A key barrier to identification of tissue biomarkers of clear cell renal cell carcinoma (ccRCC) is the heterogeneity of protein expression within tissue. However, by providing spectra for every 0.05 mm2 area of tissue, imaging mass spectrometry (IMS) reveals the spatial distribution of peptides. We sought to determine whether this approach could be used to identify and map protein signatures of ccRCC.
We constructed two tissue microarrays (TMA) with two cores each of matched tumor and normal tissue from nephrectomy specimens of 70 patients with ccRCC. Samples were analyzed by matrix-assisted laser desorption ionization (MALDI) time-of-flight mass spectrometry (MS). Peptide signatures were identified within each TMA that differentiated cancer from normal tissue and then cross-validated. MS/MS sequencing was performed to determine identities of select differentially expressed peptides, and immunohistochemistry was used for validation.
Peptide signatures were identified that demonstrated a classification accuracy within each TMA of 94.7–98.5% for each 0.05mm2 spot (spectrum) and 96.9–100% for each tissue core. Cross-validation across TMA's revealed classification accuracies of 82.6–84.7% for each spot and 88.9–92.4% for each core. We identified vimentin, histone 2A.X, and alpha-enolase as proteins with greater expression in cancer tissue, and validated this by immunohistochemistry.
IMS was able to identify and map specific peptides that accurately distinguished malignant from normal renal tissue, demonstrating its potential as a novel, high-throughput approach to ccRCC biomarker discovery. Given the multiple pathways and known heterogeneity involved in tumors such as ccRCC, multiple peptide signatures that maintain their spatial relationships may outperform traditional protein biomarkers.
MALDI; imaging mass spectrometry; renal cell carcinoma; biomarkers; proteomics
Clear cell carcinoma of the endometrium (CCC) is an uncommon histotype whose analyses have generally been hampered by its rarity and issues of interobserver diagnostic variability. In this study, we analyzed the clinicopathologic features of 50 CCCs that were assembled from multiple institutions and which we considered to be morphologically unambiguous after a rigorous review process for diagnostic accuracy. Forty-four (88%) of the 50 CCC cases showed an admixture of the classic architectural patterns (glandular, papillary, solid and cystic in decreasing order of prevalence). Mitotic indices were variable but were generally low: 60% of cases had a mitotic index of 3 or lower. The predominant cell type lining glands and papillae was invariably hobnail and/or cuboidal. Stratification of nuclei (greater than 3 cells) or columnar cells on glands and papillae were uncommon and never diffusely present. 82% of cases showed an admixture of polygonal cells with clear and eosinophilic cytoplasm; only clear cells were present in 4% and only eosinophilic cells were present in 10%. Hobnail cells were common, being identifiable in 86% of cases, and being diffuse in 60%. Only 2 cases had a predominance of nuclear grade 3 cells. Psammoma, hyaline and targetoid bodies were identified in 32%, 52% and 20% of cases respectively. Clear cell endometrial intraepithelial carcinoma was identified in 41.7% of cases with evaluable background endometrium. The 5-year progression free survival (PFS) for the entire cohort was 61%, and was 88%, 75%, 22% and 28.6% for stages I to IV respectively. On univariate analyses, age >65 years, advanced FIGO stage, and the presence of any lymph node metastases were associated with reduced PFS (p=0.02, 0.002, and 0.002 respectively). On multivariate analyses, the only variable associated with reduced PFS was age >65 years. The 5-year overall survival (OS) for the entire cohort was 78%, and was 94%, 87.5%, 66.7%, and 42.8% for stages I to IV respectively. On univariate analyses, the following factors were associated with reduced OS: age >65 years (p=0.04), advanced FIGO stage (p=0.003), distant metastases (p=0.003), myometrial invasion >30% (p=0.01), a mitotic index >4 (p=0.014), and a specific architectural pattern (at least 10% of the tumor composed of solid masses or individual infiltrating tumor cells, p=0.02). On multivariate analyses, only age >65 years and advanced stage were associated with reduced OS (p=0.023 and 0.022 respectively). In summary, endometrial CCC has a wide morphologic spectrum that is detailed and illustrated herein, but also has core cytoarchitectural features that are of high diagnostic utility. Morphologically unambiguous CCC apparently have patient outcomes that are more favorable than has previously been reported, indicating that ambiguous tumors should be classified separately. The existence of morphologically ambiguous clear-cell rich carcinomas that do not fit the conventional histotypic groupings, is a likely reflection of the biologic complexity of endometrial carcinomas in general; these cases should be reported descriptively, and studied separately from conventional CCC.
