Showing papers in "The American Journal of Surgical Pathology in 2009"
3,119 citations
TL;DR: In conclusion, similar to MRT of infancy, loss of INI1 expression is characteristic of both conventional and proximal-type ES, being detected in >90% of cases.
Abstract: INI1 (hSNF5/SMARCB1), a member of the SWI/SNF chromatin remodeling complex located on chromosome 22q11.2, is deleted or/or mutated in strictly defined malignant rhabdoid tumors (MRT) of infancy. Recent studies suggest that some epithelioid sarcomas (ES) also show inactivation of INI1. However, very
497 citations
TL;DR: DOG1 should be added into the diagnostic panel evaluating GI and other abdominal tumors, but limitations in its sensitivity and specificity should be recognized.
Abstract: Gastrointestinal stromal tumors (GISTs), KIT or platelet derived growth factor receptor alpha (PDGFRA) signaling driven mesenchymal tumors of the gastrointestinal (GI)-tract and abdomen, require a precise diagnosis so that the patients may benefit from the newly introduced tyrosine kinase inhibitor drugs. The limitations of the current main tools, KIT immunohistochemistry and KIT/PDGFRA mutation analysis, include lack of KIT expression and mutations in some GISTs. In this study we examined 1168 GISTs of different sites and histologic subtypes, and 672 other tumors and normal tissues for discovered on GIST-1 (DOG1) clone K9, a newly introduced immunohistochemical marker, a chloride channel protein. All GISTs and selected non-GISTs were independently evaluated for KIT. In the GI tract, Cajal cells and gastric surface epithelia were DOG1-positive. The overall sensitivity of DOG1 and KIT in GISTs was nearly identical: 94.4% and 94.7%, and results in GISTs were generally concordant. Gastric spindle cell GISTs was nearly uniformly positive for both markers, whereas DOG1 performed slightly better in gastric epithelioid GISTs that included PDGFRA mutant GISTs. In the intestinal GISTs, KIT was slightly more sensitive than DOG1. Negativity for both DOG1 and KIT was observed in 2.6% of GISTs of GI tract. KIT or PDGFRA mutations were detected in 11/24 DOG1-negative GISTs supporting the diagnosis of GIST. DOG1 expression was also generally present in extragastrointestinal and metastatic GISTs. DOG1 was highly specific for GIST, but exceptional DOG1-positive other mesenchymal tumors included uterine type retroperitoneal leiomyomas, peritoneal leiomyomatosis, and synovial sarcomas (positive in 5/42, 4/17, and 6/37 cases). Leiomyomas colonized by DOG1-positive Cajal cells should not be confused with GISTs. DOG1 positivity was relatively common in esophageal squamous cell and gastric carcinomas, whereas it was rare in colorectal carcinomas. DOG1 should be added into the diagnostic panel evaluating GI and other abdominal tumors, but limitations in its sensitivity and specificity should be recognized.
406 citations
TL;DR: Sufficient chromosomal alterations are present in melanoma that a limited panel of FISH probes can distinguish most melanomas from most nevi, providing useful diagnostic information in cases that cannot be classified reliably by current methods.
Abstract: Although the clinical and pathologic diagnosis of some melanomas is clear-cut, there are many histopathologic simulators of melanoma that pose problems. Over-diagnosis of melanoma can lead to inappropriate therapy and psychologic burdens, whereas under-diagnosis can lead to inadequate treatment of a deadly cancer. We used existing data on DNA copy number alterations in melanoma to assemble panels of fluorescence in situ hybridization (FISH) probes suitable for the analysis of paraffin-embedded tissue. Using FISH data from a training set of 301 tumors, we established a discriminatory algorithm and validated it on an independent set of 169 unequivocal nevi and melanomas as well as 27 cases with ambiguous pathology, for which we had long-term follow-up data. An algorithm-using signal counts from a combination of 4 probes targeting chromosome 6p25, 6 centromere, 6q23, and 11q13 provided the highest diagnostic discrimination. This algorithm correctly classified melanoma with 86.7% sensitivity and 95.4% specificity in the validation cohort. The test also correctly identified as melanoma all 6 of 6 cases with ambiguous pathology that later metastasized. There was a significant difference in the metastasis free survival between test-positive and negative cases with ambiguous pathology (P=0.003). Sufficient chromosomal alterations are present in melanoma that a limited panel of FISH probes can distinguish most melanomas from most nevi, providing useful diagnostic information in cases that cannot be classified reliably by current methods. As a diagnostic aid to traditional histologic evaluation, this assay can have significant clinical impact and improve classification of melanocytic neoplasms with conflicting morphologic criteria.
401 citations
TL;DR: IHC staining with the C52 monoclonal antibody is a highly sensitive and specific test that reliably distinguishes NMC from other forms of carcinoma.
Abstract: NUT midline carcinoma (NMC) is a uniformly lethal malignancy that is defined by rearrangement of the nuclear protein in testis (NUT) gene on chromosome 15q14 NMCs are morphologically indistinguishable from other poorly differentiated carcinomas, and the diagnosis is usually made currently by fluorescence in situ hybridization (FISH) As normal NUT expression is confined to testis and ovary, we reasoned that an immunohistochemical (IHC) stain for NUT would be useful in diagnosing NMC To this end, we raised a highly specific rabbit monoclonal antibody, C52, against a recombinant NUT polypeptide, and developed an IHC staining protocol The sensitivity and specificity of C52 staining was evaluated in a panel of 1068 tissues, predominantly diverse types of carcinomas (n=906), including 30 NMCs Split-apart FISH for NUT rearrangement was used as a "gold standard" diagnostic test for NMC C52 immunoreactivity among carcinomas was confined to NMCs IHC staining had a sensitivity of 87%, a specificity of 100%, a negative predictive value of 99%, and a positive predictive value of 100% Two new cases of NMC containing BRD4-NUT fusions were detected by C52 IHC, but missed by conventional FISH In both instances, these tumors contained cryptic BRD4-NUT rearrangements, as confirmed by FISH using a refined set of probes Some germ cell tumors, including 64% of dysgerminomas, showed weak NUT immunoreactivity, consistent with the expression of NUT in normal germ cells We conclude that IHC staining with the C52 monoclonal antibody is a highly sensitive and specific test that reliably distinguishes NMC from other forms of carcinoma The NUT antibody is being prepared for commercial release and will be available in the near future
327 citations
TL;DR: IgG4-related diseases show a greater variety of pulmonary and pleural lesions than previously thought, and it is important to know the morphologic variety and clinicopathologic characteristics of this disorder.
