Unusual lipid poor spindle cell lipoma.

Spindle cell lipomas (SCLs) containing minimal fat are rare and can be diagnostically challenging due to their similar radiographic appearance to other benign and malignant tumours. SCLs are benign lipomatous tumours that typically occur in middle aged to elderly men as slow-growing, painless masses in the subcutaneous tissue of the posterior neck, shoulders or back. However, rarely these tumours can arise in unusual locations such as the lower extremities. We present an unusual case of a lipid poor SCL occurring in the lower extremity. Initial clinical and radiographic findings were suspicious for a malignancy. Two core biopsies demonstrated benign fibro collagenous tissue, so a marginal excision was performed. Final histopathological and immunohistochemical stains confirmed the diagnosis of an SCL. Radiologists, pathologists and oncologic surgeons should be aware of this lipomatous tumour's potential to present in unusual locations with minimal fatty components to increase confidence in radiologic-pathological concordance.

MYB Labeling by Immunohistochemistry Is More Sensitive and Specific for Breast Adenoid Cystic Carcinoma than MYB Labeling by FISH.

Breast adenoid cystic carcinoma (ACC) is a primary breast carcinoma that, like salivary gland ACC, displays the t(6;9) translocation resulting in the MYB-NFIB gene fusion and immunopositivity for MYB by immunohistochemistry (IHC). However, it is not well established whether MYB immunoreactivity or rearrangement can be used to support a diagnosis of ACC in a malignant basaloid or benign cribriform breast lesion. Whole sections of primary breast ACC (n=11), collagenous spherulosis (CS; n=7), and microglandular adenosis (MGA; n=5) and tissue microarrays containing 16 basal-like, triple-negative breast carcinomas (TNBC) were labeled for MYB by IHC and underwent MYB fluorescence in situ hybridization using a break-apart probe. Strong, diffuse nuclear MYB labeling was seen in 100% ACC compared with no cases of basal-like TNBC, CS, or MGA (P=0.0001). Any degree of nuclear MYB labeling was seen in 100% ACC compared with 54% of all other cases (P=0.007), with any labeling seen in 71% CS, 63% basal-like TNBC, and 0% MGA. MYB rearrangement was detected in 89% (8/9) of evaluable ACC compared with 4% (1/26) of all other evaluable cases (P=0.0001), with a rearrangement detected in 1 (7%; n=1/15) evaluable basal-like TNBC. Strong, diffuse nuclear labeling for MYB is more sensitive than MYB fluorescence in situ hybridization for breast ACC and can be used to support a diagnosis of ACC in a cribriform or basaloid lesion in the breast. However, weak and focal labeling should be interpreted with caution as it can be seen in other benign cribriform and malignant basaloid lesions.

Utility of uroplakin II expression as a marker of urothelial carcinoma.

Uroplakins are markers of terminally differentiated urothelium. Uroplakin II (UPII) is a newly described sensitive marker for urothelial carcinoma (UC). The expression profile of UPII in different types of UC and its utility in the diagnostic setting are needed. We evaluated UPII expression in bladder tissue microarrays, including urothelial neoplasm of low malignant potential (n = 8), low-grade papillary UC (n = 72), noninvasive high-grade papillary UC (n = 77), UC in situ (n = 27), and invasive high-grade UC (INVUC) (n = 122). UPII expression in 52 breast carcinomas and 38 high-grade prostate adenocarcinomas was also assessed. UPII expression was compared with GATA binding protein 3 (GATA3) and estrogen receptor for its role in facilitating the differential diagnosis of the above 3 types of malignancy. UPII labeling was seen in 83.0% of UC overall, including 95.7% of noninvasive UC and 65.6% of INVUC. UPII labeling was not found in any breast and prostate carcinomas. In comparison, GATA3 labeling was seen in 91.6% of all UCs, including 96.4% of noninvasive UCs and 85.1% of INVUC, with stronger intensity and extent compared with UPII (P < .005). GATA3 labeled 2 (5%) of 38 high-grade prostate adenocarcinoma. Estrogen receptor nuclear labeling was seen in 13.0% of UCs and 12.5% of prostate carcinomas. UPII was highly specific (100%) but only moderately sensitive for UC and can therefore be a potentially useful marker to identify urothelial lineage and help distinguish UC from prostate cancer or, in conjunction with GATA3, from metastatic breast cancer.

