Outcomes of atypical lobular hyperplasia managed by active surveillance or immediate surgery.

BACKGROUND: Atypical lobular hyperplasia (ALH) is typically diagnosed via needle core biopsy (NCB) and is commonly removed surgically in light of upgrade to malignancy rates of 1%-5%. As studies on radiographic outcomes of ALH managed by active surveillance (AS) are limited, we investigated the upgrade rates of surgically excised ALH as well as radiographic progression during AS. METHODS: In this retrospective study, 125 patients with 127 ALH lesions diagnosed via NCB at Weill Cornell Medicine from 2015 to 2021 were included. The upgrade rate to cancer was determined for patients who had surgical management ≤6 months after biopsy. Among patients with ALH managed by AS, we investigated radiographic progression on 6-month interval imaging. RESULTS: Of 127 ALH lesions, 75% (n = 95) were immediately excised and 25% (n = 32) were observed under AS. The upgrade rate of immediately excised ALH was 2.1% (n = 2; invasive ductal carcinoma [IDC], T1N0 and IDC, and T1Nx). In the AS cohort, no ALH lesions progressed radiographically during the follow-up period of 22.5 months (median), with all remaining stable (50%, n = 16), resolving (47%, n = 15), or decreasing in size (3%, n = 1). CONCLUSIONS: In this study, NCB-diagnosed ALH had a low upgrade to malignancy rate (2.1%), and no ALH lesions managed by AS progressed radiographically during the follow-up period of 22.5 months. These results support AS as the favorable option for patients with pure ALH on biopsy, with surgical excision for lesions that progress on surveillance.

Evaluation of dual p16/Ki-67 immunostaining on anal cytology specimens.

INTRODUCTION: Dual immunostaining for p16/Ki67 is FDA-approved for use on liquid-based cervical cytology specimens; however, the utility of dual staining in anal cytology especially for ASCUS risk stratification is not well established. METHODS: We investigated dual staining performance on anal cytology specimens and correlated with subsequent cytologic interpretation, high-risk HPV status, and anal biopsy results. Dual staining for p16/Ki-67 was performed on all liquid-based anal cytology specimens from December 2021 to June 2022 (n = 43). RESULTS: Three patients had high grade squamous intraepithelial lesion (HSIL/AIN2-3) on biopsy; dual staining was positive in all three cases. All HR-HPV negative cases were negative for dual staining. Among the 12 ASCUS samples with subsequent anal biopsy results all also had HR-HPV testing. Due to small sample size of cases with squamous intraepithelial lesion (SIL) diagnosed on biopsy, the sensitivity and positive predictive value was not calculated. However, the specificity and negative predictive value of p16/Ki-67 dual staining for SIL of any grade on biopsy were 1 (95% CI: 0.66-1) and 0.9 (95% CI: 0.65-0.97) respectively, whereas the specificity and negative predictive value of HR-HPV testing for SIL of any grade on biopsy were 0.44 (95% CI: 0.14-0.79) and 0.8 (95% CI: 0.41-0.96) respectively. CONCLUSION: Dual p16/Ki-67 staining indicates transforming HPV infection and could help serve as an ancillary test for risk stratification for atypical anal cytology specimens. Among ASCUS samples, dual staining was specific for SIL of any grade with a high negative predictive value and therefore could be useful in clinical practices with limited availability for follow-up care.

Identification of Glandular (Acinar)/Tubule Formation in Invasive Carcinoma of the Breast: A Study to Determine Concordance Using the World Health Organization Definition.

CONTEXT.­: The Nottingham Grading System (NGS) developed by Elston and Ellis is used to grade invasive breast cancer (IBC). Glandular (acinar)/tubule formation is a component of NGS. OBJECTIVE.­: To investigate the ability of pathologists to identify individual structures that should be classified as glandular (acinar)/tubule formation. DESIGN.­: A total of 58 hematoxylin-eosin photographic images of IBC with 1 structure circled were classified as tubules (41 cases) or nontubules (17 cases) by Professor Ellis. Images were sent as a PowerPoint (Microsoft) file to breast pathologists, who were provided with the World Health Organization definition of a tubule and asked to determine if a circled structure represented a tubule. RESULTS.­: Among 35 pathologists, the κ statistic for assessing agreement in evaluating the 58 images was 0.324 (95% CI, 0.314-0.335). The median concordance rate between a participating pathologist and Professor Ellis was 94.1% for evaluating 17 nontubule cases and 53.7% for 41 tubule cases. A total of 41% of the tubule cases were classified correctly by less than 50% of pathologists. Structures classified as tubules by Professor Ellis but often not recognized as tubules by pathologists included glands with complex architecture, mucinous carcinoma, and the "inverted tubule" pattern of micropapillary carcinoma. A total of 80% of participants reported that they did not have clarity on what represented a tubule. CONCLUSIONS.­: We identified structures that should be included as tubules but that were not readily identified by pathologists. Greater concordance for identification of tubules might be obtained by providing more detailed images and descriptions of the types of structures included as tubules.

