Carcinoma In Situ Involving Sclerosing Adenosis on Core Biopsy: Diagnostic Pearls to Aid the Practicing Clinician and Avoid Overtreatment

INTRODUCTION: Involvement of pre-existing benign lesions by ductal carcinoma in situ (DCIS) or lobular neoplasia (LN) can present difficult diagnostic challenges, and can easily cause misdiagnosis of invasive carcinoma and over-management of localized disease. Our objective was to gather the largest case series of DCIS and LN involving sclerosing adenosis (SA), and to report the characteristic features of these lesions, in order to provide histologic criteria for the diagnostician. METHODS: Our database was searched for core biopsy material diagnosed as carcinoma in situ involving adenosis. Glass slides and pathology reports were reviewed. The cases were studied for salient features, and clinical follow-up was also obtained. RESULTS: Thirty-one cases of DCIS or LN involving SA were obtained (12 cases of DCIS, 19 cases of LN including LCIS and ALH). Histomorphologic features commonly seen with DCIS or LN involving SA included lobulocentric architecture (31/31, 100%), myoepithelial cells visible by H&E at least focally (31/31, 100%), and separate areas of SA not involved by neoplasia (29/31, 93.5%). Features that were sometimes seen included hyaline basement membranes surrounding the lesion (14/31, 45.2%), DCIS/LN apart from the area of involvement by SA (16/31, 51.6%), and calcifications associated with DCIS/LN/SA (12/31, 38.7%). Features that were not commonly seen included desmoplasia (6/31, 19.4%), dense inflammation (4/31, 12.9%), and single epithelial cells enveloped by flattened myoepithelial cells (6/31, 19.4%). Of the ten cases of DCIS with known follow-up, four showed DCIS involving either SA or a complex SA on excision (4/10, 40%), four had only DCIS (4/10, 40%), one had DCIS with a small 1.8-mm focus of predominantly tubular carcinoma (1/10, 10%), and one showed invasive ductal carcinoma on excision (1/10, 10%). The latter case of invasive ductal carcinoma occurred in a patient who had a delay of 3 years from diagnosis to surgical resection. Of the eight cases of LN with surgical follow-up, seven had LCIS (7/8, 87.5%), and one showed only fibroadenoma and SA with no residual LN in the excised specimen (1/8, 12.5%). Importantly, no invasive carcinoma was identified in any of the resections for LN involving SA. CONCLUSIONS: In our series of carcinoma in situ (CIS) involving sclerosing adenosis diagnosed on core biopsy, lobular lesions involving SA were more common than ductal lesions. Ductal and lobular carcinoma in situ involving adenosis were best diagnosed by the low-power appearance of a lobulocentric pattern of growth. The most helpful diagnostic feature was the observation of additional foci of carcinoma in situ away from the adenosis. Immunohistochemical stains for myoepithelial cells were useful in particularly difficult cases. The presence of stromal desmoplasia does not preclude the diagnosis of carcinoma in situ involving adenosis. Knowledge of these diagnostic pearls can reduce over-interpretation of CIS on core biopsy and subsequent overtreatment

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Primary porocarcinoma of the nipple with metastasis: A case report of a rare entity with molecular analysis and imaging correlation

Porocarcinoma (PC) is a rare malignant skin adnexal tumor, accounting for approximately 0.005% to 0.02% of all malignant cutaneous neoplasms. It occurs most commonly in the sun-exposed extremities. To our knowledge, only one case of a primary nipple eccrine poroma (benign counterpart of PC) has been reported in the literature. Herein we report a patient with a primary PC of the left nipple with metastasis to the left axilla

Synchronous bilateral low grade adenosquamous carcinoma with imaging and pathology correlation

Low-grade adenosquamous carcinoma is an extremely rare and histologically distinct tumor, possessing both squamous and glandular components. A variant of metaplastic carcinoma, it is locally aggressive but regional lymph node metastases are exceptional, and as such patients rarely require systemic therapy. We herein present a case of bilateral low-grade adenosquamous carcinoma, with clinical, pathology and imaging correlation highlighting the salient features of this disease