NKX3.1 is expressed in ER-positive and AR-positive primary breast carcinomas.

AIMS: NKX3.1 is an androgen-regulated tumour suppressor gene that is downregulated in prostate carcinoma. Immunohistochemistry for NKX3.1 is primarily specific for prostatic-derived tumours and tissue but is reported in a small number of breast carcinomas. NKX3.1 is also shown to inhibit estrogen receptor (ER) signalling in breast carcinoma models. Here, we investigate labelling of NKX3.1 in invasive ductal (IDC) and lobular (ILC) carcinomas of the breast with full characterisation of ER, progesterone receptor (PR), androgen receptor (AR) and Her2 status. METHODS: Tissue microarrays of 86 primary IDC and 37 ILC were labelled for NKX3.1. The IDC consisted of 20 luminal A, 7 luminal B, 14 Her2, and 45 triple negative carcinomas. The ILC consisted of 34 luminal A and 3 luminal B cases. NKX3.1 expression was scored as percentage nuclear labelling and labelling intensity. RESULTS: Nuclear NKX3.1 labelling was seen in 2 IDC (2%) and 10 ILCs (27%). labelling intensity was weak in all cases (1­100% nuclear positivity). Positive NKX3.1 labelling was significantly associated with ILC (p<0.0001). NKX3.1 labelling was seen only in ER and AR-positive carcinomas, which showed a significant correlation (p=0.0003 and p=0.0079, respectively). Expression was not correlated with tumour stage, size, Her2 expression, presence of lymph node metastases or age. CONCLUSIONS: This is the first study to evaluate NKX3.1 expression in breast carcinomas with known ER, PR, AR and Her2 status. Further studies are needed to evaluate what potential role NKX3.1 plays in ER and AR signalling and hormonal treatment response in breast carcinomas.

Clinical heterogeneity of Xp11 translocation renal cell carcinoma: impact of fusion subtype, age, and stage.

Xp11 translocation renal cell carcinomas harbor chromosome translocations involving the Xp11 breakpoint, resulting in gene fusions involving the TFE3 gene. The most common subtypes are the ASPSCR1-TFE3 renal cell carcinomas resulting from t(X;17)(p11;q25) translocation, and the PRCC-TFE3 renal cell carcinomas, resulting from t(X;1)(p11;q21) translocation. A formal clinical comparison of these two subtypes of Xp11 translocation renal cell carcinomas has not been performed. We report one new genetically confirmed Xp11 translocation renal cell carcinoma of each type. We also reviewed the literature for all published cases of ASPSCR1-TFE3 and PRCC-TFE3 renal cell carcinomas and contacted all corresponding authors to obtain or update the published follow-up information. Study of two new, unpublished cases, and review of the literature revealed that 8/8 patients who presented with distant metastasis had ASPSCR1-TFE3 renal cell carcinomas, and all but one of these patients either died of disease or had progressive disease. Regional lymph nodes were involved by metastasis in 24 of the 32 ASPSCR1-TFE3 cases in which nodes were resected, compared with 5 of 14 PRCC-TFE3 cases (P=0.02).; however, 11 of 13 evaluable patients with ASPSCR1-TFE3 renal cell carcinomas who presented with N1M0 disease remained disease free. Two PRCC-TFE3 renal cell carcinomas recurred late (at 20 and 30 years, respectively). In multivariate analysis, only older age or advanced stage at presentation (not fusion subtype) predicted death. In conclusion, ASPSCR1-TFE3 renal cell carcinomas are more likely to present at advanced stage (particularly node-positive disease) than are PRCC-TFE3 renal cell carcinomas. Although systemic metastases portend a grim prognosis, regional lymph node involvement does not, at least in short-term follow-up. The tendency for PRCC-TFE3 renal cell carcinomas to recur late warrants long-term follow-up.

GATA3 expression in breast carcinoma: utility in triple-negative, sarcomatoid, and metastatic carcinomas.