Abstract: Immunoglobulin G4 (IgG4)-related disorders can occur in the respiratory system. However, the clinicopathologic characteristics have not been well clarified. In this study, we examined clinical and pathologic features of, and follow-up data on, IgG4-related lung and pleural lesions. The patients group consisted of 17 males and 4 females with an average age of 69 years (range: 42 to 76). Pulmonary lesions in 16 patients and pleural lesions in 5 patients were examined. Histologically, all lesions showed diffuse lymphoplasmacytic infiltration. Irregular fibrosis and obliterative vascular changes were more common in solid areas. Nine cases (43%) had eosinophilic infiltration with more than 5 cells per high-power field. Immunostaining revealed numerous IgG4-positive plasma cells in inflamed areas. Sclerosing inflammation was distributed with intrapulmonary connective tissue. Pulmonary lesions showed a variety of morphologic changes according to the predominant area of inflammation. Serum IgG4 concentrations were elevated in 9 of 11 patients tested (average 6.9 g/L; range 0.3 to 18.0 g/L; normal range <1.35 g/L). Extra-pulmonary and extra-pleural IgG4-related lesions were identified in 9 patients (43%), and developed simultaneously or asynchronously during follow up. All patients treated with steroids responded, but some radiologic abnormalities remained in 3 patients. Interestingly, 1 patient was found to have a primary adenocarcinoma against a background of IgG4-related lung disease during follow up. In conclusion, IgG4-related diseases show a greater variety of pulmonary and pleural lesions than previously thought. It is important, therefore, to know the morphologic variety and clinicopathologic characteristics of this disorder.
318 citations
TL;DR: It is revealed that retroperitoneal fibrosis could be classified as IgG4-related or not, and this distinction seems important to help better characterize the biology/pathogenesis of both groups and better predict the possibility of other IgG 4-related processes at other anatomic sites.
Abstract: The possible involvement of immunoglobulin G4 (IgG4) in the pathogenesis of idiopathic sclerosing lesions has been suggested. In this study, a clinicopathologic analysis was performed to reveal characteristics of retroperitoneal fibrosis relating to IgG4. The study involved 17 patients with retroperitoneal fibrosis. Immunohistochemistry revealed numerous IgG4-positive plasma cell infiltrates in 10 cases (IgG4-related), but only a few positive cells in 7 cases (non-IgG4-related). All patients with IgG4-related retroperitoneal fibrosis were male, whereas all except 1 with unrelated lesions were female. Histologically, eosinophilic infiltration (>5 cells per high-power field) and obliterative phlebitis were commonly observed in IgG4-related lesions. Serologically, serum IgG and IgG4 concentrations were significantly higher in the IgG4-related cases, with the IgG4 concentrations all over 135 mg/dL (the upper limit of the normal range). Steroid therapy was performed in 13 cases, and was effective irrespective of IgG4. Three patients had recurrence during the follow up. Five of 10 IgG4-related cases had sclerosing lesions at other sites. The only tests that reliably distinguish the 2 groups were serum IgG4 levels or IgG4/IgG ratio in the plasma cells in a tissue biopsy. The only major clinical difference was the striking male predominance in IgG4-related cases. In conclusion, this study revealed that retroperitoneal fibrosis could be classified as IgG4-related or not. This distinction seems important to help better characterize the biology/pathogenesis of both groups and better predict the possibility of other IgG4-related processes at other anatomic sites.
275 citations
TL;DR: Tumor budding is a strong, reproducible, and independent prognostic marker of outcome that is easily assessed on hematoxylin and eosin slides and may be useful for identifying the subset of T3N0M0 patients at high risk of recurrence who may benefit from adjuvant therapy.
Abstract: BackgroundTumor budding along the advancing front of colorectal adenocarcinoma is an early event in the metastatic process. A reproducible, prognostic budding scoring system based on outcomes in early stage colorectal cancer has not been established.DesignOne hundred twenty-eight T3N0M0 colorectal c
262 citations
TL;DR: This study demonstrates that DOG1.1 is a sensitive immunohistochemical marker for GIST, comparable with KIT, with the additional benefit of detecting 36% of KIT-negative GISTs.
Abstract: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the gastrointestinal tract. Approximately 85% of GISTs harbor activating mutations in the KIT or platelet-derived growth factor receptor alpha (PDGFRA) gene and approximately 95% of GISTs are positive for KIT (CD117) b
245 citations
TL;DR: It is found that neuroendocrine carcinomas of the skin arising in association with a squamous cell carcinoma seem to be independent of MCV, and CM2B4 is a useful reagent for the diagnosis of MCC.