Active Surveillance of Atypical Ductal Hyperplasia of the Breast.

BACKGROUND: When needle core biopsy (NCB) of the breast yields atypical ductal hyperplasia (ADH), excision is typically recommended. The natural history of ADH undergoing active surveillance (AS) is not well described. We investigate the rates of upgrade to malignancy of excised ADH and the rates of radiographic progression under AS. MATERIALS AND METHODS: We retrospectively reviewed records of 220 cases of ADH on NCB. Of patients who had surgery within 6 months of NCB, we examined the malignancy upgrade rate. In the AS cohort, we examined rates of radiographic progression on interval imaging. RESULTS: The malignancy upgrade rate among patients who underwent immediate excision (n = 185) was 15.7%: 14.1% (n = 26) ductal carcinoma in situ (DCIS) and 1.6% (n = 3) invasive ductal carcinoma (IDC). Upgrade to malignancy was less common in lesions <4 mm in size (0%) or with focal ADH (5%), and more common among lesions presenting with a radiographic mass (26%). Among the 35 patients who underwent AS, median follow-up was 20 months. Two lesions progressed on imaging (incidence 3.8% at 2 years). One patient without radiographic progression was found to have IDC at delayed surgery. The remaining lesions remained stable (46%), decreased in size (11%), or resolved (37%). CONCLUSIONS: Our findings suggest that AS is a safe approach to managing ADH on NCB for most patients. This could spare many patients with ADH from unnecessary surgery. Given that AS is being investigated for low-risk DCIS in multiple international prospective trials, these results suggest that AS should also be investigated for ADH.

Metastatic melanoma in the breast and axilla: A case report.

Metastatic melanoma of the breast is rare, and demonstrates nonspecific imaging findings which may overlap with both benign and malignant pathology.1-3 Immunohistochemical stains are important to confirm the diagnosis, particularly combining S100, a sensitive marker for melanoma, with more specific tumor markers such as Melan-A and HMB-45, and lack of cytokeratin staining.4-7 We present a case of a 64-year-old female who presented for diagnostic imaging of a palpable abnormality in her right breast, with medical history notable for previously excised cutaneous melanoma, recent COVID-19 vaccination, and significant family history of breast cancer. Diagnostic mammogram of the right breast demonstrated a circumscribed mass in the lower inner quadrant corresponding to the area of palpable concern, as well as an additional non-palpable circumscribed mass in the lower inner quadrant. Targeted right breast ultrasound demonstrated corresponding circumscribed cystic versus solid masses as well as a morphologically abnormal right axillary lymph node. Pathologic results after tissue sampling of the two right breast masses and right axillary lymph node all yielded metastatic melanoma.

Mucocele-like Lesion of the Breast Diagnosed on Core Biopsy.

CONTEXT.­: Mucocele-like lesion of the breast (MLL) is an uncommon entity, and recent studies show low rates of upgrade from core needle biopsy (CNB) to excision. OBJECTIVE.­: To evaluate features associated with upgrade of MLLs diagnosed on CNB. DESIGN.­: Seventy-eight MLLs diagnosed on CNB from 1998-2019 and subsequent excisions were reviewed. Histologic parameters evaluated included the presence of atypia, presence and morphology of calcifications, and morphologic variant (classic [C-MLL], duct ectasia-like [DEL-MLL], or cystic mastopathy-like [CML-MLL]). RESULTS.­: Overall, 45 MLLs lacked atypia and 33 were associated with atypia (atypical ductal hyperplasia, 32; atypical lobular hyperplasia, 1). Most were C-MLLs (61) with fewer DEL-MLLs (14) and CML-MLLs (3). Half showed both coarse and fine calcifications, with fewer showing only coarse or fine calcifications, and some showing none. Subsequent excision or clinical follow-up was available for 25 MLLs without atypia-of which 2 (8.0%) were upgraded to ductal carcinoma in situ (DCIS)-and 23 with atypia, of which 4 (17.4%) were upgraded to DCIS. No cases were upgraded to invasive carcinoma. All upgraded cases showed coarse calcifications on CNB, and all upgraded cases were associated with residual calcifications on post-CNB imaging. CONCLUSIONS.­: Most MLLs present as calcifications and nearly half are associated with atypia. Upgrade to DCIS is twice as frequent in MLLs with atypia versus those without. A predominance of coarse calcifications and the presence of residual targeted calcifications following core biopsy may be associated with higher upgrade rates.

