Ribociclib-Induced Cutaneous Adverse Events in Metastatic HR+/HER2- Breast Cancer: Incidence, Multidisciplinary Management, and Prognostic Implication.

BACKGROUND: Ribociclib is approved for hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer (ABC) treatment, in combination with endocrine therapy. Hematological, hepatic, and cardiac adverse events (AEs) emerged from pivotal trials, but little is known about cutaneous adverse events (CAEs). PATIENTS AND METHODS: We report data from a retrospective cohort study of all patients with HR+/HER2- ABC treated with ribociclib at Humanitas Cancer Center between June 2017 and December 2022. We recorded clinical-pathological data, the incidence, and treatment of ribociclib-related CAEs. These were evaluated according to the NCI-CTCAE v5.0 classification. Progression-free survival (PFS) was estimated by Kaplan-Meier method and the log-rank test was used to analyze differences between groups. RESULTS: Thirteen of 91 patients (14.3%) experienced treatment-related CAEs (mean time to the occurrence: 3.9 months). The most frequent CAEs were eczematous dermatitis (53.8%) and maculo-papular reaction (15.4%). Itch was reported by all 13 patients. The grade was G3 in 8 cases, G2 in 4, and G1 in 1. An integrated approach based on ribociclib dose modulation and dermatological interventions (oral antihistamine, moisturized cream, topical, and/or systemic steroids) could prevent ribociclib discontinuation in most patients. At a median follow-up of 20 months, the median PFS was 13 months (range, 1-66) with a better PFS curves for patients experiencing CAEs (P = .04). CONCLUSION: We mapped frequency and types of ribociclib-induced CAEs. An interdisciplinary management of CAEs incorporated into routine care may reduce the rate of drug discontinuation thus potentially contributing to better long-term outcomes.

Digital Pathology During the COVID-19 Outbreak in Italy: Survey Study.

BACKGROUND: Transition to digital pathology usually takes months or years to be completed. We were familiarizing ourselves with digital pathology solutions at the time when the COVID-19 outbreak forced us to embark on an abrupt transition to digital pathology. OBJECTIVE: The aim of this study was to quantitatively describe how the abrupt transition to digital pathology might affect the quality of diagnoses, model possible causes by probabilistic modeling, and qualitatively gauge the perception of this abrupt transition. METHODS: A total of 17 pathologists and residents participated in this study; these participants reviewed 25 additional test cases from the archives and completed a final psychologic survey. For each case, participants performed several different diagnostic tasks, and their results were recorded and compared with the original diagnoses performed using the gold standard method (ie, conventional microscopy). We performed Bayesian data analysis with probabilistic modeling. RESULTS: The overall analysis, comprising 1345 different items, resulted in a 9% (117/1345) error rate in using digital slides. The task of differentiating a neoplastic process from a nonneoplastic one accounted for an error rate of 10.7% (42/392), whereas the distinction of a malignant process from a benign one accounted for an error rate of 4.2% (11/258). Apart from residents, senior pathologists generated most discrepancies (7.9%, 13/164). Our model showed that these differences among career levels persisted even after adjusting for other factors. CONCLUSIONS: Our findings are in line with previous findings, emphasizing that the duration of transition (ie, lengthy or abrupt) might not influence the diagnostic performance. Moreover, our findings highlight that senior pathologists may be limited by a digital gap, which may negatively affect their performance with digital pathology. These results can guide the process of digital transition in the field of pathology.

Orbital metastases from breast cancer: A single institution case series.

BACKGROUND AND OBJECTIVES: Among orbital tumors, metastatic lesions have a prevalence of 1% to 13%; on the other hand, breast cancer is the most common malignancy causing orbital metastases. The aim of this study is to present our experience dealing with orbital metastases caused by breast cancer, to assess characteristics and clinic-pathological data of patients suffering from this rare occurrence and to find indexes related with their prognosis and survival. METHODS: Records of 28 patients diagnosed with orbital metastases from breast cancer at the Department of Ophthalmology, Humanitas Clinical and Research Centre of Milano over a 27-year period (1992-2018) were retrieved and analyzed. RESULTS: Mean patients' age at breast cancer diagnosis was 56.29 ± 14.63 years. Mean time interval between breast cancer diagnosis and orbital metastasis occurrence was 5 ± 4.17 years. All lesions were estrogen receptor-positive; 79% of patients harbored progesterone receptor-positive lesions. Interestingly, the majority of deceased patients presented orbital lesions with MIB-1 index >50% (P = .0265) and had concomitant lung metastases (P = .0452). CONCLUSIONS: The occurrence of orbital metastasis from breast cancer represents a challenging finding. Patients' clinical picture can include exophthalmos, edema, tumefaction, proptosis and/or diplopia. Significant symptomatic improvement can be achieved through surgery and other adjuvant treatments, such as radiation therapy and chemotherapy.

