Cindy Mak

Programmed death ligand 1 expression in triple-negative breast cancer is associated with tumour-infiltrating lymphocytes and improved outcome.

Triple‐negative breast cancer (TNBC) patients generally have a poor outcome; there is a pressing need to identify more effective therapeutic strategies. Clinical trials targeting programmed death 1/programmed death ligand 1 (PD1/PDL1) in melanoma and non‐small‐cell lung cancer have reported high response rates, and tumoral PDL1 expression has been suggested as a potential biomarker to enrich for patient response to these treatments. There are only very limited data to date reporting the expression of PDL1 in TNBC.

Recent insights into the molecular pathogenesis of mammary phyllodes tumours

Phyllodes tumours (PTs) of the breast are true biphasic neoplasms within which interactions between the epithelium and stroma are critical for tumour development and progression. Despite numerous studies reporting the results of ancillary marker investigations in PTs, the current histological grading systems remain unreliable at predicting clinical outcome even when supplemented by these markers. As a consequence, there has been much interest in the prospect of using molecular/genetic techniques to develop a more robust “grading” system. This review focuses on recent cytogenetic and molecular studies investigating the pathogenesis of PTs and those correlating molecular findings with clinicopathological features of the tumours. Recent data highlight that intratumoural genetic heterogeneity is common in PTs and may account for the reported lack of correlation between histological grading and clinical behaviour. The entire spectrum of molecular aberrations in PTs are yet to be fully defined, however recent array-based studies using comparative genomic hybridisation have reported that copy number changes increase with the progression from benign PT to malignancy. Tumour recurrence and progression is likely to reflect the presence of under-recognised subclones. p16INK4a (CDKN2A) inactivation also appears to be important in PT pathogenesis. Further additional studies will be required to identify and validate new prognostic markers and therapeutic targets in order to improve the diagnosis, classification, prediction of outcome and management of patients with this rare neoplasm. Data generated from modern sequencing technologies are likely to provide new insights into the disease and assist in this endeavour.

Preservation or division of the intercostobrachial nerve in axillary dissection for breast cancer: Meta-analysis of Randomised Controlled Trials

PURPOSE Management of the ICBN during axillary dissection is controversial and the division of ICBN is often trivialised. The effect of dividing the ICBN, and its association with sensory disturbance, is unclear. A systematic review and meta-analysis was performed to evaluate the effect of preserving the ICBN during axillary dissection. METHODS A systematic literature review and meta-analysis is performed according to the PRISMA and Cochrane Collaboration guidelines. RESULTS Three RCTs and four non-RCTs were reviewed. A meta-analysis demonstrated that the incidence of sensory disturbance was significantly lower with preservation of ICBN compared to division of the ICBN with Mantel-Haenzel combined odds ratio 0.31 (0.17-0.57, 95% CI). There was relatively low level of heterogeneity (I(2) = 19%, χ(2) = 2.48, df = 2). The sensory disturbance was more likely to be hyposensitivity when compared to hypersensitivity (p < 0.0001). No difference on number of lymph nodes dissected or operating time was noted. CONCLUSION This meta-analysis demonstrates that division of the ICBN is associated with higher risk of sensory disturbance, and that the nature of this sensory disturbance is more likely to be hyposensitivity, attributable to reduced nerve function.

MicroRNA-related DNA repair/cell-cycle genes independently associated with relapse after radiation therapy for early breast cancer

PURPOSE Local recurrence and distant failure after adjuvant radiation therapy for breast cancer remain significant clinical problems, incompletely predicted by conventional clinicopathologic markers. We had previously identified microRNA-139-5p and microRNA-1274a as key regulators of breast cancer radiation response in vitro. The purpose of this study was to investigate standard clinicopathologic markers of local recurrence in a contemporary series and to establish whether putative target genes of microRNAs involved in DNA repair and cell cycle control could better predict radiation therapy response in vivo. METHODS AND MATERIALS With institutional ethics board approval, local recurrence was measured in a contemporary, prospectively collected series of 458 patients treated with radiation therapy after breast-conserving surgery. Additionally, independent publicly available mRNA/microRNA microarray expression datasets totaling >1000 early-stage breast cancer patients, treated with adjuvant radiation therapy, with >10 years of follow-up, were analyzed. The expression of putative microRNA target biomarkers--TOP2A, POLQ, RAD54L, SKP2, PLK2, and RAG1--were correlated with standard clinicopathologic variables using 2-sided nonparametric tests, and to local/distant relapse and survival using Kaplan-Meier and Cox regression analysis. RESULTS We found a low rate of isolated local recurrence (1.95%) in our modern series, and that few clinicopathologic variables (such as lymphovascular invasion) were significantly predictive. In multiple independent datasets (n>1000), however, high expression of RAD54L, TOP2A, POLQ, and SKP2 significantly correlated with local recurrence, survival, or both in univariate and multivariate analyses (P<.001). Low RAG1 expression significantly correlated with local recurrence (multivariate, P=.008). Additionally, RAD54L, SKP2, and PLK2 may be predictive, being prognostic in radiation therapy-treated patients but not in untreated matched control individuals (n=107; P<.05). CONCLUSIONS Biomarkers of DNA repair and cell cycle control can identify patients at high risk of treatment failure in those receiving radiation therapy for early breast cancer in independent cohorts. These should be further investigated prospectively, especially TOP2A and SKP2, for which targeted therapies are available.