Abstract: Merkel cell carcinoma (MCC) is the eponym for primary cutaneous neuroendocrine carcinoma. Recently, a new polyoma virus has been identified that is clonally integrated in the genome of the majority of MCCs, with truncating mutations in the viral large T antigen gene. We examined the presence of Merkel cell polyomavirus (MCV) in a set of 17 frozen tumor samples by quantitative polymerase chain reaction; 15 of them (88%) were positive. Sections from corresponding archival material were analyzed by immunohistochemistry (IHC) with the novel monoclonal antibody CM2B4, generated against a predicted antigenic epitope on the MCV T antigen, and tested for the expression of cytokeratin 20 (CK20). Sufficient archival material for IHC was available in only 15 of the 17 cases whose frozen tissue samples had been studied by polymerase chain reaction. Of the 15 tumors analyzed immunohistochemically, 10 (67%) showed positive labeling with CM2B4, 14 (93%) expressed CK20. A tissue microarray of 36 MCCs, 7 combined squamous and neuroendocrine carcinomas of the skin, and 26 pulmonary neuroendocrine carcinomas were also examined by IHC. Of the 36 MCCs assembled on a microarray, 32 (89%) tumors expressed CK20, and 27 (75%) were immunoreactive with CM2B4. The skin tumors with a combined squamous and neuroendocrine phenotype and all pulmonary neuroendocrine carcinomas failed to react with CM2B4. Our study shows that CM2B4 is a useful reagent for the diagnosis of MCC. It labels the majority of MCCs, but fails to react with pulmonary neuroendocrine carcinomas. We also found that neuroendocrine carcinomas of the skin arising in association with a squamous cell carcinoma seem to be independent of MCV.
237 citations
TL;DR: Pathologic stage is an important prognostic factor in urachal carcinoma, and surface urothelial involvement by carcinoma and presence of cystitis cystica/glandularis do not necessarily exclude the diagnosis of urachAL carcinoma.
Abstract: BackgroundUrachal carcinomas occur mostly in the bladder dome, comprising 22% to 35% of vesical adenocarcinomas, and are generally treated by partial cystectomy with en bloc resection of the median umbilical ligament and umbilicus. Detailed pathologic studies with clinical outcome correlation are fe
TL;DR: The authors' model shows that approximately 43% of CRCs have a MSI probability score of 1 or less and hence have little likelihood of being MSI-H, so its use could improve the efficiency of expensive diagnostic testing.
Abstract: Our model shows that approximately 43% of CRCs have a MSI probability score of 1 or less and hence have little likelihood (<3%) of being MSI-H. While this model is not perfect in predicting microsatellite instability, its use could improve the efficiency of expensive diagnostic testing.
TL;DR: It is demonstrated that dedifferentiation in SFT, comparable with that in other low grade/intermediate soft-tissue tumors, poses a higher risk of tumor recurrence and/or metastasis, most notably in large and deep-seated tumors.
Abstract: Dedifferentiation is a well recognized, if sometimes controversial, form of tumor progression in certain types of soft tissue and bone sarcoma, and confers a worse prognosis when compared with the low-grade counterpart. To date, dedifferentiation has not been described in solitary fibrous tumor (SFT). Among 948 cases of both intrathoracic and extrathoracic SFTs in our files accessioned between 1988 and 2008, we identified 8 cases of conventional SFT with a discrete anaplastic component, which we believe represents dedifferentiation. These occurred in 3 men and 5 women, 40 to 76 years old (median 60 y), and measured 3.4 to 20.0 cm (median 8.5 cm). Two cases were intrathoracic, 2 were located in the deep soft tissue of thigh, and single cases were located in the omentum, scalp, retroperitoneum, and abdominal wall. In addition to typical features of benign-appearing SFT there was an abrupt transition to nondistinctive high-grade sarcoma in all cases. The latter included epithelioid, round cell, and/or spindle cell components with increased mitotic activity, necrosis, and cystic degeneration. By immunohistochemistry, 7 of 8 cases were CD34 positive in the usual SFT areas, whereas 5 showed loss of CD34 in the poorly differentiated component. Six of 7 cases stained for p53 and p16 showed either negative or scattered positive cells in well-differentiated SFT areas, in contrast to positive or stronger and more diffuse staining in the high-grade component. Follow-up information available in 7 patients ranged from 1 to 58 months (mean 24 mo). Three patients with the largest tumors (9.0, 17.0, and 20.0 cm) died of disease, whereas 3 patients whose tumors measured 8.0 cm or less were treated by surgical excision only, and show no evidence of disease but with only limited follow-up. One patient with an 11.5 cm intrathoracic tumor is alive with disease at 58 months after recurrence and metastasis. We describe, apparently for the first time, what seems, at least in our view, to be dedifferentiation in primary SFT. Our results demonstrate that dedifferentiation in SFT, comparable with that in other low grade/intermediate soft-tissue tumors, poses a higher risk of tumor recurrence and/or metastasis, most notably in large and deep-seated tumors. Similar to other dedifferentiated sarcomas, abrupt transition between low grade and high-grade areas is typically observed with loss of CD34 positivity. The p53 and p16 overexpression in the high-grade component is common as in other dedifferentiated lesions, perhaps pertaining to the underlying molecular mechanism.
TL;DR: Comprehensive histologic assessment is a powerful tool that seems to be a promising way to determine whether multiple lung adenocarcinomas or squamous cell carcinomas are metastatic or multiple primaries, which has great clinical implications for staging and therapeutic management of lung cancer patients with multiple tumors.