GATA3 plays an integral role in breast luminal cell differentiation and is implicated in breast cancer progression. GATA3 immunohistochemistry is a useful marker of breast cancer; however, its use in specific subtypes is unclear. Here, we evaluate GATA3 expression in 86 invasive ductal carcinomas including triple-negative, Her-2, and luminal subtypes, in addition to 13 metaplastic carcinomas and in 34 fibroepithelial neoplasms. In addition, we report GATA3 expression in matched primary and metastatic breast carcinomas in 30 patients with known estrogen receptor (ER), progesterone receptor (PR), and Her-2 status, including 5 with ER and/or PR loss from primary to metastasis. Tissue microarrays containing 5 to 10 cores per tumor were stained for GATA3, scored as follows: 0 (0-5%), 1+ (6%-25%), 2+ (26%-50%), 3+ (51%-75%), and 4+ (>75%). GATA3 labeling was seen in 67% (66/99) of primary ductal carcinomas including 43% of triple-negative and 54% of metaplastic carcinomas. In contrast, stromal GATA3 labeling was seen in only 1 fibroepithelial neoplasm. GATA3 labeling was seen in 90% (27/30) of primary breast carcinomas in the paired cohort, including 67% of triple-negative carcinomas. GATA3 labeling was overwhelmingly maintained in paired metastases. Notably, GATA3 was maintained in all "luminal loss" metastases, which showed ER and/or PR loss. In conclusion, GATA3 expression is maintained between matched primary and metastatic carcinomas including ER-negative cases. GATA3 can be particularly useful as a marker for metastatic breast carcinoma, especially triple-negative and metaplastic carcinomas, which lack specific markers of mammary origin. Finally, GATA3 labeling may help distinguish metaplastic carcinoma from malignant phyllodes tumors.

Lymphoproliferative disorders of the kidney on fine-needle aspiration: cytomorphology and radiographic correlates in 33 cases.

BACKGROUND: Unless renal lesions present in the setting of widespread lymphoma, biopsy can be indicated to differentiate from metastases, hypovascular renal cell carcinoma, urothelial carcinoma or infection. We review our experience with lymphoproliferative disorders in the kidney diagnosed by fine-needle aspiration (FNA), and focus on clinicopathologic and radiographic features. DESIGN: All cases of non-Hodgkin lymphoma diagnosed on renal FNA at 2 academic institutions between 1989 and 2011 were reviewed. Clinical history, radiographic and cytomorphologic features, and follow-up were assessed. RESULTS: 33 cases were identified, with 15 primary tumors and 18 recurrences/secondary tumors including 1 acute lymphoblastic lymphoma. The majority were aggressive/high-grade lesions (25/33). 25 cases were substantiated by positive flow cytometry results. Most were detected at follow-up/incidentally. 22 cases showed multiple renal and/or retroperitoneal masses or a significant component of adenopathy; others showed a solitary renal mass. Salient radiologic features included hypodense, infiltrative and ill-defined masses. Cytomorphology showed a monotonous population of large atypical lymphoid cells, often with lymphoglandular bodies. CONCLUSION: Cytologic diagnosis of renal lymphoma requires analysis of morphological, clinical and immunophenotypic information. Helpful features for diagnosis include: multiple masses on computed tomography, a monotonous population of abnormal cells in a background of lymphoglandular bodies and immunophenotyping demonstrating light chain restriction.

Neural crest transcription factor Sox10 is preferentially expressed in triple-negative and metaplastic breast carcinomas.

The transcription factor Sox10 mediates the differentiation of neural crest-derived cells, and Sox10 labeling by immunohistochemistry (IHC) is used clinically primarily to support the diagnosis of melanoma. Sox10 expression by IHC has been previously documented in benign breast myoepithelial cells but not in breast carcinomas. Here, we report the first systematic study of Sox10 expression in invasive ductal carcinomas subclassified by IHC-defined molecular subtype (100 cases), as well as in 24 cases of ductal carcinoma in situ and 44 mammary fibroepithelial neoplasms. Tissue microarrays containing 168 primary breast tumors were subjected to IHC for Sox10. The extent of nuclear Sox10 labeling was scored by percentage labeling as follows: 0 (0%), 1+ (1%-25%), 2+ (25%-50%), 3+ (50%-75%), and 4+ (>75%). Overall, 40 (40%) of 100 invasive breast carcinomas demonstrated Sox10 immunoreactivity, which was seen primarily in the basal-like, unclassified triple-negative, and metaplastic carcinomas. Sox10 labeling was seen in 66% (38/58) of the basal-like, unclassified triple-negative, and metaplastic carcinomas as compared with 5% (2/42) of the luminal A, luminal B, and Her-2 carcinomas (P < .00001). Sox10 labeling was seen in 1 (4%) of 24 cases of ductal carcinoma in situ, which was negative for estrogen receptor/progesterone receptor. No labeling was seen in the stromal component of phyllodes tumors or fibroadenomas. These findings show that breast carcinoma must be considered in the differential diagnosis of melanoma for an S100-positive, Sox10-positive metastatic malignant neoplasm. Sox10 expression in the basal-like, unclassified triple-negative, and metaplastic carcinomas types supports the concept that these neoplasms show myoepithelial differentiation.