A case report of invasive ductal carcinoma of the breast with prominent sebaceous differentiation.

Background Sebaceous carcinoma of the breast is a rare entity, with only nine examples reported previously (WHO, 2012). Sebaceous carcinoma is defined as a breast carcinoma with prominent sebaceous differentiation in no less than 50% of cells (WHO, 2012). Limited data is available regarding the significance of sebaceous differentiation. Aim To present a case of diagnostic interest. Method and results We present a case of a 77-year-old woman with a self-detected left breast mass. After an initial core biopsy she underwent a mastectomy with sentinel lymph node biopsy. His-topathology confirmed an ER-positive/PR-positive/Her2-equiv-ocal invasive ductal carcinoma, with prominent sebaceous differentiation, and negative sentinel nodes. Discussion The amount of sebaceous differentiation falls just short of the greater than 50% required for diagnosis of sebaceous carcinoma. The differential diagnosis includes carcinoma with apocrine differentiation, lipid-rich carcinoma, and liposarcoma. A review of the available literature highlights the scarcity of knowledge of this rare entity. Very little is understood about the clinical course and prognosis of sebaceous carcinoma, and follow up data is limited. There is an association in the cases reported, with high grade tumours and high mitotic counts, and the predominant type of breast cancer associated is ductal. The two cases that have reported metastasis have been late in onset, and have occurred in sites which are not common for breast malignancies (scalp and skin). The significance of sebaceous differentiation is difficult to establish, and further research is warranted.

Positive anterior margins in breast conserving surgery: Does it matter?: A systematic review of the literature

Positive margins are associated with an increased risk of ipsilateral breast tumor recurrence (IBTR); therefore re-excision of positive margins is recommended. Involvement of anatomically non-breast margins, such as anterior margins, has been associated to a lower risk of IBTR than radial margins. Although many surgeons do not re-excise positive anterior margins (PAM); there is no consensus regarding this approach. The objective of this study is to find evidence that assesses this practice. A systemic literature review was performed through six databases from January 1995 to July 2014. Studies that discussed anatomical location of involved margins in BCS were included. Six studies were identified evaluating PAM. One study reported a 2.5% rate of IBTR in patients with non-negative margins treated with radiotherapy (of which 23% had a PAM). Another study showed 4% of residual disease after re-excision of PAM, but did not report IBTR rates. A later observational study reported that 87.5% of positive anterior and posterior margins were re-excised. One survey from America and one from the UK showed that 47% and 71% of surgeons would not re-excise PAM, respectively. A later survey in the UK reported that 43.8% of surgeons would not re-excise PAM in DCIS, whilst 29.2% would not for invasive carcinoma. Common surgical practices to not re-excise PAM contradict current guidelines that recommend obtaining negative margins to reduce the risk of IBTR. However, there is little evidence detailing the relationship between PAM and IBTR rates. Low residual disease after re-excision of PAM supports the limited benefit of re-excise this margin; however further studies are required to evaluate this topic.