Clear cell carcinoma; endometrium; morphologic features
Dedifferentiation is a phenomenon that is well characterized in a variety of tumors and is defined by the occurrence of a high-grade or undifferentiated tumor, typically unrecognizable regarding its line of differentiation, from a low-grade/borderline neoplasm. This phenomenon has previously been described in 2 uterine leiomyosarcomas, but both were devoid of heterologous elements. The authors describe herein a case of a dedifferentiated leiomyosarcoma of the uterus with osteoid heterologous elements, believed to be the first such reported case. The original tumor was a high-grade leiomyosarcoma with large low-grade and leiomyoma-like areas and whose constituent cells displayed intense nuclear immunoreactivity for both estrogen receptor (ER) and progesterone receptor (PR) in approximately 30% of cells. The tumor recurred six months after its resection as an undifferentiated sarcoma that was negative for smooth muscle markers, but which remained positive for ER and PR. Osteoid production was only identified in the recurrent tumor and was significant in extent therein. This case highlights the immunophenotypic changes that may occur in dedifferentiated leiomyosarcomas, and this possibility should be a consideration when an apparently undifferentiated sarcoma is identified in a patient with a history of uterine leiomyosarcoma. In our case, the expression of ER and PR provided significant supportive evidence of the uterine origin of the recurrent tumor.
Recent morphologic and molecular genetic studies have led to a paradigm shift in our conceptualization of the carcinogenesis and histogenesis of pelvic (non-uterine) serous carcinomas. It appears that both low-grade and high-grade pelvic serous carcinomas that have traditionally been classified as ovarian in origin, actually originate, at least in a significant subset, from the distal fallopian tube. Clonal expansions of the tubal secretory cell probably give rise to serous carcinomas, and the degree of ciliated conversion is a function of the degree to which the genetic hits deregulate normal differentiation. In this article, the authors review the evidentiary basis for aforementioned paradigm shift, as well as its potential clinical implications.
Ovarian cancer; Fallopian tube; Carcinogenesis; Serous carcinoma; p53 signatures
SWI/SNF chromatin-modification complexes use the energy of ATP hydrolysis to remodel nucleosomes and to affect transcription and several cellular processes. Accordingly, their loss of function has been associated with malignant transformation. ARID1A (the expression of whose product, BAF250a, a key complex component, is lost when mutated) has recently been identified as a tumor suppressor gene that is mutated in 46-57% of ovarian clear cell carcinoma (CCC). The purposes of this study are to assess the frequency of loss of BAF250a expression in endometrial CCC and whether this loss has any discernable clinicopathologic implications. 34 endometrial carcinomas with a CCC component (including 22 pure CCC, 8 mixed carcinomas with a 10% CCC component, and 4 carcinosarcomas with a CCC epithelial component), were evaluated by immunohistochemistry using a monoclonal antibody directed against the human BAF250a protein. 5 (22.7%) of the 22 pure CCC were entirely BAF250a negative, whereas the remainder showed diffuse immunoreactivity. None of 4 carcinosarcomas and only 1 (12.5%) of the 8 mixed carcinomas were BAF250a negative. There was no discernable relationship between BAF250a immunoreactivity status and tumor architectural patterns (solid, papillary or tubulocystic areas) or cell type (flat, hobnail or polygonal). Of the 22 patients with pure CCC, 14, 2, 3, and 3 were International Federation of Gynecology and Obstetrics stages 1, II, III and IV respectively. Interestingly, all 5 BAF250a negative cases were late stage [stages III or IV] as compared with 1 of 17 BAF250a positive cases (p=0.0002). Thus, 83% (5/6) of all late stage cases were BAF250a [-], as compared with 0 (0%) of the 16 early stage (I or II) cases (p=.0002). BAF250a negative and positive cases did not show any statistically significant difference regarding patient age and frequency of lymphovascular invasion or myometrial invasion. As may be anticipated from the concentration of late stage cases in the BAF250a negative group, patient outcomes were worsened in that group on univariate analysis. In conclusion, we found in this pilot assessment that 22.7% of endometrial CCC displays complete loss of BAF250a expression. There was a disproportionate concentration of BAF250a negative cases in the late stage group, with the attendant possibility of an associated worsened prognosis for those CCC patients whose tumors are BAF250a negative. These preliminary findings suggest the need for larger analyses to evaluate the prognostic significance, if any, of the loss of BAF250a expression in this rare histotype of endometrial cancer.