Pleomorphic hyalinizing angiectatic tumor: imaging findings.

Pleomorphic hyalinizing angiectatic tumor (PHAT) is a rare soft tissue tumor of low malignant potential, which most often arises in the lower extremities. To the best of our knowledge, there have been no prior descriptions of the imaging features of this neoplasm. In this case series, we report the imaging findings in three patients. Two patients had a lower extremity subcutaneous PHAT, while the third patient had an intramuscular upper extremity PHAT. While imaging features are variable, a diagnosis of PHAT should be considered when encountering an enhancing, subcutaneous tumor with ill-defined margins, particularly in the extremity.

F-18 FDG PET/CT and Tc-99m sulfur colloid SPECT imaging in the diagnosis and treatment of a case of dual solitary fibrous tumors of the retroperitoneum and pancreas.

Although FDG PET is increasingly used for the staging of many types of sarcoma, little has been written regarding the FDG PET imaging characteristics of solitary fibrous tumor. We report a patient undergoing FDG PET/CT surveillance for squamous cell carcinoma of the tongue who was incidentally found to have two soft tissue masses in the retroperitoneum and pancreatic tail. Due to their low degree of FDG avidity, they were followed conservatively for approximately one year as they gradually increased in size. Technetium-99m sulfur colloid SPECT helped confirm that the pancreatic tail mass was not a splenule, after which both lesions were surgically resected and found to be extrathoracic solitary fibrous tumors without malignant features. These findings suggest that, as with other low-grade sarcomas, benign extrathoracic solitary fibrous tumors exhibit relatively little glycolytic metabolism in vivo.

Clear cell adenocarcinoma of the lower urinary tract: cytopathologic characteristics and differential diagnoses.

Clear cell adenocarcinomas (CCAs) of the lower urinary tract are uncommon neoplasms that may present in routinely processed urinary cytology specimens. There is only limited discussion of the features of CCA of the lower urinary tract in the cytology literature. The authors report a series of 3 cases of this unusual tumor, and correlate cytomorphology with histologic specimens. Two of the cases were diagnosed accurately as adenocarcinoma, and 1 case was diagnosed as atypical cells of undetermined significance. Cytomorphologic features included variably cellular samples with 3-dimensional fragments of malignant cells that had enlarged nuclei, prominent nucleoli, and occasional hobnail configurations. Some fragments showed luminal formation with collections of neutrophils. CCA must be included in the differential diagnosis of malignant cells in a urinary specimen, particularly if the features are not typical of urothelial carcinoma. Other diagnostic considerations include metastatic adenocarcinomas, nephrogenic adenomas, and benign glandular lesions involving the bladder and urinary tract such as mullerianosis.

Nodular lymphocyte-predominant Hodgkin lymphoma: cytopathologic correlates on fine-needle aspiration.

BACKGROUND: Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), a rare subtype of Hodgkin lymphoma, is an indolent tumor with frequent instances of disease recurrence but a favorable prognosis. To the best of the authors' knowledge, there are only limited descriptions of NLPHL in the cytology literature because it was only formally recognized as a distinct entity in 1994. METHODS: In the current study, all cases of NLPHL diagnosed on excisional biopsy (n = 6 cases) at the study institution between 2000 and 2011 that had undergone previous fine-needle aspiration (FNA) were reviewed, with a focus on cytomorphologic features. RESULTS: Four of 6 cases were termed benign on FNA; however, there was retrospective recognition of characteristic LP cells in all cases. Unlike classical Hodgkin lymphoma, the tumor cells of NLPHL were often found to be mononucleate and presented in a background of small lymphocytes. Other features identified included epithelioid histiocytes and numerous bare atypical nuclei. CONCLUSIONS: Cases of NLPHL are commonly misdiagnosed as benign reactive lymphoid tissue and therefore a careful search using high magnification for LP cells is recommended in the evaluation of lymph node FNAs.