Tattoo Pigment–Induced Granulomatous Lymphadenopathy Mimicking Lymphoma

Background: Decorative tattooing is associated with acute complications, such as pain, infection, and hypersensitivity. Delayed reactions also occur, including regional lymphadenopathy that may masquerade as malignant disease (13). Objective: To describe a case of tattoo pigmentinduced lymphadenopathy that mimicked the clinical and radiologic features of lymphoma. Case Report: A 30-year-old woman presented to our clinic reporting a 2-week history of bilateral axillary lumps noted on self-examination. She had no fever, night sweats, weight loss, or pulmonary symptoms. She had a history of cluster headaches and had had breast augmentation surgery at age 19 years. Her only medication was an oral contraceptive pill. She was a nonsmoker with no relevant family history. On examination, numerous rubbery nontethered nodes up to 1.5 cm in diameter were felt in both axillae, with no other palpable lymphadenopathy. Her chest was clear to auscultation, and no hepatosplenomegaly was present. A large black-ink tattoo that had been present for 15 years covered her back. Another black-ink tattoo on her left shoulder was 2.5 years old. Blood tests included a complete blood count and serum tests of electrolytes, renal and liver function, autoimmune antibodies, protein electrophoresis, C-reactive protein, and angiotensin-converting enzyme. All results were within normal ranges. Her erythrocyte sedimentation rate was mildly elevated at 18 mm/h. She had no risk factors for tuberculosis, and the results of the interferon-release assay were negative. Her chest radiograph showed no abnormalities. Positron emission tomographycomputed tomography (PET-CT) revealed multiple enlarged lymph nodes in the axillary, hilar, and mediastinal areas, with a peak standardized uptake value of 17.7 (markedly glucose-avid) and maximal size of 1323 mm. We interpreted these findings as consistent with lymphoma. Fine-needle aspiration was nondiagnostic. Subsequent excisional biopsy of a left axillary node with a standardized uptake value of 16 revealed an enlarged, black node (281713 mm) (Figure 1). Microscopically, the nodal architecture was replaced by well-formed epithelioid granulomas with scattered multinucleate giant cells. Collections of black pigmentladen macrophages were noted within the paracortex (Figure 2). Stains for mycobacteria and fungi and immunohistochemistry for malignant disorders were negative. Flow cytometry did not detect an abnormal lymphoid population. We concluded that the diagnosis was granulomatous lymphadenitis, which was probably a hypersensitivity reaction to tattoo pigment. The patient recalled that her tattoos became transiently pruritic and raised in areas for a few days each month. She has been monitored for 10 months, and the previously palpable axillary lymph nodes are no longer evident. Figure 1. Enlarged, black axillary lymph node that was surgically excised. Figure 2. Lymph node showing epithelioid granulomas and pigment-laden macrophages. Hematoxylineosin stain; original magnification, 20. Discussion: Decorative tattooing is common, with almost 15% of Australians aged 16 to 64 years reporting having a tattoo (4). In the acute setting, tattoo pigment elicits an inflammatory reaction in the epidermis and dermis, occasionally leading to reactive local lymphadenopathy (1). Some cases of delayed lymphadenopathy caused by tattoo pigment have been reported, including one that occurred 30 years after tattooing (2). In these reports, lymphadenopathy was initially mistaken for malignant disease, particularly for melanoma, which also causes pigmented nodes (13). Histologic characteristics range from normal node architecture (1) to reactive nodes with follicular hyperplasia (2, 3), with the dark tattoo pigment deposited both extracellularly and within macrophages. Granulomatous reactions to tattoo pigment are well-described and histologically can be foreign-body type, sarcoidal, or necrobiotic. Sarcoidal granulomas usually involve the tattooed skin and may represent a localized reaction or the first presentation of systemic sarcoidosis (5). The case we describe is unique in that there was no skin reaction, only granulomatous changes in the lymph nodes. In addition, no cutaneous, pulmonary, or systemic symptoms were observed to suggest systemic sarcoidosis. We report a case of tattoo pigment hypersensitivity causing widespread lymphadenopathy 15 years after the tattoo was initially inked. To the best of our knowledge, the PET-CT findings of markedly glucose-avid nodes in multiple areas have not previously been described. This feature in combination with the clinical findings mimicked lymphoma. We believe that this case highlights the importance of a careful tattoo history and physical examination.

A lack of actionable mutations in phyllodes tumours of the breast

Aims: Phyllodes tumours (PT) are rare fibro-epithelial lesions of the breast for which clinical behaviour is not reliably predicted by the pathological features. They have an unpredictable risk of recurrence and potential for metastatic spread, with no effective therapies if surgical control is not possible. New therapeutics that target specific mutant tyrosine kinase receptors have been developed and used successfully in a range of malignancies. We assessed 30 PT for the presence of common, actionable mutations using a sensitive, high-throughput mass spectrometry based assay which detects a panel of 238 specific mutations in 19 oncogenes. Methods: DNA was extracted from four fibroadenomas (FA), 18 benign (low grade), six borderline and six malignant PT, prepared using the Oncocarta v1.0 kit and processed on the Sequenom compact MassARRAY platform. Results: Analysis of four FA and 30 PT revealed that there were no targeted mutations, including within a malignant PT with heterologous differentiation, and two recurrent tumours (one borderline and one malignant PT). Conclusions: This study highlights the ongoing complexity in understanding the pathogenesis of PT, which lack common, actionable mutations. We are currently undertaking further studies utilising more comprehensive next generation mutation panels on this group of tumours.