BAF250a; ARID1A; endometrial cancer
Fallopian tube carcinoma (FTCA) is a very rare cancer type, but may be a useful platform for investigating high grade serous tumors of the pelvis that originate from a serous tubal intraepithelial carcinoma (STIC) precursor. Metastatic tumors from a patient diagnosed with Stage IIIC high grade serous FTCA (P0) were transplanted via intraperitoneal (IP) injection into a small cohort of mice (passage, P1). Patient information was obtained from the medical record. Tumors were grown, harvested and re-implanted or archived through P3. The P3 cohort was treated with saline (n=8) or cisplatin, 5 mg/kg (n=8), weekly for 4 weeks. After sacrifice, tumors from each passage and treatment group were passaged further, frozen or paraffin embedded. The patient underwent optimal cytoreductive surgery for Stage IIIC high grade serous FTCA in the presence of a STIC. The FTCA, areas of STIC and normal appearing FT stained positive for p53, PAX8, pH2AX and mib-1. The patient remained in remission 9 months after platinum-based chemotherapy. IP tumor propagation was readily achieved up to P3 in the mice. Similar to the patient, orthotopic tumors were identified along peritoneal and mesenteric surfaces. Tumor histopathological and molecular features were confirmed and maintained through P3. The P3 cisplatin-treated mice had fewer tumor implants, higher levels of pH2AX and lower levels of mib-1 expression compared to controls. This orthotopic model of platinum sensitive high grade serous FTCA is a viable platform to study the biology and treatment of FTCA and other STIC-related pelvic serous carcinomas.
Fallopian tube carcinoma; pelvic serous carcinoma; STIC; orthotopic model
Low and high-grade ductal carcinoma in-situ (DCIS) are known to be highly disparate by a multitude of parameters, including progression potential, immunophenotype, gene expression profile and DNA ploidy. In this study, we analyzed a group of intermediate and high-grade DCIS cases to determine how well the core biopsy predicts the maximal pathology in the associated excisions, and to determine if there are any core biopsy morphologic features that may predict a close (≤ 0.2 cm) or positive margin in the subsequent excision. Forty-nine consecutive paired specimens [core biopsies with a maximal diagnosis of DCIS, and their corresponding excisions, which included 20 and 29 specimens from mastectomies and breast conserving surgeries respectively] were evaluated in detail. In 5 (10%) of 49 cases, no residual carcinoma was found in the excision. In another 4 cases, the changes were diagnostic only of atypical ductal hyperplasia. There were 4 and 3 respective cases of invasive and microinvasive carcinoma out of the 49 excision specimens, for an overall invasion frequency of 14%. In 28 cases where a sentinel lymph node evaluation was performed, only 1 was found to be positive. Among the 40 cases with at least residual DCIS in the excision, there were 5 cases in which comedo-pattern DCIS was present in the excision but not in the core biopsy, attributed to the lower maximal nuclear grade in the biopsy proliferation in 4 cases and the absence of central necrosis in the 5th. For the other main histologic patterns, in 8 (20%) of 40 cases, there were more patterns identified in the core biopsy than in the corresponding excision. For the other 32 cases, 100%, 66%, 50%, 33% and 25% of the number of histologic patterns in the excisions were captured in 35%, 5%, 17.5%, 15% and 7.5% of the preceding core biopsies respectively. Therefore, the core biopsy reflected at least half of the non-comedo histologic patterns in 77.5% of cases. In 6(15%) of the 40 cases, the maximum nuclear grade of the excision (grade 3) was higher than that seen in the core biopsy (grade 2). Overall, however, the maximum nuclear grade in the excision was significantly predicted by maximum nuclear grade in the core biopsy (p = 0.028), with a Phi of 0.347, indicating a moderately strong association. At a size threshold of 2.7 cm, there was no significant association between lesional size and core biopsy features. Furthermore, the clear margin width of the cases with lesional size ≤ 2.7 cm (mean 0.69 cm) was not significantly different (p = 0.4) from the cases with lesional size > 2.7 cm (mean 0.56 cm). Finally, among a variety of core biopsy features that were evaluated, including maximum nuclear grade, necrosis, cancerization of lobules, number of tissue cores with DCIS, number of DCIS ducts per tissue core, total DCIS ducts, or comedo-pattern, only necrosis was significantly associated with a positive or close (≤ 0.2 cm) margin on multivariate analysis (Phi of 0.350). It is concluded that a significant change [to invasive disease (14%) or to no residual disease (10%)] is seen in approximately 24% of excisions that follow a core biopsy diagnosis of intermediate or high-grade DCIS. Core biopsy features are of limited value in predicting a close or positive margin in these lesions.