Abstract: The pathologic classification of nonsmall cell lung cancer (NSCLC) is evolving. Lung adenocarcinoma is morphologically heterogeneous, with mixtures of acinar, papillary, bronchioloalveolar, and solid patterns in more than 80% of cases. In case of synchronous or metachronous multiple NSCLC, the distinction of intrapulmonary metastases from independent primary tumors is of great clinical importance as it influences staging and potentially the therapeutic strategy. Here we took advantage of a cohort of 20 patients with 42 multiple NSCLC tumors (24 potential pair comparisons) that were annotated molecularly using genomic and mutational profiling to evaluate the value of comprehensive histologic assessment in this setting. Using the Martini-Melamed criteria, paired tumors were characterized as multiple primary NSCLCs in 21 cases and as intrapulmonary metastases in 3 cases. Genomic and mutational data led to a diagnosis of multiple primaries in 14 cases and of metastases in 8 cases; 2 cases could not be assessed. This molecular characterization contradicted the Martini-Melamed diagnosis in 7 (32%) of the 22 assessable comparisons. Adenocarcinoma was found in 32 (76%) of the 42 tumors. After review in a blinded fashion, semiquantitative comprehensive histologic assessment of paired tumors was different in 16 and similar in 8 paired tumors. We found that comparing adenocarcinomas is a complex issue that requires assessment not only of percentages of the histologic subtypes, but also the recording of additional histologic details such as cytologic features, patterns of stroma, necrosis, discrete nodularity versus miliary growth and variants such as clear cell, signet ring, mucinous, and fetal patterns. We also found that paired squamous cell carcinomas could be compared based on histologic subtyping in addition to cytologic and stromal characteristics. Considering histologically different tumors as multiple primaries, and similar tumors as metastases, comprehensive histologic subtyping was consistent with the molecular characterization in 20 (91%) of the 22 pairs comparisons. In summary, based on a well characterized cohort with detailed clinical, pathologic and molecular data, we found comprehensive histologic assessment is a powerful tool that seems to be a promising way to determine whether multiple lung adenocarcinomas or squamous cell carcinomas are metastatic or multiple primaries. This has great clinical implications for staging and therapeutic management of lung cancer patients with multiple tumors. Given its high correlation with molecular characterization of such tumors, it may provide a much cheaper and faster method to address this problem.
TL;DR: Test and validate a set of antibodies that could aid in the diagnosis of CCC, using a series of cases from different centers in North America, and found a panel of 3 immunomarkers can serve as a diagnostic aid in problematic cases.
Abstract: The distinction of ovarian clear cell carcinomas (CCCs) from high-grade serous carcinomas (HG-SCs) is sometimes a diagnostic challenge. With the recognition that CCCs respond poorly to conventional chemotherapy there are efforts to initiate clinical trials for CCC, making accurate diagnosis critical. The purpose of this study was to test and validate a set of antibodies that could aid in the diagnosis of CCC, using a series of cases from different centers in North America. Using a test set of 133 CCCs, we identified the following markers: Cyclin E, estrogen receptor, hepatocyte nuclear factor (HNF)-1beta, Ki-67, p21, p53, and Wilms tumor (WT)1 that show significant discrimination from 200 HG-SCs. For validation, these markers were characterized on an independent set of 104 CCCs from 3 other centers. There were no significant differences in expression of these 7 markers between the independent test and validation sets of CCC. Combining all CCC cases (N=237), HNF-1beta showed the highest sensitivity (82.5%) and specificity (95.2%) for CCC, and WT1 for HG-SC (sensitivity: 79.9%, specificity: 97.4%). A diagnostic panel consisting of WT1, ER, and HNF-1beta demonstrated nearly identical performance as a panel using all 7 markers in distinguishing CCCs from HG-SCs, correctly classifying 84% of cases. Three percent of cases were misclassified and 13% carried an uninformative triple negative immunophenotype. CCCs show a distinct, reproducible immunophenotype, compared with HG-SCs, and a panel of 3 immunomarkers can serve as a diagnostic aid in problematic cases.
TL;DR: This study confirms the low reliability of the diagnosis and grading of central chondrosarcoma and proposes a classification model that, combined with a tailored radiologic assessment, may improve reliability ofThe diagnosis of cartilaginous tumors.
Abstract: The distinction between benign and malignant cartilaginous tumors of bone is one of the most difficult subjects in surgical pathology. The grading of chondrosarcoma also seems to vary considerably among pathologists. However, clinical management differs. The purpose of this study was (1) to investigate interobserver variability in histological diagnosis and grading of central cartilaginous tumors and (2) to assess the diagnostic value of defined histologic parameters in differentiating enchondroma and central grade I chondrosarcoma. The interobserver variability was assessed using a set of 16 cases evaluated by 18 specialized pathologists. Subsequently, 20 enchondromas and 37 central grade I chondrosarcomas diagnosed in a multidisciplinary team with full clinical, radiologic, and pathologic data available with 10 years of follow-up were collected. Cytologic and tissue-architectural features were assessed to find an optimal set of parameters to differentiate enchondroma from central grade I chondrosarcoma. We demonstrate considerable variation in the histologic assessment of cartilaginous tumors (weighted kappa=0.78). The distinction between enchondroma and grade I chondrosarcoma was shown to be the most disconcordant (kappa coefficient=0.54), and also the differentiation between grade I and grade II chondrosarcoma was subjected to variation (kappa coefficient=0.80). The application of a combination of 5 parameters (high cellularity, presence of host bone entrapment, open chromatin, mucoid matrix quality, and age above 45 y) allowed optimal differentiation between enchondromas and central grade I chondrosarcomas. With a classification tree based on 2 parameters (mucoid matrix degeneration more than 20% and/or host bone entrapment present), 54 of the 57 (94.7%) cases were assessed correctly (sensitivity 95% and specificity 95%). Our study confirms the low reliability of the diagnosis and grading of central chondrosarcoma. However, these classifications guide therapeutic decision making in daily practice. Therefore, we propose a classification model that, combined with a tailored radiologic assessment, may improve reliability of the diagnosis of cartilaginous tumors.
TL;DR: The expression of PD-1 and other TFH cell markers in CSTCLs are reported for the first time and suggest that B-cell stimulation by FTH could also take place in some cutaneous T-cell lymphomas.