Metastases to breast simulating ductal carcinoma in situ: Report of two cases and review of the literature

The breast is an uncommon site for metastases. Nevertheless, it is important to differentiate primary from secondary tumors of the breast, because clinical management and expected outcomes are vastly different. We report two examples of tumors with a papillary histologic pattern metastasing to the breast. One of the cases occurred in a 31-year-old woman with a primary renal cell carcinoma, the other was in a 42-year-old woman with an ovarian papillary serous adenocarcinoma. In the first case, the patient\u27s previous history of cancer was not known to the pathologist. The cases highlight the difficulty in distinguishing primary from metastatic tumors in the breast. In both cases the tumors infiltrated in a pattern that mimicked in situ ductal carcinoma changes. Additionally, in both cases, the metastasing tumor was unusual with the tumor cells diffusely permeating the lymphatic spaces, not in a solid mass. These cases and a review of the literature indicated that breast metastases, although rare, must be recognized and differentiated from primary, breast tumors to avoid unnecessary radical surgery to the breast. Moreover, the presence of changes similar to in situ carcinoma of the breast are not conclusive evidence that one is evaluating a primary, breast carcinoma. When there is any unusual histomorphology, a good degree of suspicion is necessary. © 2001 by W.B. Saunders Company

Primary Signet Ring Cell/Histiocytoid Carcinoma of the Eyelid: Clinicopathologic Analysis with Evaluation of the E-Cadherin/β-Catenin Complex and Associated Genetic Alterations

Signet Ring Cell (SRC)/Histiocytoid carcinoma of the eyelid is a rare neoplasm that shares histological and immunohistochemical similarities with diffuse gastric cancer and breast lobular carcinoma. The CDH1 gene, which encodes the E-cadherin protein, is the best known gene associated with these tumors. The structural and functional integrity of E-cadherin is regulated by interconnecting molecular pathways which might participate in the development of this disease. Hence, we analyzed the protein expression in key genes in E-cadherin-related pathways associated with primary SRC/Histiocytoid carcinoma of the eyelid. SRC/Histiocytoid carcinoma diagnosed in the eyelid/orbit at MD Anderson Cancer Center from 1990 to 2016 were evaluated. Clinicopathologic findings were studied to confirm the primary site of origin. Immunohistochemical studies for the expression of E-cadherin, β-catenin, c-Myc, Cyclin D1, Src, and p53 were analyzed. Next generation sequencing for the detection of somatic mutations was performed on each tumor with matched normal tissue, examining 50 cancer-related genes. Four primary SRC/Histiocytoid carcinomas of the eyelid were diagnosed in four male patients aged 40-82 years. Immunohistochemically, two tumors with loss of E-cadherin expression had weak β-catenin and low cytoplasmic staining for Src while the other two cases with intact E-cadherin showed strong β-catenin expression and high cytoplasmic expression for Src. Cyclin D1 was focally positive in three cases. Somatic mutations in CDH1, PIK3CA, and TP53 genes were detected in two cases. Our results suggest an abnormality in the convergence of E-cadherin/β-catenin pathways which may promote tumorigenesis by inducing expression of oncogenes such as Cyclin D1 and C-Myc. Mutations in CDH1, PIK3CA, and TP53 genes could induce E-cadherin dysfunction which takes part in the development and progression of this malignancy

Prognostic Significance of Occult Axillary Lymph Node Metastases After Chemotherapy-induced Pathologic Complete Response of Cytologically Proven Axillary Lymph Node Metastases From Breast Cancer