Endometrial serous carcinomas (ESC) constitute only approximately 10% of endometrial cancers, but have a substantially higher case-fatality rate than their more common endometrioid counterparts. The precise composite of factors driving endometrial serous carcinogenesis and progression remain largely unknown, but we attempt to review the current state of knowledge in this report. ESC probably do not evolve through a single pathway, and their underlying molecular events probably occur early in their evolution. TP53 gene mutations occur in 22.7 to 96% of cases, and p53 protein overexpression is seen in approximately 76%. By gene expression profiling, p16 is upregulated in ESC significantly above both normal endometrial cells and endometrioid carcinomas, and 92–100% of cases display diffuse expression of the p16 protein by immunohistochemistry (IHC). Together, these findings suggest dysregulation of both the p16INKA/Cyclin D-CDK/pRb-E2F and the ARF-MDM2-p53 cell cycle pathways in ESC. By IHC, HER2/neu is overexpressed (2+ or 3+) in approximately 32.1% of ESC, and approximately 54.5% of cases scored as 2+ or 3+ by IHC display c-erbB2 gene amplification as assessed by fluorescent in situ hybridization. Genetic instability, typically manifested as loss of heterozygosity in multiple chromosomes, is a common feature of ESC, and one study found loss of heterozygosity at 1p32-33 in 63% of cases. A subset of ESC display protein expression patterns that are characteristic of high grade endometrial carcinomas, including loss of the metastasis suppressor CD82 (KAI-1) and epithelial-to-mesenchymal transformation, the latter manifested as E-cadherin downregulation, P-cadherin upregulation, and expression of epithelial-to-mesenchymal transformation-related molecules such as zinc-finger E-box-binding homeobox 1 (ZEB1) and focal adhesion kinase. Preliminary data suggests differential patterns of expression in ESC of some isoforms of claudins, proteases, the tumor invasiveness and progression-associated oncofetal protein insulin-like growth factor II mRNA-binding protein 3 (IMP3), as well as a variety of other molecules. At the morphologic level, evidence that indicates that endometrial glandular dysplasia (EmGD) is the most likely morphologically recognizable precursor lesion to ESC is presented. We advocate use of the term endometrial intraepithelial carcinoma (EIC, or its other appellations) only as a morphologic descriptor and never as a diagnostic/pathologic statement of biologic potential. Given its potential for extrauterine extension, we consider the lesions described as EIC, when present in isolation, as examples of localized ESC, and patients should be managed as such. Morphologically normal, p53 immunoreactive endometrial cells (the so-called “p53 signatures”), show a statistically significant association with ESC, display p53 mutations in a significant subset, and form the start of a progression model, outlined herein, from p53 signatures to EmGD to localized ESC to the more conventionally invasive neoplasm. The identification of a morphologically-recognizable precursor holds the promise of early detection of ESC, with the attendant reduction in its overall associated mortality rate. Deciphering the molecular basis for endometrial serous carcinogenesis should uncover potential targets for diagnosis, therapy, and/or disease surveillance.
Endometrial serous carcinoma; endometrial glandular dysplasia; endometrial intraepithelial carcinoma; p53; cadherins; claudins; CDKs; MDM2 and HER2/neu (erb-B2)
A variety of novel endometrial ablation technologies are now in routine use. A subset of uteri that had previously undergone these treatments will ultimately be evaluated by the pathologist. However, the full spectrum of histologic changes that may result from these treatments has received only sporadic attention. The NovaSure™ [Hologic Corporation, Marlborough, MA, USA] endometrial ablation system is one of several available second-generation technologies and its particular endometrial ablative power is based on the delivery of radiofrequency energy. The present analysis was designed to decipher any histologic changes (if any) associated with the NovaSure™ endometrial ablation system relative to benign smooth muscle tumors of the uterine corpus. Over a one-year period, 3 uteri that had previously undergone the NovaSure™ endometrial ablation and which also had leiomyomatous mass lesions were evaluated. The leiomyomatous mass lesions were extensively sampled and were evaluated for cellular shapes (epithelioid change, cellular rounding, extraordinary cytoplasmic eosinophilia, clear cell change, cytoplasmic vacuolation), nuclear changes (nucleomegaly, nucleolomegaly, multinucleation, hyperchromasia, symplastic changes), necrosis (coagulative and/or infarct), mitotic activity, apoptotic bodies or pyknotic cells, myxoid change, hyalinization. The three uteri were resected 61, 47 and 74 (mean 60.7) days post-ablation. After a detailed evaluation of multiple submucosal, intramural and subserosal leiomyomata from these 3 uteri, no noteworthy histologic changes were identified in the tumors. Since the presence or absence of tumor necrosis is one histologic criterion by which malignant potential is assigned to uterine smooth muscle neoplasms, defining any extrinsic processes that may establish, or contribute to this finding is clinically relevant. The findings reported herein suggests that if a leiomyoma that was obtained from a patient that had recently undergone the NovaSure™ endometrial ablation displays any degenerative changes such as necrosis, the changes are probably not attributable to the ablation.