Abstract: Cutaneous CD4 small/medium-sized pleomorphic T-cell lymphoma (CSTCL) is a cutaneous T-cell lymphoma defined by a predominance of small-to-medium-sized CD4 pleomorphic T cells, with a favorable clinical course. Cases are also characterized by the presence of a rich infiltrate of reactive B cells. Recently, it has been reported that follicular helper T cells (TFH cells) display a distinct gene expression profile, positive for PD-1, CXCL13, and BCL-6. We report for the first time the expression of PD-1 and other TFH cell markers in CSTCLs and discuss its biologic significance. Sixteen CSTCLs were included in this study, and also 20 reactive inflammatory conditions, 10 primary cutaneous marginal zone, 10 follicular center lymphomas, and 5 primary CD30 cutaneous lymphomas. They were immunohistochemically analyzed for a large panel of markers. Double immunoperoxidase labeling of paraffin sections was performed for PD-1, OCT-2, and BCL-6. Clonal Ig and T-cell receptor rearrangements and Epstein-Barr virus-encoded RNA expression were also evaluated. Morphologic and clinical data were reviewed. Histologic examination showed a dense polymorphic lymphoid infiltrate throughout the dermis. Atypical large CD4 cells were positive for PD-1, CXCL13, and BCL-6 in all cases, and were attached in small clusters, or formed rosettes around CD30/OCT-2+ B blast cells. Epstein-Barr virus was not apparent in any of the cases. A dominant T-cell clone was identified in 14 cases, whereas polymerase chain reaction IgH gene rearrangement studies showed that all cases were polyclonal. None of the patients had lymphadenopathy or showed any evidence of systemic disease, nor did they have any previous history of mycosis fungoides or drug reactions. FTH cell markers are not exclusive to angioimmunoblastic lymphadenopathy but may also be seen in neoplastic cells of CSTCLs. Moreover, these findings suggest that B-cell stimulation by FTH could also take place in some cutaneous T-cell lymphomas.
TL;DR: It is indicated that SALL4 is a novel sensitive and relatively specific marker for testicular GCTs and is a more sensitive marker than AFP and glypican-3 for YST.
Abstract: The diagnosis of testicular germ cell tumors (GCTs) sometimes can be challenging without ancillary markers. Here we performed an immunohistochemical study of a novel stem cell marker SALL4 in a large series of 110 primary testicular GCTs (65 pure and 45 mixed) containing the following types of tumors and/or tumor components: 50 intratubular germ cell neoplasias (ITGCNs), 62 classic seminomas, 2 spermatocytic seminomas, 39 embryonal carcinomas (EC), 5 pediatric and 26 postpubertal yolk sac tumors (YST), 7 pediatric and 25 postpubertal teratomas, and 5 choriocarcinomas. We compared SALL4 with OCT4 in all GCTs, and SALL4 to alpha-fetoprotein (AFP) and glypican-3 in all YSTs. To test SALL4 specificity, 23 testicular non-GCTs (10 Leydig cell tumors, 4 Sertoli cell tumors, 3 adenomatoid tumors, 3 paratesticular rhabdomyosarcomas, 2 diffuse large B-cell lymphomas, and 1 rete testis papillary cystadenoma) and 275 nontesticular tumors (158 metastatic carcinomas, 12 metastatic melanomas, 11 primary and 2 metastatic mesotheliomas, and 72 primary and 20 metastatic sarcomas) were also stained for SALL4. All ITGCNs, classic seminomas, and ECs demonstrated strong SALL4 and OCT4 staining in more than 90% tumor cells. All 31 YSTs (5 pediatric and 26 postpubertal) showed strong positive SALL4 staining in more than 90% tumor cells but had negative OCT4 staining. Both spermatocytic seminomas showed positive SALL4 staining in 80% to 95% tumor cells in all 3 types of tumor cells with weak-to-moderate staining intensity. Mononucleated trophoblastic cells were variably positive for SALL4 staining in all 5 choriocarcinomas. Focal SALL4 staining was seen in 4 of 7 pediatric and 23 of 27 postpubertal teratomas. OCT4 staining was not seen in any spermatocytic seminoma, choriocarcinoma, or teratoma. No SALL4 staining was seen in all 23 testicular non-GCTs. Of 275 nontesticular tumors, only 10 carcinomas and 1 sarcoma showed focal (<25% tumor cells) weak SALL4 staining. The only non-neoplastic cells within the testis stained with SALL4 were spermatogonia and few primary spermatocytes. AFP staining was seen in 29 of 31 YST but it was often focal and patchy. Although all 31 YSTs showed glypican-3 staining, 14 (45%) show staining in less than 30% tumor cells. Our findings indicate that SALL4 is a novel sensitive and relatively specific marker for testicular GCTs. SALL4 is a more sensitive marker than AFP and glypican-3 for YST.
TL;DR: Epithelioid component, epithelial cysts, and microscopic AML foci are strongly associated with TSC and the presence of all 3 features should raise strong suspicion for TSC.
Abstract: The majority of renal angiomyolipoma (AML) is sporadic and occasionally it occurs as part of tuberous sclerosis complex (TSC). Epithelioid AML (EAML), an uncommon variant, is considered potentially malignant based on anecdotal case reports. The prognostic significance of epithelioid component in an otherwise typical AML is uncertain. We studied 194 AMLs for the clinicopathologic features of epithelioid and TSC-associated AMLs. Epithelioid component was present in 15 cases (7.7%) with an average amount of 51% (range: 10% to 100%). Histologically, the epithelioid tumor cells were categorized into small, intermediate, and large cell type based on the cell size. Worrisome histologic features were seen in many EAMLs, including coagulative tumor necrosis in 27% (4/15), nuclear atypia in 93% (14/15), mitosis in 47% (7/15), and atypical mitosis in 1 case. All 15 EAML patients had a mean follow-up time of 5.1 years and none had local recurrence or distant metastasis. Sixteen (8.2%) AMLs occurred in patients with definitive TSC. Three histologic features, namely microscopic AML foci, epithelioid component, and epithelial cysts, were present in 10 (62.5%), 4 (25%), and 44% (7/16), respectively, of TSC-associated AMLs, compared with 11 (6.2%), 11 (6.2%), and 6 (3.4%), respectively, in non-TSC-associated AMLs (P value all <0.01). In summary, all 15 cases of EAMLs in our study had benign clinical outcomes despite adverse pathologic features. Epithelioid component, epithelial cysts, and microscopic AML foci are strongly associated with TSC and the presence of all 3 features should raise strong suspicion for TSC.
