Purpose: A comprehensive comparison of biomarker expression between patients' primary breast carcinoma (PBC) and their metastatic breast carcinomas (MBC) has not been done. Experimental Design: We did rapid autopsies (postmortem intervals,1-4 hours) on10 consenting patients who died of MBC.We constructed single-patient tissue microarrays from the patients' archived PBC and multiple different MBCs harvested at autopsy, which were immunohistochemically labeled for multiple biomarkers. Methylation of multiple gene promoters was assessed quantitatively on dissected PBC and MBC samples. Results: Extensive heterogeneity was observed between PBC and their paired MBC, as well as among multiple MBC from the same patient. Estrogen and progesterone receptors tended to be uniformly down-regulated in metastases. E-cadherin was down-regulated in a subset of the MBC of one case.Variable overexpression in MBC compared with the PBC was observed for cyclooxygenase-2 (five cases), epidermal growth factor receptor (EGFR; four cases), MET (four cases), and mesothelin (four cases). No case strongly overexpressed HER-2/neu by immunohistochemistry, but eight cases showed variable protein expression ranging from negative to equivocal (2+) in different MBC. In one case, variable low-level HER-2/neu gene amplification was found. EGFR and METoverexpression were restricted to the four basal-type cancers. EGFR protein overexpression did not correlate with EGFR gene amplification. Multigene promoter hypermethylation of RASSF1a, HIN1, cyclin D2,Twist, estrogen receptor a, APC1, and RARb was overall very similar in the PBC and all MBCs in all cases. Conclusions: Therapeutic targets identified in the PBC or even some MBC may not reflect targets present in all metastatic sites.
We obtained 22 sessile serrated adenomas (SSAs) and 19 hyperplastic polyps (HPs) and performed immunolabeling for cytokeratins (CKs) 7 and 20, CDX2, beta-catenin, and p53 to determine the role of these markers in aiding distinction of lesions with neoplastic potential. Patients with SSAs more frequently had a prior or coexistent tubular adenoma (P = .004) that was right-sided (P = .00001) and larger (P = .03). No difference in CK7, CK20, or p53 labeling was found after correction for colonic location. However, CDX2 labeling was significantly lower in SSAs (P = .02) and was predominantly confined to the crypt bases, whereas it was diffusely positive in HPs (P < .001). Surprisingly, aberrant nuclear labeling for beta-catenin was found in 9 (41%) of the SSAs but in none of the HPs (P < .002). We propose that beta-catenin and/or CDX2 immunolabeling may have diagnostic usefulness in the evaluation of serrated polyps. These findings also suggest that Wnt signaling has a role in SSA development.
The BRAF mutation is uniformly distributed in various types of nevi. Its presence in congenital and anogenital nevi points to mechanisms of induction other than sun exposure. Its ubiquitous presence suggests that it poses no significant threat of malignant transformation, raising doubts about its relevance in melanoma development and its suitability as a target of directed therapy in patients with melanoma.
We report a case of a patient with invasive breast carcinoma which demonstrated HER-2 gene amplification on core biopsy, who relapsed while on adjuvant Trastuzumab therapy following her mastectomy and ultimately died 15 months after diagnosis. Surprisingly, analysis of multiple metastases harvested at rapid autopsy demonstrated no evidence of HER-2 gene amplification. Retrospective examination of the carcinoma in the patient’s mastectomy specimen revealed only focal HER-2 amplification within the tumor, localized to the region of the prior core biopsy site. This case highlights several important issues in HER-2 testing of breast cancer, including core biopsy-excision specimen discordance, primary-metastasis discordance, and potential selection for unamplified portions of a heterogeneously-amplified tumors by Trastuzumab.
Background Cutaneous B‐cell lymphoproliferative lesions can pose diagnostic challenges. This study investigates the utlility of flow cytometry in 42 cases of suspected cutaneous B‐cell lymphoma. Methods All available cases were reviewed [World Health Organization‐European Organization for Research and Treatment of Cancer (WHO‐EORTC) classification]. Flow cytometry, immunohistochemistry and polymerase chain reaction‐immunoglobulin H (PCR‐IgH) analysis of blood and/or lesional skin were performed on primary cutaneous B‐cell lymphoma (pcBCL, 17 cases), secondary cutaneous BCL (scBCL, 8 cases) and atypical lymphoid hyperplasia (ALH, 17 cases). Results Flow cytometry of skin detected a B‐cell clone in 3/13 cases of ALH, 8/8 cases of pcBCL and 4/4 cases of scBCL, while PCR detected a clone in 3/14 cases of ALH, 4/15 cases of pcBCL and 6/8 cases of scBCL. Of eight cases of pcBCL analyzed by both methods, all eight were positive by flow while only three were positive by PCR. All cases positive by PCR were also positive by flow. Of five cases with both flow and light chain immunohistochemistry, all five showed light chain restriction by flow, while only two were positive by immunohistochemistry. Conclusion Flow cytometry is more sensitive than PCR in detecting B‐cell lymphoproliferative disorders (12/12 cases, 100% vs. 10/23 cases, 43%; p < 0.001). Furthermore, flow cytometry complements immunohistochemistry in the detection of light chain restriction.
Graft-versus-host disease is the leading cause of non-relapse mortality after allogeneic bone marrow transplantation. The cell-mediated immune mechanisms that underlie the pathogenesis of graft-versus-host disease remain unclear. In this study, 47 skin biopsies representing graft-versus-host disease grades 0–III, lichenoid, and sclerodermoid were included from 31 allogeneic bone marrow transplantation recipients. RNA from paraffin-embedded tissue was harvested. Transcript levels of the following markers were assessed and correlated with grade and survival: CD3, CD20, FoxP3, IL-17, γ-interferon (IFN-γ), transforming growth factor-β (TGF-β), IL-6, connective tissue growth factor (CTGF), allograft inflammatory factor-1(AIF-1), and IL-13. Levels of three markers significantly correlated with the length of survival (TGF-β, correlation coefficient −20.8, P = 0.016; AIF-1, 13.2, P = 0.016; and CD20, 66, P = 0.027). CD20 expression was limited to lichenoid cases. Levels of TGF-β, AIF-1, and IFN-γ appeared to correlate with histological progression, but did not reach statistical significance. Expression of FoxP3 correlated with worse survival, and approached statistical significance (P = 0.053). Two potential mechanistic pathways were identified: the ‘scleroderma’ group (AIF-1 and TGF-β) and the ‘B-cell’ group (CD20). Transcript levels of these markers were implicated in the progression from acute to chronic disease, and also correlated significantly with the duration of survival. Identification of these three markers may direct therapy selection with targeted agents, including the use of rituximab when B-lymphocytes are implicated.
Distant metastasis from differentiated thyroid carcinoma needs to be considered in the differential diagnosis of destructive skull base lesions, regardless of the patient's age. Histopathologic tissue diagnosis should always be attempted, followed by total thyroidectomy, radioiodine, or external beam radiation, and chronic thyroid-stimulating hormone suppression. Surgical resection of the metastatic lesion should only be performed in carefully selected cases because it is associated with significant morbidity.
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