BACKGROUND: Primary systemic chemotherapy has been a standard of care for the management of locally advanced breast cancer (LABC) patients and has increasingly been used for patients with large operable breast cancer. Pathologic complete response (pCR) of axillary lymph node metastases predicted an excellent probability of long-term disease-free and overall survival. Although the clinical significance of occult lymph node metastases in patients with breast cancer was extensively studied, their prognostic value in patients with LABC after primary chemotherapy was not known. This study evaluated the detection rate and clinical significance of occult lymph node metastases in lymph nodes that contained metastatic carcinoma at the time of initial diagnosis and converted to negative based on routine pathologic examination after primary systemic chemotherapy. METHODS: Fifty-one patients with LABC and cytologically involved axillary lymph nodes that converted to negative after preoperative chemotherapy were identified from 2 prospective clinical trials. All lymph node sections were reviewed, I deeper level hematoxylin and eosin-stained section of each lymph node was obtained and immunohistochemical staining for cytokeratin (CK) was performed. A total of 762 lymph nodes were evaluated for occult metastases. Kaplan-Meier survival curves were used for calculating disease-free and overall survival times. RESULTS: Occult axillary lymph node metastases were identified in 8 of 51 (16%) patients. In 6 patients, occult metastases were found in only 1 lymph node. In 7 patients, only isolated CK-positive cells were identified. In all cases, occult carcinoma cells were embedded within areas of fibrosis, foreign body giant cell reaction, and extensive histiocytosis. Patients with occult lymph node metastases tended to have a higher frequency of residual primary breast tumors than those without occult metastases (4 of 8 vs 7 of 43, respectively). There was no statistically significant difference in disease-free or overall survival times between patients with and without occult metastases after a median follow-up 63 months. CONCLUSIONS: Persistent occult axillary lymph node metastases were not uncommon in patients with axillary lymph node-positive LABC who experienced a pCR in involved lymph nodes after preoperative chemotherapy. However, such occult metastases did not adversely affect the good prognosis associated with axillary lymph node pCR. Therefore, routine lymph node CK evaluation was not recommended after primary chemotherapy. Cancer 2009;115:1605-12. (C) 2009 American Cancer Society

The value of secondary pathology review

6 Background: Improving the value of cancer care is a major focus for the Alliance of Dedicated Cancer Centers (ADCC). Looking to align with the Institute of Medicine’s (IOM) initiative to “Develop and deploy approaches to identify, learn from, and reduce diagnostic errors and near misses in clinical practice,” the ADCC implemented a study to examine the clinical impact of expert secondary pathology review. The goal of this project was to: 1) demonstrate the value of secondary review of outside pathological specimens by ADCC subspecialty pathologists in identifying significant errors that can potentially impact treatment; and 2) create an opportunity to improve patient cancer care. Methods: All consult slides from patients referred to each ADCC center were reviewed by designated pathologists. Patient-level data for original and revised diagnoses were collected for two months in 2014. Discrepancies were classified as: 1) major - diagnosis changes treatment or surveillance; or, 2) minor - diagnosis does not change affect treatment or surveillance. To verify these assessments, disease-specific, multi-center teams of clinical experts reviewed each discrepant case and provided treatment recommendations for the original and revised diagnoses. Results: A total of 13,109 cases were collected across all ADCC centers and the discrepancy rate was 11% (1,488/1309); 3% (359/13,109) were major and 9% (1,129/13,109) were minor. The most common discrepancy was reclassification of the neoplasm cell type. The highest discrepancy rate was shown in the neuro-oncology and head and neck cases, with a 7% and 4% major discrepancy rate respectively. Conclusions: We identified an overall discrepancy rate of 11%, with 3% of cases leading to a change in treatment or surveillance. This demonstrates the importance of expert pathology review and that secondary pathology review can significantly improve clinical outcomes through precise and accurate pathological diagnoses. As indicated in the recent IOM report, this project further demonstrates that “diagnostic errors may cause harm to patients by preventing or delaying appropriate treatment, providing unnecessary or harmful treatment, or resulting in psychological or financial repercussions.