TL;DR: The results suggest that IgG4 does not play an important role in the pathogenesis of IMT, and the evaluation of IgG 4+ plasma cells and the ratio of Igg4+/IgG+ plasma Cells and the presence of obstructive phlebitis may be useful for the differential diagnosis between IMT and IgG3-related sclerosing disease.
Abstract: Inflammatory pseudotumor (IPT) is a heterogeneous group of lesions occurring in various organs, which is histologically characterized by fibroblastic and myofibroblastic proliferation with inflammatory infiltrate. Inflammatory myofibroblastic tumor (IMT) is a neoplastic counterpart of IPT, which shows aberrant expression of ALK and its gene translocation. In contrast, the concept "immunoglobulin (Ig)G4-related IPT" in the lung, liver, and pancreas has recently been proposed as a member of IgG4-related sclerosing disease. In this study, we compared the histopathologic features with an emphasis on IgG4 expression between 22 cases of IMT and 16 cases of IgG4-related sclerosing disease, including chronic sclerosing sialadenitis (n=8), mass-forming autoimmune pancreatitis (n=3), sclerosing cholangitis (n=1), retroperitoneal fibrosis (n=2), and chronic sclerosing dacryoadenitis (n=2). Bland-looking spindle cell proliferation with fibrosis and inflammatory infiltrate of lymphocytes and plasma cells was the common morphologic feature in both lesions. Obstructive phlebitis was observed in all of the IgG4-related sclerosing lesions, but in only 1/22 (4.5%) of IMT. The immunohistochemical expression of ALK was observed in 15/22 (68.2%) of IMT and 0/16 (0%) of IgG4-related sclerosing disease. The number of IgG4-positive plasma cells and the ratio of IgG4+/ IgG+ plasma cells were each significantly lower in IMT than in IgG4-related sclerosing disease [mean 6.4/HPF vs. 178.3/HPF (P<0.0001), 3.0% vs. 67.5% (P<0.0001), respectively]. The results suggest that IgG4 does not play an important role in the pathogenesis of IMT. In addition, the evaluation of IgG4+ plasma cells and the ratio of IgG4+/IgG+ plasma cells and the presence of obstructive phlebitis may be useful for the differential diagnosis between IMT and IgG4-related sclerosing disease.
TL;DR: In light of the distinctive clinicopathologic features and a low but definite metastatic potential, this unique subtype of renal cell carcinoma deserves formal recognition in the contemporary classification of renal neoplasms.
Abstract: A distinctive tumor described under the terms Bellini duct carcinoma and low-grade collecting duct carcinoma has been referred to by us and others as tubulocystic carcinoma. This renal cell carcinoma subtype is not recognized in the World Health Organization 2004 classification. Herein, we present a
TL;DR: Uterine tumors classified as STUMPs using criteria proposed by Stanford investigators are usually clinically benign but should be considered tumors of low malignant potential because they can occasionally recur, in some cases, years after hysterectomy.
Abstract: BackgroundThe current World Health Organization classification indicates that a uterine smooth muscle tumor that cannot be histologically diagnosed as unequivocally benign or malignant should be termed “smooth muscle tumor of uncertain malignant potential” (STUMP). STUMPs represent a heterogeneous g
TL;DR: Tumor morphology (TM- MMR) along with IHC-MMR enhances the detection of EC patients at risk of HNPCC, and hence H NPCC in EC.
Abstract: Women with hereditary nonpolyposis colorectal cancer (HNPCC) have a high risk for endometrial cancer (EC) and frequently present with a gynecologic cancer as their first or sentinel malignancy. Identification of these patients is important given their personal and family risk for synchronous and metachronous tumors. The revised Bethesda Guidelines provide screening criteria for HNPCC in colorectal cancers. However, there are currently no such screening recommendations for women with endometrial carcinoma. We applied some of the colorectal cancer screening criteria, including age and tumor morphology, to endometrial endometrioid carcinoma. The purpose of this study was to describe patient and tumor characteristics and to assess the ability of these criteria to enhance detection of mismatch repair (MMR) deficiency, and hence HNPCC in EC. Immunohistochemistry (IHC) for DNA mismatch repair (IHC-MMR) proteins was performed in a defined subset of patients with EC. This included women younger than 50 years of age and women >or=50 years whose tumors showed morphologic features suggestive of MMR deficiency (TM-MMR). The extent of IHC-MMR in the older patient group was compared with that in a comparison group of EC >or=50 years that was previously analyzed for microsatellite instability status. Seventy-one patients met the selection criteria for IHC testing; 32 (45%) showed abnormal results. The rate of IHC abnormality in the younger group was approximately 30% with a nearly equal distribution of MLH1/PMS2 and MSH2/MSH6 abnormalities. In the older age group, TM-MMR triggered IHC analysis in 31 of 34 cases. Of these, 18 cases showed loss of IHC-MMR (58% of cases), 7 with loss of MSH2/MSH6. In contrast, the rate of microsatellite instability in the comparison group was only 21%. The IHC abnormal group showed more frequent tumor infiltrating lymphocytes, dedifferentiated EC, more tumors centered in the lower uterine segment, and more frequent synchronous clear cell carcinomas of the ovary than tumors with a normal immunophenotype. Although many of the patients with loss of IHC-MMR showed personal and/or family history (13 of 32) of HNPCC-associated tumors, most did not. Tumor morphology (TM-MMR) along with IHC-MMR enhances the detection of EC patients at risk of HNPCC.
TL;DR: This rare form of PTCL-F has an immunophenotype indicative of derivation from TFH cells, is associated with t(5;9) in a proportion of cases, and shows some overlapping features with angioimmunoblastic T-cell lymphoma, raising the question of a possible relationship.
