Mary Ann Sanders

Dectin-1 Activation by a Natural Product β-Glucan Converts Immunosuppressive Macrophages into an M1-like Phenotype.

Tumor-associated macrophages (TAM) with an alternatively activated phenotype have been linked to tumor-elicited inflammation, immunosuppression, and resistance to chemotherapies in cancer, thus representing an attractive target for an effective cancer immunotherapy. In this study, we demonstrate that particulate yeast-derived β-glucan, a natural polysaccharide compound, converts polarized alternatively activated macrophages or immunosuppressive TAM into a classically activated phenotype with potent immunostimulating activity. This process is associated with macrophage metabolic reprograming with enhanced glycolysis, Krebs cycle, and glutamine utilization. In addition, particulate β-glucan converts immunosuppressive TAM via the C-type lectin receptor dectin-1–induced spleen tyrosine kinase–Card9–Erk pathway. Further in vivo studies show that oral particulate β-glucan treatment significantly delays tumor growth, which is associated with in vivo TAM phenotype conversion and enhanced effector T cell activation. Mice injected with particulate β-glucan–treated TAM mixed with tumor cells have significantly reduced tumor burden with less blood vascular vessels compared with those with TAM plus tumor cell injection. In addition, macrophage depletion significantly reduced the therapeutic efficacy of particulate β-glucan in tumor-bearing mice. These findings have established a new paradigm for macrophage polarization and immunosuppressive TAM conversion and shed light on the action mode of β-glucan treatment in cancer.

Clinical Implications of Subcategorizing BI-RADS 4 Breast Lesions associated with Microcalcification: A Radiology–Pathology Correlation Study

Abstract:  Currently radiologists have the option of subcategorizing BI‐RADS 4 breast lesions into 4A (low suspicion for malignancy), 4B (intermediate suspicion of malignancy), and 4C (moderate concern, but not classic for malignancy). To determine the clinical significance of BI‐RADS 4 subcategories and the common pathologic changes associated with these mammographic lesions, a retrospective review of 239 consecutive stereotactic‐needle core biopsies (SNCB) for microcalcifications was performed. All 239 SNCBs were BI‐RADS 4 lesions, and of these, 191 were subcategorized to 4A, 4B or 4C. Ninety‐four of 191 (49%) were 4A, 73 (38%) were 4B, and 24 (13%) were 4C. Fibrocystic change was the most common finding (66/239; 28%) followed by ductal carcinoma in situ (DCIS) accounting for 23% of cases. This was followed by columnar cell alteration with or without atypia (47/239; 19%), and fibroadenoma (45/239; 19%). While 70% (17/24) of BI‐RADS 4C category lesions were DCIS, only 21% (15/73) of BI‐RADS 4B and 10% (10/94) of BI‐RADS 4A were DCIS. Without sub‐categorization, carcinoma was diagnosed in 23% (55/239) of all cases with BI‐RADS 4. Therefore, subcategorizing BI‐RADS 4 lesions is important since it not only benefits the patient and clinician in understanding the level of concern for carcinoma, but will also alert the pathologist.

Paget disease of the breast with invasion from nipple skin into the dermis: an unusual type of skin invasion not associated with an adverse outcome.

CONTEXT Paget disease is an uncommon skin manifestation of breast cancer, associated with either invasive carcinoma or ductal carcinoma in situ in the underlying breast. In very rare cases, tumor cells within the epidermis invade through the basement membrane of the skin into the dermis. OBJECTIVES To identify a series of cases of Paget disease with direct dermal invasion and to investigate the clinicopathologic features and outcome. DESIGN Cases were identified during a 6-year period from the files of 2 hospitals. The clinical histories, imaging studies, and pathology reports were reviewed. RESULTS Seven patients were identified, 5 with microinvasion (<0.1 cm) and 2 with 0.2- or 0.3-cm invasive carcinomas in the dermis. No lymphovascular invasion was seen. Sentinel nodes were negative in 3 patients who underwent biopsy. Five patients were treated with breast conservation with radiation. Three patients were at high risk for breast cancer because of prior breast cancer, Li-Fraumeni syndrome, or radiation for Hodgkin disease. The latter 2 patients underwent bilateral mastectomies. Three patients received hormonal therapy and 1 oophorectomy. No patient received chemotherapy. At follow-ups ranging from 4 to 66 months (median, 20 months), there have been no recurrences. CONCLUSIONS Patients with direct dermal invasion from Paget disease had a favorable outcome during the available follow-up period. This type of dermal involvement must be distinguished from locally advanced invasive carcinomas with skin invasion classified as T4b in the American Joint Cancer Commission staging system, as cancers with other types of skin invasion are associated with a poor prognosis.