Lymphoepithelioma-like carcinoma (LELC) of the urinary bladder is often mixed with conventional transitional cell carcinoma and/or other histotypes. The pathologist’s determination of the morphologic purity of a given LELC at the biopsy stage is a clinically relevant endeavour, because there is some anecdotal evidence suggesting that pure or predominant LELC may be comparatively chemosensitive and have a favorable prognostic profile, which may potentially offer the possibility of effective therapy without bladder resection. The precise degree of cellular pleomorphism that is allowed in a pure LELC is unclear. We describe herein an otherwise conventional and pure LELC that showed, in a localized area that constituted approximately 25% of the overall tumor volume, a two to six fold variation in nuclear size, including multinucleated tumor cells. These pleomorphic areas were set in the same lymphoplasmacytic infiltrate as their conventional counterparts, and similarly displayed cellular syncytia. We performed a detailed immunophenotypic comparison between the conventional areas and the pleomorphic areas. No significant differences were found between the 2 areas in overall lymphoplasmacytic or histiocytic density, lymphocytic CD4/CD8 ratio, and lymphoplasmacytic kappa/lambda ratio. Similarly, both displayed similar qualitative and quantitative staining indices for p53, Ki67, cytokeratin AE1/AE3 and p16INKa. Scattered cells were cytoplasmically beta-catenin positive exclusively in the pleomorphic areas; however these cells were not notably larger than the cells in the conventional areas. Both components were immunohistochemically negative for HMB-45, CD1a, the estrogen receptor, Epstein-Barr virus, CD117, D2-40, CD56, cytokeratin 20 and chromogranin. Clinicopathologic analysis of a series of cases is required to establish if there is any significance to nuclear pleomorphism in LELC. However, the phenotypic similarity between the 2 areas in this case, the intimate admixture of the pleomorphic cells with the lymphoplasmacytic infiltrate, and their syncytial pattern of growth, all suggest that pure LELC may display marked nuclear pleomorphism, and that this finding may not, in of itself, be a valid basis for removing a case from the “pure” group.
Bladder; lymphoepithelioma; lymphoepithelioma-like
Mucocele-like tumor was originally described in 1986 as a benign breast proliferation consisting of multiple dilated cysts lined by cytologically bland, flat to cuboidal cells. Subsequent reports described the coexistence of, including the morphologic inter-transitions between, mucocele-like tumor and a variety of other breast proliferations, including intraductal carcinoma, invasive carcinoma, atypical ductal hyperplasia, and hyperplasia of the usual type. The spectrum of breast alterations characterized by variably enlarged terminal-ductal lobular units lined by variably hyperplastic and variably atypical columnar cells has been the subject of significant discussion in the recent literature. In one scheme, these lesions may be classified into four groups, that is, columnar cell change with and without atypia and columnar cell hyperplasia with and without atypia. Morphologic and molecular observations suggest an association, perhaps in a nonobligate precursor role, between some columnar cell lesions and a variety of other neoplastic lesions.
We describe the case of a 43-year-old woman whose breast tumor contained areas diagnostic of mucocele-like tumor and columnar cell hyperplasia, with morphologic transitions in between.
Our case represents the second broadly similar case that has been reported, and suggests a potential relationship between these two enigmatic lesions.
The pathologic distinction of atypical fibroxanthomas (AFXs) from cutaneous spindle cell/sarcomatoid squamous cell carcinomas (SCSCCs) may occasionally pose a significant diagnostic challenge, given the substantial clinicopathologic overlap between these lesions. Recent studies indicate that p63 and CD10 are expressed in significant proportions of SCSCC and AFX, respectively. The purpose of this study is to investigate the utility of CD10 and p63 in distinguishing cutaneous SCSCCs and AFXs. The immunohistochemical expression of p63, CD10, cytokeratin AE-1/3, cytokeratin 5/6 and a cytokeratin cocktail (Kermix) was evaluated in an archived group of 23 AFXs and 10 SCSCCs. CD10 was positive in 18/23 AFXs (78%), with most demonstrating strong and/or diffuse staining. Three of 23 AFXs (13%), all negative for cytokeratins, showed focal and weak nuclear staining for p63. Two of 23 AFXs (9%) demonstrated very focal or weak staining for only one cytokeratin; in both cases, p63 and CD10 were negative. One AFX was negative with all immunostains. CD10 was positive in 6/10 SCSCCs (60%), with half demonstrating strong and/or diffuse staining. P63 was positive in 9/10 SCSCCs (90%), with most demonstrating strong and diffuse staining. One SCSCC was negative for p63, but positive with two cytokeratin immunostains. In conclusion, the expression of any of the cytokeratins evaluated herein significantly distinguished AFX from SCSCC. CD10 used in isolation, however, was not useful in making this distinction (positive in 18/23 AFXs versus 6/10 SCSCCs, p=0.4). The addition of CD10 to a panel that includes p63 did not provide any additional information to that obtained from the latter alone. Overall, the most effective combination to distinguish AFX from SCSCC was p63 and cytokeratin AE-1/3. Positivity for both p63 and cytokeratin AE-1/3 was seen in 9/10 SCSCCs (90%) and was not observed in any of the 23 AFXs (p<0.0001). The usefulness of CD10 in this differential diagnosis is limited.