The Effect of Topical Tacrolimus on Pedicled Flap Survival: A Histological Analysis.

PURPOSE: Our previous rodent study demonstrated significantly decreased full-thickness necrosis in pedicled dorsal skin flaps with topical tacrolimus as compared with petroleum jelly. The pathophysiology of tissue necrosis involves lymphatic congestion, followed by venous congestion and ultimately arterial insufficiency. Topical tacrolimus has been shown to increase growth of lymphatic collateral vessels and decrease lymphedema, potentially obviating one contributor to necrosis. The purpose of this study was to investigate the vascular and histological differences between these 2 groups to identify the etiology of our research findings. METHODS: A 3 × 10-cm cranially based dorsal skin flap was raised and reinset on 22 Sprague Dawley rats. They were randomized to receive 0.2 g of either topical petroleum jelly or topical 0.1% tacrolimus ointment daily to the flaps. The rats were killed 7 days postoperatively. Two blinded reviewers marked the total flap area as well as areas of viable tissue, reversible ischemia, and necrotic tissue. Full-thickness biopsies of each area were taken from 2 randomly chosen animals in each group. Paraffin-embedded tissue was sectioned to generate hematoxylin and eosin-stained slides. Representative images of each area of the flap were taken less than 40× magnification using light microscopy. Arteries, veins, and lymphatics in the dermal layer were quantified under blinded conditions by a trained pathologist and calculated per cross-sectional area using Fiji software. RESULTS: The average area of the dorsal flaps in the control and tacrolimus groups was 22.5 and 23.9 cm2, respectively. Total necrotic area was significantly lower in rats receiving topical tacrolimus as compared with controls (P = 0.015). In the control cohort, average total number of vessels was 12.5, 6, and 0, in the areas of viable tissue, reversible ischemia, and necrosis, respectively. In the tacrolimus cohort, average total number of vessels increased was 20, 11.5, and 5.4, in the areas of viable tissue, reversible ischemia, and necrosis, respectively. CONCLUSIONS: On a histological level, topical tacrolimus is correlated with increased vascular growth in areas most susceptible for ischemic damage as compared with topical control. Future work is needed to investigate vascular biomarkers and increase the power of our study.

Honeybees use the skyline in orientation.

In view-based navigation, animals acquire views of the landscape from various locations and then compare the learned views with current views in order to orient in certain directions or move toward certain destinations. One landscape feature of great potential usefulness in view-based navigation is the skyline, the silhouette of terrestrial objects against the sky, as it is distant, relatively stable and easy to detect. The skyline has been shown to be important in the view-based navigation of ants, but no flying insect has yet been shown definitively to use the skyline in this way. Here, we show that honeybees do indeed orient using the skyline. A feeder was surrounded with an artificial replica of the natural skyline there, and the bees' departures toward the nest were recorded from above with a video camera under overcast skies (to eliminate celestial cues). When the artificial skyline was rotated, the bees' departures were rotated correspondingly, showing that the bees oriented by the artificial skyline alone. We discuss these findings in the context of the likely importance of the skyline in long-range homing in bees, the likely importance of altitude in using the skyline, the likely role of ultraviolet light in detecting the skyline, and what we know about the bees' ability to resolve skyline features.

Honeybees can learn the relationship between the solar ephemeris and a newly experienced landscape: a confirmation.

Honeybees learn the spatial relationship between the sun's pattern of movement and the landscape immediately surrounding their nest, which allows bees to locate the sun under overcast skies by reference to the landscape alone. Surprisingly, when bees have been transplanted from their natal landscape to a rotated twin landscape - such as from one treeline to a similar but differently oriented treeline - they fail to learn the relationship between the sun and the second landscape. This raises the question of whether bees can ever learn the relationship between the sun's pattern of movement and a landscape other than their natal one. Here we confirm, with new and necessary controls, that bees can indeed learn the relationship between the sun's pattern of movement and a second (that is, non-natal) landscape, if the second landscape is panoramically different from the bees' natal site. We transplanted bees from their natal site to a panoramically different second site and, 3 days later, tested the bees' knowledge of the relationship between the sun and the second landscape. The test involved observing the bees' communicative dances under overcast skies at a third site that was a rotated twin of the second. These bees oriented their dances using a memory of the sun's course in relation to the second landscape, indicating that they had learned this relationship. Meanwhile, control bees transplanted directly from the natal site to the third site, skipping the second, danced differently, confirming the importance of the experimental bees' experience at the second site.

The depth of the honeybee's backup sun-compass systems.