Embryonal rhabdomyosarcoma of the uterine cervix in a 41-year-old woman treated with radical hysterectomy and adjuvant chemotherapy

BACKGROUND Cervical embryonal rhabdomyosarcoma (ERMS) mostly affects young girls. The current treatment protocols are based on trials done on patients under 21 years old. ERMS in women over 40 is rare, and studies on treatment and outcome are limited. CASE We report a case of a 41 year-old woman with cervical ERMS who was treated with radical hysterectomy followed by chemotherapy. She is currently disease-free. CONCLUSION Cervical ERMS in women over the age of 40 can be treated using protocols established for the pediatric population.

Targeting aberrant expression of Notch-1 in ALDH+ cancer stem cells in breast cancer†

We have previously reported that high aldehyde dehydrogenase (ALDH) enzyme activity in breast cancer cells results in breast cancer stem cell (BCSC) properties by upregualting Notch‐1 and epithelial mesenchymal markers. This results in chemoresistance in breast cancer. Here, we examined the functional and clinical significance of ALDH expression by measuring the ALDH levels in breast cancer tissues by immunohistochemistry. There was a significantly higher ALDH expression in higher grade breast cancer tumor tissues (Grade‐ II and III) versus normal breast tissues. Injection of BCSC (ALDH+ and CD44+/CD22−) cells resulted in aggressive tumor growth in athymic mice versus ALDH− cells. The ALDH+ and CD44+/CD22− tumors grow rapidly and are larger than ALDH− tumors which were slow growing and smaller. Molecularly, ALDH+ tumors expressed higher expression of Notch‐1 and EMT markers than ALDH− tumors. Oral administration of the naturally occurring Psoralidin (Pso, 25 mg/kg of body weight) significantly inhibited the growth in ALDH+ and ALDH− tumors as well. Psoralidin inhibited Notch‐1 mediated EMT activation in ALDH+ and ALDH− tumors‐this confirms our in vitro findings. Our results suggest that Notch‐1 could be an attractive target and inhibition of Notch‐1 by Psoralidin may prevent pathogenesis of breast cancer as well as metastasis.

Assessment of CK17 as a Marker for the Diagnosis of Differentiated Vulvar Intraepithelial Neoplasia.

Differentiated vulvar intraepithelial neoplasia (dVIN), precursor of vulvar squamous cell carcinoma, is human papilloma virus independent and often found in a background of lichen sclerosus (LS) and lichen simplex chronicus (LSC). Subtle histologic findings make the diagnosis of dVIN difficult, and, although the use of p53 and Ki-67 has been of some value, there is a need for a better immunohistochemical marker. Cytokeratin 17 (CK17), a cytoskeletal intermediate filament protein, has previously been used in the diagnosis of anogenital lesions. Here we evaluated CK17 in dVIN in comparison with LS, LSC, and usual VIN (uVIN/HSIL). Twenty-nine cases of dVIN, 9 cases of uVIN, 8 cases of LS, and 7 of LSC were evaluated using CK17, Ki-67, and p53. All 29 dVIN cases displayed immunoreactivity for CK17, with 27 (93%) showing intermediate to strong and diffuse reactivity. No cases of uVIN displayed diffuse CK17 expression, whereas 63% of LS and 29% of LSC displayed intermediate to strong diffuse immunoreactivity, confined to the upper half of the epithelium. P53 and Ki-67 expression was present in varying degrees in all types of lesions, displaying limited discriminatory power for dVIN. Our findings suggest that CK17, although not specific for dVIN, when combined with histologic findings, Ki-67, and p53 immunohistochemistry, can be a marker of vulvar dysplasia and serve as an adjunct in the diagnosis of dVIN. Specifically, in small biopsies, the presence of diffuse suprabasal or full thickness expression strongly favors a diagnosis of dVIN over LSC, whereas focal and/or superficial expression supports a diagnosis of LSC.

Decline in Frozen Section Diagnosis for Axillary Sentinel Lymph Nodes as a Result of the American College of Surgeons Oncology Group Z0011 Trial

CONTEXT -Results of the American College of Surgeons Oncology Group Z0011 trial showed that patients with early-stage breast cancer and limited sentinel node metastasis treated with breast conservation and systemic therapy did not benefit from axillary lymph node dissection. Subsequently, most pathology departments have likely seen a decrease in frozen section diagnosis of sentinel lymph nodes. OBJECTIVE -To determine the effect of the Z0011 trial on pathology practice and to examine the utility of intraoperative sentinel lymph node evaluation for this subset of patients. DESIGN -Pathology reports from cases of primary breast cancer that met Z0011 clinical criteria and were initially treated with lumpectomy and sentinel lymph node biopsy from 2009 to 2015 were collected. Clinicopathologic data were recorded. RESULTS -Sentinel lymph node biopsies sent for frozen section diagnosis occurred in 22 of 22 cases (100%) in 2009 and 15 of 22 cases (68%) in 2010 during the pre-Z0011 years, and in 3 of 151 cases (2%) collected in 2011 through 2015, considered to be post-Z0011 years. Of the 151 post-Z0011 cases, 28 (19%) had sentinel lymph nodes with metastasis, and 147 (97%) were spared axillary lymph node dissection. CONCLUSIONS -Following Z0011, intraoperative sentinel lymph node evaluation has significantly decreased at our institution. Prior to surgery, all patients had clinically node-negative disease. After sentinel lymph node evaluation, 97% (147 of 151) of the patients were spared axillary lymph node dissection. Therefore, routine frozen section diagnosis for sentinel lymph node biopsies can be avoided in these patients.

