterine placenta, 1 ectopic ovarian tumor separate from a genetically distinct third trimester intrauterine placenta, and 2 ectopic fallopian tube tumors. Five gestational tumors were biparental3 (2 XX, 1 XY) intraplacental choriocarcinomas genetically related to the placenta and 2 uterine tumors without accompanying placental tissue after term deliveries (1 XX 4 weeks postpartum and 1 XYY with allelic imbalances 1 year postpartum; prior placentas not available for analysis). Three tumors were nongestationalall XX with allelic imbalances; 2 ovarian, 1 pelvic. Gestational choriocarcinoma can be androgenetic or biparental. Most are androgenetic/homozygous XX, often associated with a genetically related concurrent or prior CHM, and thus of molar-associated type. These findings support that homozygous XX CHMs are associated with some risk of significant gestational trophoblastic disease. Intraplacental choriocarcinomas are biparental and genetically related to the placenta. Biparental choriocarcinoma detected in a postpartum uterine sample is consistent with undetected intraplacental choriocarcinoma. Eutopic or ectopic androgenetic choriocarcinoma separate from a concurrent intrauterine placenta is not derived from intraplacental tumor and is consistent with either a form of dispermic twin gestation (molar-type choriocarcinoma and coexistent nonmolar fetus) or origin from an antecedent molar pregnancy. While fallopian tube tumors are usually gestational, tumors in other sites (ovary, pelvis) can be nongestational and should not be assumed to be metastatic from a regressed or occult intrauterine or intraplacental gestational tumor.
Ovarian endometrioid carcinomas (OEC) of low grade have characteristic morphologic features, but high-grade tumors can mimic high-grade serous and undifferentiated carcinomas. We reviewed tumors ...initially diagnosed as OEC to determine whether a combination of pathologic and immunohistochemical features can improve histologic subclassification. Tumors initially diagnosed as OEC were reviewed using World Health Organization criteria. We also noted the presence of associated confirmatory endometrioid features (CEFs)(i) squamous metaplasia; (ii) endometriosis; (iii) adenofibromatous background; and (iv) borderline endometrioid or mixed Mullerian component. A tissue microarray was constructed from 27 representative tumors with CEF and 14 without CEF, and sections were stained for WT-1, p16, and p53. Of 109 tumors initially diagnosed as OEC, 76 (70%) tumors were classified as OEC. The median patient age was 55 years, and 75% of patients were younger than 60 years. Ninety-two percent presented with disease confined to the pelvis, and 87% of tumors were unilateral. The median tumor size was 11.8 cm. Only 3% of tumors were high grade (grade 3of 3). Eighty percent of cases had at least 1 CEF, and 59% had at least 2 CEFs. Eleven percent overexpressed p16, 0% overexpressed p53, and 3% expressed WT-1. Only 10% of patients died of disease at last follow-up. Thirty-three (33) tumors, or 30% of tumors originally classified as endometrioid, were reclassified as serous carcinoma (OSC). The median patient age was 54.5 years, and 59% of patients were younger than 60 years of age. Only 27% had disease confined to the pelvis at presentation, 52% of tumors were unilateral, and the median tumor size was 8 cm. Associated squamous differentiation, endometrioid adenofibroma, and endometrioid or mixed Mullerian borderline tumor (CEFs) were not present in any case, but 6% of patients had endometriosis. Approximately one half of the reclassified OSC demonstrated SET-pattern morphology (combinations of glandular, cribriform, solid, and transitional cell–like architecture) and were immunophenotypically indistinguishable from OSCs with papillary architecture. Sixty percent of OSC overexpressed p16, 50% overexpressed p53, and 82% expressed WT-1. At last follow-up, 52% had died of disease. Compared with OSC, OEC patients more frequently presented below 60 years of age (P=0.046), had low-stage tumors (P<0.001), were more frequently unilateral (P<0.001), more frequently had synchronous endometrial endometrioid carcinomas (P<0.001); and had no evidence of disease at last follow-up (P<0.001). Their tumors were of lower grade (P<0.001), had more CEFs (P<0.001), and less frequently overexpressed p16 and p53 (P=0.003 and P<0.001, respectively) and less frequently expressed WT-1 (P<0.001). This analysis emphasizes the diagnostic value of CEFs, the presence of a low-grade gland-forming endometrioid component, and WT-1 negativity, as valid, clinically relevant criteria for a diagnosis of OEC. Glandular and/or cribriform architecture alone may be seen in both OECs and OSCs and are therefore not informative of diagnosis. Further study is needed to elaborate the characteristics of the exceedingly rare high-grade OEC.
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