Atypical fibroxanthoma; p63; CD10; skin; sarcomatoid/spindle cell squamous cell carcinoma
In recent years, a group of tumors that have been designated "perivascular epithelioid cell tumors" (PEComa) have been reported with increasing frequency from a wide variety of anatomic locations. The uterus and retroperitoneum appear to be the most frequent sites of origin for these lesions. PEComas belong to an identically named family of tumors comprised of conventional angiomyolipomas, clear cell sugar tumors, lymphangiomyomatosis and clear cell myomelanocytic tumor of the falciform ligament/ligament teres, and are also known as PEComa-NOS. This article is a primer for clinicians on the most salient clinicopathologic features of uterine PEComas, as most of the debate and discussion have taken place in the pathologic literature. The author appraises in detail the current state of knowledge on PEComas of the uterus based on a review of published data on the 44 previously reported cases, and comments on areas of controversy. The latter are centered predominantly on the significant morphologic and immunophenotypic overlap that exists between uterine PEComa and some smooth muscle tumors of the uterus. The clinicopathologic features of cases reported as epithelioid smooth muscle tumors and cases reported as uterine PEComas are compared and contrasted, and a practical approach to their reporting is proposed.
In this article, the authors briefly review the historical evolution of the various putative precursor lesions for Type II endometrial cancers, with an emphasis on the newly defined "Endometrial Glandular Dysplasia (EmGD)". The evidentiary basis for delineating serous EmGD as the most probable precursor lesions to endometrial serous carcinoma is reviewed in detail. An argument is advanced for the discontinuation of the term serous "endometrial intraepithelial carcinoma (EIC)" as a descriptor for a supposedly intraepithelial, precancerous lesion. Preliminary evidence is also presented that suggests that there is a morphologically recognizable "clear cell EmGD" that probably represents a precancerous lesion to endometrial clear cell carcinomas.
The authors report herein two diagnostically challenging cases centered on the myeloid/natural killer (myeloid/NK) cells, a variant of myeloblasts, to illustrate the importance of advanced flow cytometric immunophenotyping and an updated understanding of surface markers in hematopoietic malignancies. Myeloid/NK cell acute leukemia is a very rare subtype of leukemia. Although its NK-cell nature is debatable, it represents a variant of leukemia with distinct morphological and immunophenotypical features. The first case is a de novo myeloid/NK-cell acute leukemia with a striking clinical, morphologic and immunophenotypic resemblance to acute promyelocytic leukemia (APL), but which could be distinguished by its CD11a, CD18, CD117 and CD9 expression. This case illustrates the importance of utilizing the APL surrogate surface phenotype of HLA-DRlow, CD11alow and CD18low by flow cytometric study to rule in/out APL immunophenotypically. In the second case, we show that myeloid/NK-cell blasts can present as a variant of blasts in a preleukemic disease as refractory anemia with excess blasts-1 (RAEB-1), where the blasts were negative for CD34, CD117 and HLA-DR. The recognition of such blast variant is important in appropriately classifying such preleukemic diseases by blast percentage.
Acute leukemia; flow cytometric immunophenotyping; myeloblast; natural killer cell
Dedifferentiated liposarcomas may display a variety of “heterologous” lines of differentiation, including osseous, vascular, skeletal, and/or smooth muscular. There have been six previously reported examples of leiomyosarcomas associated with high levels of serum human chorionic gonadotropin (hCG) production, comprised of cases originating from the retroperitoneum, spermatic cord, small intestine, and uterus. This report describes the first example of a dedifferentiated liposarcoma that combined both of the aforementioned features: extensive heterologous (leiomyosarcomatous) differentiation and
β-hCG production (maximum serum levels 1046 mIU/ml, reference <5 mIU/ml). The tumor, which originated in the retroperitoneum in the region of the right kidney, was rapidly progressive and ultimately fatal within three months of its diagnosis. In addition to characteristic morphologic features, lipogenic and smooth muscle differentiation were confirmed with immunohistochemical stains for MDM2 and smooth muscle actin, respectively. The tumor also displayed diffuse immunoreactivity for β-hCG in both primary and metastatic sites. This case further expands the clinicopathologic spectrum of lipogenic tumors.