Feasibility of the Less Is More Approach in Treating Low-Risk Ductal Carcinoma In Situ Diagnosed on Core Needle Biopsy: Ten-Year Review of Ductal Carcinoma In Situ Upgraded to Invasion at Surgery

CONTEXT - Ductal carcinoma in situ (DCIS) represents 20% of screen-detected breast cancers. The likelihood that certain types of DCIS are slow growing and may never progress to invasion suggests that our current standards of treating DCIS could result in overtreatment. The LORIS (LOw RISk DCIS) and LORD (LOw Risk DCIS) trials address these concerns by randomizing patients with low-risk DCIS to either active surveillance or conventional treatment. OBJECTIVE - To determine the upgrade rate of DCIS diagnosed on core needle biopsy to invasive carcinoma at surgery and to evaluate the safety of managing low-risk DCIS with surveillance alone, by characterizing the pathologic and clinical features of upgraded cases and applying criteria of the LORD and LORIS trials to these cases. DESIGN - A 10-year retrospective analysis of DCIS on core needle biopsy with subsequent surgery. RESULTS - We identified 1271 cases of DCIS on core needle biopsy: 200 (16%) low grade, 649 (51%) intermediate grade, and 422 (33%) high grade. Of the 1271 cases, we found an 8% upgrade rate to invasive carcinoma (n = 105). Nineteen of the 105 upgraded cases (18%) had positive lymph nodes. Low-grade DCIS was least likely to upgrade to invasion, comprising 10% (10 of 105) of upgraded cases. Three of the 105 upgraded cases (3%) met criteria for the LORD trial, and all were low-grade DCIS on core needle biopsy with favorable biology on follow-up. CONCLUSIONS - There is a clear risk of upgrade to invasion on follow-up excision; however, applying strict criteria of the LORD trial effectively decreases the likelihood of a missed invasive component or missed aggressive pathologic features.

Clear Cell Adenocarcinoma Arising in an Adenomyoma of the Broad Ligament

Extrauterine adenomyomas are extremely rare benign tumors of smooth muscles, endometrial glands, and endometrial stroma. Ectopic endometrial glands can undergo malignant change. The ovary is the most common site of malignant change in endometriosis. Cancer arising in extraovarian endometriosis is a rare event with limited cases in the literature. To the best of our knowledge, we present the first case of a clear cell adenocarcinoma arising from foci of ectopic endometrial tissue in an adenomyoma of the broad ligament. It supports the association between endometriomas and clear cell adenocarcinoma. Therefore, patients with a significant history of endometriosis may benefit from close follow-up or definitive surgery.

Paget Disease of the Breast With Invasion From Nipple Skin Into the Dermis

To the Editor.—Many laboratory tests have similar, soundalike names. Although the confusion and errors caused by soundalike medications have been written about for years, there is virtually no literature, to our knowledge, about the confusion and errors caused by soundalike test names. We present an example of this issue from our own laboratory, as well as possible solutions that improve laboratory use and patient care. Cyclosporine is a common immunosuppressive medication, for which serum concentrations are often tracked in patients with transplants. Cycloserine is a rarely used, second-line tuberculosis antibiotic not stocked in our inpatient pharmacy. Cycloserine serum levels concentrations are tracked to avoid neurotoxicity. At the Hershey Medical Center, computerized physician order-entry (CPOE) is performed through the electronic health record system. Orders can be searched by entering partial words. By typing ‘‘cyclos,’’ the CPOE brings up both the orders for ‘‘cyclosporine level’’ and ‘‘cycloserine level.’’ The physician can then select the appropriate order. A search of all hospital orders from January 1, 2010, to January 1, 2012, was performed for cycloserine orders and for information about the patients undergoing these tests. Twenty orders for cycloserine level were made during the 2-year period. None of those patients who had a cycloserine level test ordered was taking cycloserine; all were taking cyclosporine at the time of order. Thus, it was concluded that all (100%) of the 20 orders were in error. The pharmacy department verified that no inpatient was on cycloserine during the previous 3 years. We removed the test from the CPOE order menu, thereby eliminating the possibility that a cycloserine level test would be ordered in error when a clinician desired a cyclosporine level, leading to a delay in obtaining the necessary result. A clinician may still order cycloserine level for a patient using the CPOE as a ‘‘miscellaneous laboratory test’’ and by entering the request in a free-text box. In the 6 months following this change, no orders for cycloserine levels were entered. Cyclosporine level ordering remained unchanged. Cycloserine level is a send-out test that costs our laboratory more than