Abstract: Rare cases of peripheral T-cell lymphomas with follicular growth pattern (PTCL-F) have been recently reported, and their association with t(5;9)(q33;q22) involving ITK and SYK has been suggested. However, the clinicopathologic aspects of PTCL-F are poorly described and the normal cell counterpart of this subgroup of lymphoma is still unknown. Therefore, we analyzed the pathologic, phenotypic, and cytogenetic features of a series of 30 patients (range: 33 to 88 y) that showed histopathologic features of PTCL-F in at least 1 biopsy (n=30), either at initial presentation (n=26) or at relapse (n=4). Neoplastic cells were medium-sized clear cells that were CD4+ (24/27, 89%), CD10+ (21/29, 72%), BCL-6+ (14/19, 74%), and expressed programed death-1 (27/27, 100%), CXCL13 (23/27, 85%), and ICOS (11/11, 100%), markers of follicular helper T cells (TFH). Four of 22 patients (18%) had t(5;9)(q33;q22) detected by fluorescence in situ hybridization. Patients with clinical data available had multiple lymphadenopathies (25/28, 89%), stage III to IV diseases (17/26, 65%), B symptoms (7/27, 26%), and skin lesions (6/23, 26%). Three patients with sequential biopsies disclosed clinical and histopathologic features of angioimmunoblastic T-cell lymphoma at initial presentation. Our results show that this rare form of PTCL-F (1) has an immunophenotype indicative of derivation from TFH cells, (2) is associated with t(5;9) in a proportion of cases, and (3) shows some overlapping features with angioimmunoblastic T-cell lymphoma, raising the question of a possible relationship.
TL;DR: Appendiceal mucinous neoplasms can be stratified into 4 distinct risk groups on the basis of a careful histopathologic assessment of cytoarchitectural features and extent of disease at presentation.
Abstract: The classification and nomenclature of appendiceal mucinous neoplasms are controversial. To determine the outcome for patients with appendiceal mucinous neoplasms and further evaluate whether they can be stratified into groups that provide prognostic information, the clinicopathologic features of 116 patients (66 with clinical follow-up) with appendiceal mucinous neoplasms were studied. From a wide variety of histopathologic features assessed, the important predictors that emerged on univariate statistical analysis were presence of extra-appendiceal neoplastic epithelium (P=0.01), high-grade cytology (P<0.0001), architectural complexity (P<0.001), and invasion (P<0.001). Stratification using a combination of these predictors resulted in a 4-tiered classification scheme. All 16 patients with mucinous neoplasms confined to the appendix and lacking high-grade cytology, architectural complexity, and invasion were alive with no recurrences at median 59 months follow-up (=mucinous adenoma). One of 14 patients with low-grade cytology and acellular peritoneal mucin deposits developed recurrent tumor within the peritoneum at 45 months with no patient deaths to date (median, 48-mo follow-up) (=low-grade mucinous neoplasm with low risk of recurrence). None of the 2 patients with acellular peritoneal mucinous deposits outside of the right lower quadrant developed recurrence at 163 and 206 months. Twenty-seven patients with low-grade mucinous neoplasms with extra-appendiceal neoplastic epithelium had 1-year, 3-year, 5-year, and 10-year overall survival rates of 96%, 91%, 79%, and 46%, respectively, at median 53 months follow-up (=low-grade mucinous neoplasm with high risk of recurrence). Three of the 4 patients with extra-appendiceal epithelium limited to the right lower quadrant developed full-blown peritoneal disease at 6, 41, and 99 months follow-up and 1 patient eventually died of disease. Nine patients with appendiceal neoplasms with invasion or high-grade cytology and follow-up showed 1-year, 3-year, and 5-year overall survival rates of 86%, 57%, and 28% (=mucinous adenocarcinoma). At 10 years, all patients with mucinous adenocarcinoma were either dead or lost to follow-up. Appendiceal mucinous neoplasms can be stratified into 4 distinct risk groups on the basis of a careful histopathologic assessment of cytoarchitectural features and extent of disease at presentation.
TL;DR: It is concluded that conventional myxoid liposarcoma is by far the most common subtype of liposArcoma in young patients, with an excellent prognosis.
Abstract: Liposarcomas typically occur in middle aged to older adults. Altogether, approximately 50 bona fide liposarcomas have been reported in children and adolescents, most of which have represented myxoid liposarcomas, with a good prognosis. We undertook a retrospective study of 82 liposarcomas occurring in patients below 22 years of age. Clinicopathologic and follow-up information was obtained. Fluorescence in situ hybridization for FUS, EWSR1, CHOP (DDIT3), and MDM2 was performed in 30 cases. The tumors occurred in 28 males and 54 females (5 to 22 y of age) and involved many locations. Fifty-six cases were typical myxoid liposarcomas, including 2 with round cell areas. The tumors were grade 1 (56 cases) and grade 3 (2 cases). Thirty-seven of 38 patients with follow-up are alive without disease and 1 is alive with disease (median 59 mo follow-up duration, range: 8 to 108 mo). Six cases showed myxoid liposarcoma with spindled growth ("spindle cell myxoid liposarcoma"); these arose in 5 females and 1 male (median age 14 y) and involved the thigh in 40% of cases. All were grade 1. Follow-up (4 of 6 patients) showed local recurrences in 2 cases and metastases in 1 case. Twelve tumors consisted of conventional myxoid liposarcoma and pleomorphic liposarcoma ("pleomorphic myxoid liposarcoma"); these arose in 4 males and 8 females (10 to 22 y of age) and often involved the mediastinum. Tumor grades were 2 (4 cases) and 3 (8 cases). Follow-up (10 patients) showed 7 dead of disease, 1 alive with disease, and 2 disease free. Four atypical lipomatous tumors were seen including 2 with low-grade dedifferentiation. Two local recurrences were seen; all patients are disease free. Two conventional pleomorphic liposarcomas were seen; 1 patient with follow-up is disease free. FUS-CHOP and EWSR1-CHOP rearrangements were identified by fluorescence in situ hybridization in 15/23 and 2/23 conventional myxoid liposarcomas, respectively, and in no other tumors. Amplification for MDM2 was absent in all cases. We conclude that conventional myxoid liposarcoma is by far the most common subtype of liposarcoma in young patients, with an excellent prognosis. Two apparently novel subtypes of liposarcoma, termed pleomorphic myxoid liposarcoma and spindle cell myxoid liposarcoma comprise considerable percentages of liposarcomas in this age group and should be distinguished from conventional myxoid liposarcoma and conventional pleomorphic liposarcoma. Pleomorphic myxoid liposarcoma and spindle cell myxoid liposarcoma most likely represent high-grade and low-grade variants of myxoid liposarcoma, respectively. Additional study of such cases will be necessary for definitive classification.