Variant discovery in patients with Mendelian vascular anomalies by next-generation sequencing and their use in patient clinical management.

OBJECTIVE: An accurate "molecular" diagnosis and classification of similar but distinct diseases is sometime challenging but often crucial for the definition of the appropriate patient medical management and treatment as well as for genetic counseling and risk assessment in families. The advent of next-generation sequencing (NGS), which analysed all known disease-associated genes in parallel in a cost- and time-effective manner, eased this process of disease definition and also for vascular anomalies that are a heterogeneous group of vascular tumors and congenital circulatory malformations and often characterized by overlapping phenotypes. METHODS: We designed a NGS-based screening of the 25 currently most prevalent genes identified in patients with vascular anomalies with Mendelian inheritance and applied this panel to study the DNA of 150 patients affected with vascular anomalies for autosomal recessive and autosomal dominant variants and to analyse the paired blood and DNA from intralesional biopsy specimens in 17 patients for somatic unbalance. Results were confirmed with Sanger sequencing. RESULTS: We identified 14 pathogenic variants in 13 of 150 patients. Eight variants were previously reported as a disease-causing variant, and six were new. In 55 additional probands we detected 75 variants with unknown significance. Moreover, a previously reported somatic variant was detected in five of 17 available tissue biopsy specimens. CONCLUSIONS: Our results show that many genes can cause a wide variety of syndromic and nonsyndromic disorders, confirming that genetic testing by NGS is the approach of choice to diagnose heritable vascular anomalies, especially, but not only, when an intralesional biopsy specimen is available. The identification of the causative genes and the possibility of tracing somatic variants in tissues provide important information about etiology, patient clinical management, and treatment, and it could highlight otherwise unsuspected clinical situations.

Morbihan Disease: A Rare Case of Periorbital Bilateral Edema with Histopathological Findings of Chronic Inflammation and Demodex Localization.

BACKGROUND Morbihan disease, also known as Morbihan syndrome, is a rare medical condition characterized by chronic facial edema predominantly affecting the upper two-thirds of the face. Despite being recognized in medical literature for decades, its true prevalence and underlying pathophysiology remain poorly understood. Various hypotheses, including impaired lymphatic drainage, abnormal vascular permeability, immune dysregulation, and inflammatory reactions to demodex infestation, have been proposed to explain the etiology. CASE REPORT We present a case of a 61-year-old man with organized periocular edema of the upper third of the face, ultimately leading to Morbihan disease diagnosis. The patient underwent a midface lift, allowing for tissue retrieval for histopathological examination of the eyelid edematous skin, which revealed chronic inflammation, ectasia of small lymphatic vessels, and features of demodex intrafollicular localization. These findings were not specific, but consistent with the diagnostic hypothesis. The patient was referred to a rheumatologist for further evaluation and treatment. He did not respond well to systemic corticosteroids and immunosuppressive therapy. Rather, this resulted in extension of the edema to the upper eyelid. The patient opted not to undergo further treatment. CONCLUSIONS Morbihan disease is often misdiagnosed due to its rarity and overlapping clinical features with other facial conditions. Its management is challenging and can require a combination of medical and surgical interventions. Systemic corticosteroids, immunosuppressive agents, and topical treatments have had varying success. Surgical procedures, such as blepharoplasty or laser therapy, can be considered in severe cases. Early recognition and appropriate management are crucial to improving patient outcomes and quality of life.

Recurrence of Basal Cell Carcinoma Treated with Surgical Excision and Histopathological Analysis with Frozen Section Technique with Complete Margin Control (CMC-FS): A 15-Year Experience of a Reference Center.