The growth response to androgen receptor signaling in ERα-negative human breast cells is dependent on p21 and mediated by MAPK activation.

INTRODUCTION: Although a high frequency of androgen receptor (AR) expression in human breast cancers has been described, exploiting this knowledge for therapy has been challenging. This is in part because androgens can either inhibit or stimulate cell proliferation in pre-clinical models of breast cancer. In addition, many breast cancers co-express other steroid hormone receptors that can affect AR signaling, further obfuscating the effects of androgens on breast cancer cells. METHODS: To create better-defined models of AR signaling in human breast epithelial cells, we took estrogen receptor (ER)-α-negative and progesterone receptor (PR)-negative human breast epithelial cell lines, both cancerous and non-cancerous, and engineered them to express AR, thus allowing the unambiguous study of AR signaling. We cloned a full-length cDNA of human AR, and expressed this transgene in MCF-10A non-tumorigenic human breast epithelial cells and MDA-MB-231 human breast-cancer cells. We characterized the responses to AR ligand binding using various assays, and used isogenic MCF-10A p21 knock-out cell lines expressing AR to demonstrate the requirement for p21 in mediating the proliferative responses to AR signaling in human breast epithelial cells. RESULTS: We found that hyperactivation of the mitogen-activated protein kinase (MAPK) pathway from both AR and epidermal growth factor receptor (EGFR) signaling resulted in a growth-inhibitory response, whereas MAPK signaling from either AR or EGFR activation resulted in cellular proliferation. Additionally, p21 gene knock-out studies confirmed that AR signaling/activation of the MAPK pathway is dependent on p21. CONCLUSIONS: These studies present a new model for the analysis of AR signaling in human breast epithelial cells lacking ERα/PR expression, providing an experimental system without the potential confounding effects of ERα/PR crosstalk. Using this system, we provide a mechanistic explanation for previous observations ascribing a dual role for AR signaling in human breast cancer cells. As previous reports have shown that approximately 40% of breast cancers can lack p21 expression, our data also identify potential new caveats for exploiting AR as a target for breast cancer therapy.

Prevalence of the alternative lengthening of telomeres telomere maintenance mechanism in human cancer subtypes.

Approximately 10% to 15% of human cancers lack detectable telomerase activity, and a subset of these maintain telomere lengths by the telomerase-independent telomere maintenance mechanism termed alternative lengthening of telomeres (ALT). The ALT phenotype, relatively common in subtypes of sarcomas and astrocytomas, has rarely been reported in epithelial malignancies. However, the prevalence of ALT has not been thoroughly assessed across all cancer types. We therefore comprehensively surveyed the ALT phenotype in a broad range of human cancers. In total, two independent sets comprising 6110 primary tumors from 94 different cancer subtypes, 541 benign neoplasms, and 264 normal tissue samples were assessed by combined telomere-specific fluorescence in situ hybridization and immunofluorescence labeling for PML protein. Overall, ALT was observed in 3.73% (228/6110) of all tumor specimens, but was not observed in benign neoplasms or normal tissues. This is the first report of ALT in carcinomas arising from the bladder, cervix, endometrium, esophagus, gallbladder, kidney, liver, and lung. Additionally, this is the first report of ALT in medulloblastomas, oligodendrogliomas, meningiomas, schwannomas, and pediatric glioblastoma multiformes. Previous studies have shown associations between ALT status and prognosis in some tumor types; thus, further studies are warranted to assess the potential prognostic significance and unique biology of ALT-positive tumors. These findings may have therapeutic consequences, because ALT-positive cancers are predicted to be resistant to anti-telomerase therapies.

Relationship between molecular subtype of invasive breast carcinoma and expression of gross cystic disease fluid protein 15 and mammaglobin.