TL;DR: ITPNs can be considered to represent a new disease entity encompassing intraductal tubular carcinoma as a morphologic variant as well as several features of acinar cell carcinoma, except for the tubulopapillary growth pattern.
Abstract: We have encountered cases of unusual intraductal pancreatic neoplasms with predominant tubulopapillary growth. We collected data on 10 similar cases of “intraductal tubulopapillary neoplasms (ITPNs)” and analyzed their clinicopathologic and molecular features. Tumor specimens were obtained from 5 me
TL;DR: Among lung adenocarcinomas, histologic assessment of invasive growth may provide valuable prognostic information, and tumors with invasion under 0.6 cm have a more indolent clinical course after resection.
Abstract: Current classification of pulmonary adenocarcinoma includes noninvasive bronchioloalveolar carcinoma, mixed subtype adenocarcinoma, and several patterns of invasive carcinoma. The extent of invasion in mixed subtype adenocarcinoma is variable, and prior studies suggest that estimates of extent of de
TL;DR: It is found that SALL4 is strongly positive in more than 90% tumor cells in all YSTs, dysgerminomas, gonadoblastomas, and embryonal carcinomas and better than AFP, glypican-3, CK7, and EMA.
Abstract: Ovarian primitive germ cell tumors (GCTs) are uncommon tumors and sometimes pose diagnostic challenges. Among them, yolk sac tumor (YST) poses the greatest diagnostic difficulty and can be mistaken for clear cell carcinoma (CCC). Current immunohistochemical markers such as alpha-fetoprotein (AFP), glypican-3, cytokeratin (CK) 7, and epithelial membrane antigen (EMA) used to distinguish YST from CCC lack adequate sensitivity and specificity. Here by immunohistochemistry, we investigated a novel marker SALL4 in 98 GCTs (29 YSTs, 18 dysgerminomas, 6 gonadoblastomas, 6 embryonal carcinomas, 15 immature and 12 mature teratomas, 7 carcinoid tumors, 3 strumal carcinoids, and 2 struma ovarii) with particular interest of exploring SALL4 to distinguish YST from CCC. One hundred sixty-three non-GCTs including 45 CCCs were also stained. We found that SALL4 is strongly positive in more than 90% tumor cells in all YSTs, dysgerminomas, gonadoblastomas, and embryonal carcinomas. Variable SALL4 staining is seen in 11 of 15 immature teratomas. All other GCTs included in this study are negative for SALL4. Except 3 CCCs with focal SALL4 staining (<15% tumor cells), SALL4 is negative in the remaining 160 non-GCTs. We also compared SALL4 with AFP, glypican-3, CK7, and EMA in all YSTs and CCCs. AFP and glypican-3 are positive in 24 (83%) and 20 (69%) YSTs, respectively, whereas 16 (35%) and 13(28%) CCCs show positive AFP and glypican-3 staining, respectively. Three (10%) and 4 (14%) YSTs show focal (<2% tumor cells) CK7 and EMA staining, respectively. CK7 and EMA are positive in all 45 CCCs but 3 (7%) and 1 (2%) cases show staining in less than 30% tumor cells, respectively. Our findings indicate that SALL4 is a novel sensitive and specific marker for ovarian primitive GCTs. SALL4 is particularly useful in distinguishing YST from CCC and better than AFP, glypican-3, CK7, and EMA.
TL;DR: Results indicate that early-onset carcinomas commonly show pathologic features associated with aggressive behavior and posttranslational regulation of mRNA and subsequent protein expression may be particularly important to the development of colorectal carcinomas in young patients.
Abstract: The incidence of colorectal carcinoma has increased among patients or =40 years of age served as controls. Cases were evaluated for clinical risk factors of malignancy and pathologic features predictive of outcome. The tumors were immunohistochemically stained for O6-methylguanine methyltransferase, MLH-1, MSH-2, MSH-6, beta-catenin, chemokine (C-X-C motif) receptor 4, epidermal growth factor receptor, TP53, p16, survivin, and alpha-methylacyl-CoA racemase; assessed for microsatellite instability and mutations in beta-catenin, APC, EGFR, PIK3CA, KRAS, and BRAF; evaluated for micro-RNA expression (miR-21, miR-20a, miR-183, miR-192, miR-145, miR-106a, miR-181b, and miR-203); and examined for evidence of human papillomavirus infection. One study patient each had ulcerative colitis and hereditary nonpolyposis colorectal cancer. Ninety-two percent of tumors from young patients occurred in the distal colon (P=0.006), particularly the rectum (58%, P=0.02), and 75% were stage III or IV. Tumors from young patients showed more frequent lymphovascular (81%, P=0.03) and/or venous (48%, P=0.003) invasion, an infiltrative growth pattern (81%, P=0.03), and alpha-methylacyl-CoA racemase expression (83%, P=0.02) compared with controls. Carcinomas in this group showed significantly increased expression of miR-21, miR-20a, miR-145, miR-181b, and miR-203 (P< or =0.005 for all comparisons with controls). These results indicate that early-onset carcinomas commonly show pathologic features associated with aggressive behavior. Posttranslational regulation of mRNA and subsequent protein expression may be particularly important to the development of colorectal carcinomas in young patients.