Studies evaluating the routine Papanicolaou (Pap) test have traditionally used as the reference gold standard, the diagnoses on the follow-up histologic samples. Since the latter are typically obtained days to weeks after the Pap test, the accuracy of the resultant comparison may be affected by interim factors, such as regression of human papillomavirus, new lesion acquisitions or colposcopy-associated variability. A subset of our clinicians have routinely obtained cervical cytology samples immediately prior to their colposcopic procedures, which presented a unique opportunity to re-evaluate the test performance of liquid-based cervical cytology in detecting the most clinically significant lesions (i.e. cervical intraepithelial neoplasia 2 or worse: CIN2+), using as gold standard, diagnoses on cervical biopsies that were essentially obtained simultaneously. For each patient, cytohistologic non-correlation between the Pap test and biopsy was considered to be present when either modality displayed a high-grade squamous intraepithelial lesion (HGSIL)/CIN2+ while the other displayed a less severe lesion. Therefore, HGSIL/CIN2+ was present in both the Pap test and biopsy in true positives, and absent in both modalities in true negatives. In false positives, the Pap test showed HGSIL while the biopsy showed less than a CIN2+. In false negatives, Pap tests displaying less than a HGSIL were associated with biopsies displaying CIN2+. Combinations associated with “atypical” interpretations were excluded. A cytohistologic non-correlation was present in 17 (4.8%) of the 356 combinations reviewed. The non-correlation was attributed, by virtue of having the less severe interpretation, to the Pap test in all 17 cases. There were 17, 322, 0, and 17 true positives, true negatives, false positives and false negatives respectively. The sensitivity, specificity, positive predictive value and negative predictive value of the Pap test, at a diagnostic threshold of HGSIL, in identifying a CIN2+ lesion were 50%, 100%, 100% and 95% respectively. Even in Pap test/biopsy combinations obtained on the same day by the same colposcopist and evaluated by the same pathologist, there is a 4.8% (17/356) false negative rate associated with the Pap test. Our findings suggest that there may be an intrinsic error rate associated with this test modality.
Cytohistologic correlation; Pap test; accuracy; sensitivity; specificity; performance; colposcopy
The current investigation was conducted to evaluate the proportional distribution of the various histologic subtypes (including newly recognized variants) of male breast carcinomas, to determine whether any histologic subtypes occur with a frequency that is markedly discordant with the expected frequencies from published data on parallel female breast tumors. We also aimed to document the distribution of malignancies metastatic to the breast. Seven hundred fifty-nine archived cases of primary invasive carcinoma involving the male breast were retrieved and subcategorized into histologic subtypes according to contemporary criteria. Six hundred forty-three (84.7%) tumors were pure infiltrating ductal carcinoma (IDC) not otherwise specified. The most common of the remainder included papillary carcinoma with invasion in the form of IDC (n = 34), mixed IDC and mucinous carcinoma (n = 26), and pure mucinous carcinoma (n = 21). In 19 cases, metastases from other sites involved the breast, most commonly (58%) cutaneous melanoma. Invasive carcinoma of the male breast appears to display a morphologic spectrum and distribution of histologic subtypes that is comparable to those of the female breast, with some expected variation. Compared with published experience on their female counterparts, there is a two-fold increase in the frequency of invasive papillary carcinoma in the male breast. Finally, the most common tumor metastatic to the male breast in this series was cutaneous melanoma.
Male; Breast; Carcinoma; Papillary; Cancer
Sarcomas constitute less than 1% of all cervical malignancies. With over 150 reported cases, rhabdomyosarcomas represent the most commonly reported sarcoma at this location. In this report, a select group of the more uncommon sarcomas of the uterine cervix are reviewed, including all previously reported examples of leiomyosarcoma, liposarcoma, alveolar soft part sarcoma, Ewing sarcoma/primitive neuroectodermal tumor, undifferentiated endocervical sarcoma, and malignant peripheral nerve sheath tumor (MPNST). Emphasis is placed on any distinctive clinicopathologic features of these entities at this unusual location.