We investigated the expression of gross cystic disease fluid protein 15 (GCDFP) and mammaglobin (MGB) by immunohistochemical analysis in 71 invasive breast carcinomas (IBCs) subtyped into luminal (A and B), HER2, basal-like carcinoma (BLC), and unclassified triple-negative carcinoma (UTNC) by established surrogate immunohistochemical profiles. GCDFP and MGB were less likely to be expressed in BLC than in HER2 cancers (P = .000021 and P = .013, respectively) or luminal cancers (P = .00002 and P = .00008, respectively). However, the difference in GCDFP or MGB expression between HER2 and luminal cancers was not significant (P = 1.0 and P = .671, respectively). Our results suggest that luminal cancers demonstrate similar degrees of apocrine differentiation as HER2 cancers. Most BLCs and UTNCs are negative for MGB and GCDFP. Correlation with clinical findings may be needed to exclude the possibility of a metastasis to the breast when BLCs or UTNCs are encountered in a limited sample such as a core biopsy sample.

Shorter telomeres in luminal B, HER-2 and triple-negative breast cancer subtypes.

Telomeres are nucleoprotein structures that protect chromosome ends from degradation and recombination. Cancers often have critically shortened telomeres, contributing to genomic instability. Many of these tumors activate telomerase to stabilize telomeric ends and achieve a capacity for unlimited replication. Telomere shortening has been reported in in situ and invasive carcinomas, including breast, and has been associated with disease recurrence after surgical resection. However, previous studies have not evaluated breast cancer subtypes. The objective of this study was to evaluate telomere lengths in different subtypes of breast cancer. Breast carcinomas (n=103) identified between 2001 and 2010 from patients seen at the Johns Hopkins Hospital were categorized into luminal A (n=18), luminal B (n=28), HER-2-positive (n=20) and triple-negative carcinomas (n=37) based on tumor characteristics. Telomere lengths were assessed directly at the single cell level by fluorescence in situ hybridization, and patient groups were compared using Fisher's exact tests. ER-negative status (P=0.022), PR-negative status (P=0.008), HER-2-positive status (P=0.023) and p53-positive status (P=0.022) were associated with shorter telomere length. A larger proportion of luminal A cancers had normal or long telomere lengths as compared with luminal B cases (P=0.002), HER-2-positive cases (P=0.011) or triple-negative cases (P=0.0003). Luminal B, HER-2-positive and triple-negative cases did not differ significantly. Telomere length was shorter in more aggressive subtypes, such as luminal B, HER-2-positive and triple-negative tumors, suggesting that tumor telomere length may have utility as a prognostic and/or risk marker for breast cancer.

Incidental minimal atypical lobular hyperplasia on core needle biopsy: correlation with findings on follow-up excision.

INTRODUCTION: Atypical lobular hyperplasia (ALH), often an incidental finding in breast core biopsies, is largely considered to be a risk factor for carcinoma rather than a direct precursor. However, management of ALH is controversial. We review our experience with incidental minimal ALH on core biopsy, and correlate with excision and follow-up results. DESIGN: We evaluated all cases of ALH on core biopsy from 1999 to 2009 from our institution, focusing on cases with < or =3 foci of ALH (minimal), paired excision, and no other lesion on the core biopsy that by itself would require excision. Cases with discordant clinical/radiologic impressions, suggesting that a suspicious lesion had been missed on biopsy, were excluded. Therefore, the excisions were performed because of the diagnosis of ALH. RESULTS: Of 56 cases with ALH on biopsy and paired excision, 42 showed minimal ALH. On excision, 26 had residual ALH and 13 were benign. Three cases had other atypical lesions: lobular carcinoma in situ (2 cases) and mild atypical ductal hyperplasia separate from the biopsy site (1 case). On follow-up, only 1 patient developed subsequent ALH in the same breast. No other ipsilateral lesions were later diagnosed (mean follow-up 3.2 y). CONCLUSIONS: No case with ALH on biopsy had a lesion on excision requiring further treatment, suggesting that these patients can be managed more conservatively. Furthermore, no patients were diagnosed with a higher grade lesion in the same breast on follow-up. We propose that, if there is close radiologic correlation and follow-up, minimal incidental ALH on core biopsy (< or =3 foci) does not require excision.