Honeybees have at least three compass mechanisms: a magnetic compass; a celestial or sun compass, based on the daily rotation of the sun and sun-linked skylight patterns; and a backup celestial compass based on a memory of the sun's movements over time in relation to the landscape. The interactions of these compass systems have yet to be fully elucidated, but the celestial compass is primary in most contexts, the magnetic compass is a backup in certain contexts, and the bees' memory of the sun's course in relation to the landscape is a backup system for cloudy days. Here we ask whether bees have any further compass systems, for example a memory of the sun's movements over time in relation to the magnetic field. To test this, we challenged bees to locate the sun when their known celestial compass systems were unavailable, that is, under overcast skies in unfamiliar landscapes. We measured the bees' knowledge of the sun's location by observing their waggle dances, by which foragers indicate the directions toward food sources in relation to the sun's compass bearing. We found that bees have no celestial compass systems beyond those already known: under overcast skies in unfamiliar landscapes, bees attempt to use their landscape-based backup system to locate the sun, matching the landscapes or skylines at the test sites with those at their natal sites as best they can, even if the matches are poor and yield weak or inconsistent orientation.

Honeybees can learn the relationship between the solar ephemeris and a newly-experienced landscape.

Many species learn the sun's daily pattern of azimuthal movement (the solar ephemeris function) for use in sun-compass orientation. In honeybees, this learning is accomplished with much innate guidance and yields stubborn, imprinting-like retention of certain aspects of the stored information. One such case involves the failure of transplanted bees to update their memories of the relationship between the solar ephemeris and a new landscape, even after many days' experience at the new site. In the present study, I ask whether the bees in previous transplantation experiments failed to update their memories of the relationship between the sun and landscape because the source and recipient landscapes were (rotated) panoramic twins of each other, each dominated by a conspicuous treeline. To test this hypothesis, I transplanted bees from their natal site at the bottom of a valley to a panoramically different, treelined site and later tested the bees' knowledge of the sun's course in relation to the treeline. The test involved observing the bees' communicative dances under overcast skies at a second treeline that was a mirror image of the first. The cloudy-day dances show that the bees had indeed learned the relationship between sun's pattern of movement and the (panoramically novel) treelined site, indicating that the bees' memory of the relationship between the ephemeris function and the landscape is not incapable of revision as the earlier results had suggested. I discuss these results in the context of a brief summary of our current understanding of solar ephemeris learning in bees.

The connection between landscapes and the solar ephemeris in honeybees.

Honeybees connect the sun's daily pattern of azimuthal movement to some aspect of the landscape around their nests. In the present study, we ask what aspect of the landscape is used in this context--the entire landscape panorama or only sectors seen along familiar flight routes. Previous studies of the solar ephemeris memory in bees have generally used bees that had experience flying a specific route, usually along a treeline, to a feeder. When such bees were moved to a differently oriented treeline on overcast days, the bees oriented their communicative dances as if they were still at the first treeline, based on a memory of the sun's course in relation to some aspect of the site, possibly the familiar route along the treeline or possibly the entire landscape or skyline panorama. Our results show that bees lacking specific flight-route training can nonetheless recall the sun's compass bearing relative to novel flight routes in their natal landscape. Specifically, we moved a hive from one landscape to a differently oriented twin landscape, and only after transplantation under overcast skies did we move a feeder away from the hive. These bees nonetheless danced accurately by memory of the sun's course in relation to their natal landscape. The bees' knowledge of the relationship between the sun and landscape, therefore, is not limited to familiar flight routes and so may encompass, at least functionally, the entire panorama. Further evidence suggests that the skyline in particular may be the bees' preferred reference in this context.

Does swarming cause honey bees to update their solar ephemerides?

Spatial orientation in the social insects offers several examples of specialized learning mechanisms that underlie complex learning tasks. Here we study one of these systems: the processes by which honey bees update, or fail to update, their memories of the sun's daily pattern of movement (the solar ephemeris function) in relation to the landscape. Specifically, we ask whether bees that have initially learned the solar ephemeris function relative to a conspicuous treeline at their natal site can later realign the ephemeris to a differently oriented treeline. We first confirm and clarify an earlier finding that bees transplanted passively (by being carried) do not re-learn the solar ephemeris in relation to the new treeline. When they cannot detect the sun directly, as on overcast days, these transplanted bees use a solar ephemeris function appropriate for their natal site, despite days or weeks of experience at the new site. We then ask whether bees put through a swarming process as they are transplanted are induced to re-learn the solar ephemeris function at the new site, as swarming is a natural process wherein bees transplant themselves. Most of the swarmed bees failed to re-learn, even though they did extensive learning flights (in comparison with those of non-swarmed controls) as they first emerged from the hive at the new site. We hypothesize that the bees' representation of the solar ephemeris function is stored in an encapsulated cognitive module in which the ephemeris is inextricably linked to the reference landscape in which it was learned.