The epithelial proliferations that are designated adenoid basal carcinoma (ABC) in the current classification from the World Health Organization represent <1% of all cervical malignancies. These lesions may be associated, and occasionally show morphologic transitions with, conventional cervical malignancies. The determination of the precise frequency with which these so-called ABCs show this association is hampered by the inherent selection bias in the reported cases. However, this frequency appears to be substantial (>15%). The biologic course of ABCs that are associated with separate malignancies is largely dependent on the clinicopathologic parameters of the associated malignancies. Morphologically pure lesions, in contrast, have largely been associated with favorable patient outcomes, as none of the 66 reported patients have experienced tumor recurrence, metastases or tumor-associated death, irrespective of the modality of treatment. Although the finding of genome integrated high-risk human papillomavirus (HPV) types and p53 alterations in adenoid basal lesions (ABL) argue in support of their neoplastic nature, we identified no lines evidence that suggest an inherent malignancy for morphologically pure lesions. The finding of morphologic transitions between ABLs and conventional malignancies and shared HPV types in these areas, suggest that ABLs have some malignant potential. However, the precise magnitude of this potential is not readily quantifiable and should not dictate the management of morphologically pure lesions that are entirely evaluable. ABLs continue to occupy a unique position in human oncology in which the term carcinoma (without an in-situ suffix) is applied to a tumor that has not been shown to recur, metastasize or cause death. We concur with a previous proposal that the term ABC should be discarded and replaced with Adenoid Basal Epithelioma (ABE). In our opinion, there is insufficient evidence at present time to expose patients with morphologically pure lesions to the ominous implications – social, psychological, medical, financial – of a "carcinoma" diagnosis. Morphologically impure lesions should not be designated ABC or ABE. Furthermore, given the uncertainties regarding the frequency with which ABE are associated with separate malignancies, we suggest that the ABE designation only be applied when the tumor in question is entirely evaluable e.g in a hysterectomy specimen or in an excisional biopsy with negative margins. Otherwise, the generic designation Adenoid Basal Tumor is preferable. This approach strikes an appropriate balance between the need to prevent over-treatment of pure lesions on one hand, and the need to ensure that the lesions are indeed pure on the other.
Non-mass forming, neoplastic intraepithelial proliferations (dysplasia) represent the most well-accepted precursor lesions to gallbladder adenocarcinomas. They are typically small, localized, grossly unrecognizable lesions that have been identified in the epithelium adjacent to up to 79% of gallbladder adenocarcinomas. Morphologic variants that have been reported include flat, micropapillary, papillary and cribriform. We have recently encountered a morphologically distinctive, previously unreported lesion to which we have applied the designation eosinophilic dysplasia. This lesion was identified in a gallbladder with diffuse mural fibrosis and calcification (porcelain gallbladder). The dysplastic focus was confined to one tissue section, and was comprised of a localized true papilla [i.e with a fibrovascular core], measuring approximately 1.2 mm in greatest dimension and an adjacent, flat, 7-cell epithelial segment. These foci were lined by cells displaying significant nuclear enlargement [1.5–4 times the adjacent benign cells], nuclear pleomorphism, occasional multinucleation, hyperchromasia and nuclear membrane irregularities. Nucleoli were present but inconspicuous. These cells also showed voluminous eosinophilic to granular cytoplasm, such that the overall nuclear-to-cytoplasmic ratio was generally not increased. The cells displayed diffuse and marked nuclear immunoreactivity for p53, and approximately 70% of the cells showed nuclear positivity for Ki-67. The cells were also positive for cytokeratin 7 and were entirely negative for carcinoembryonic antigen (CEA) and chromogranin A. The cells of the adjacent normal epithelium were positive for cytokeratin 7 and CEA, negative for p53 and chromogranin A and showed a Ki-67 labeling index of <10%. Marked overexpression of the p53 protein as well as its high proliferative index are strong arguments in favor of the dysplastic nature of this lesion. However, further studies are required to elucidate its true clinical significance and to determine whether or not its association with a porcelain gallbladder, as noted herein, is entirely fortuitous. However, such studies can only be performed with an increased recognition by practitioners of this distinctive variant.
Ichthyosis uteri is an exceedingly rare condition in which the entire surface of the endometrium is replaced by stratified squamous epithelium. Originally described as an endometrial response to iatrogenically-introduced caustic substances, similar changes have since been described in association with a variety of inflammatory conditions of the endometrium. We describe herein a heretofore undescribed example of a moderately differentiated squamous cell carcinoma of the uterine cervix associated with extensive ichthyosis uteri-like changes of the entire adjacent endometrium. Additionally, the squamous epithelium of the latter also showed multifocal changes diagnostic of a low-grade squamous intraepithelial lesion. The potential genesis of this composite of findings is discussed, as is the neoplastic potential of ichthyosis uteri. It is concluded that a squamous cell carcinoma of the cervix extended proximally into the endometrium, and that there was a colonization of a pre-existing ichthyosis uteri by associated human papillomavirus. The possibility of significant cervical pathology should be considered when plaques of squamous epithelium with low grade dysplastic changes are identified in an endometrial biopsy or curettage.