BACKGROUND: Basal cell carcinoma (BCC) is the most common type of eyelid malignancy and it is considered to be dangerous due to its proximity to functionally essential organs. Early diagnosis and complete excision of the primary lesion are crucial to prevent infiltration and metastasis. The study aims to evaluate the extent of recurrence in subjects affected by BCC of the upper third of the face treated with surgical eradication and the frozen section technique with complete margin control (CMC-FS), in comparison with the gold standard Mohs micrographic surgery (MMS). MATERIALS AND METHODS: The study included 111 patients with 111 biopsy-proven eyelid BCCs. On clinical examination, all lesions were removed with 2 mm margins clinically free of neoplasm. Prior to reconstruction, CMC-FS analysis of all surgical margins was performed on each tumor for histopathologic confirmation. Subsequently, all margins were presented for the permanent paraffin sections. RESULTS: There were 69 primary carcinomas and 42 secondary carcinomas among the 111 samples. No recurrence occurred in 109 tumors followed-up for at least 5 years, with a total recurrence rate of 1.8%. The median time between lesion excision and diagnosis of recurrence was 20 months. CONCLUSIONS: at 5-year follow-up, CMC-FS guided excision of BCCs of the eyelids resulted in recurrence rates equivalent to MMS. Intraoperative microscopic control of all margins reduced the recurrence rate of the upper third of the facial BCCs, correlating with easier reconstruction with better esthetic and functional outcome.

Long-Term Sequential Digital Dermoscopy of Low-Risk Patients May Not Improve Early Diagnosis of Melanoma Compared to Periodical Handheld Dermoscopy.

Sequential digital dermoscopy (SDD) enables the diagnosis of a subgroup of slow-growing melanomas that lack suspicious features at baseline examination but exhibit detectable change on follow-up. The combined use of total-body photography and SDD is recommended in high-risk subjects by current guidelines. To establish the usefulness of SDD for low-risk individuals, we conducted a retrospective study using electronic medical records of low-risk patients with a histopathological diagnosis of cutaneous melanoma between 1 January 2016 and 31 December 2019, who had been referred and monitored for long-term follow-up of clinically suspicious melanocytic nevi. We sought to compare the distribution of "early" cutaneous melanoma, defined as melanoma in situ and pT1a melanoma, between SDD and periodical handheld dermoscopy in low-risk patients. A total of 621 melanomas were diagnosed in a four-year timespan; 471 melanomas were diagnosed by handheld dermoscopy and 150 by digital dermoscopy. Breslow tumor thickness was significantly higher for melanomas diagnosed by handheld compared to digital dermoscopy (0.56 ± 1.53 vs. 0.26 ± 0.84, p = 0.030, with a significantly different distribution of pT stages between the two dermoscopic techniques. However, no significant difference was found with respect to the distribution of pT stages, mean Breslow tumor thickness, ulceration, and prevalence of associated melanocytic nevus in tumors diagnosed on periodical handheld dermoscopy compared to SDD. Our results confirm that periodical dermoscopic examination enables the diagnosis of cutaneous melanoma at an earlier stage compared to first-time examination as this was associated in our patients with better prognostic features. However, in our long-term monitoring of low-risk subjects, Breslow tumor thickness and pT stage distribution did not differ between handheld periodical dermoscopy and SDD.

A Case of Pulmonary Sarcoidosis during First-Line Targeted Therapy with Dabrafenib Plus Trametinib in BRAF V600E-Mutated Metastatic Melanoma.

BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi) exert a cytotoxic and immune-mediated effect on metastatic melanoma. The immune-mediated mechanism can lead to some adverse events, including panniculitis, erythema, keratitis, vitiligo-like lesions, or, more rarely, sarcoid-like skin reactions. In particular, sarcoidosis-related manifestations during melanoma treatment are characterized mainly by skin involvement and are seldom associated with chest or lymph node lesions. Overall, managing these adverse events can be very challenging from the diagnostic and therapeutic points of view. We present a case of pulmonary sarcoidosis; it is the first without skin involvement and initially only with lung presentation, diagnosed during treatment with BRAFi and MEKi for metastatic cutaneous melanoma. After about 2 years of treatment, with an oncological complete response, a histologically confirmed form of pulmonary sarcoidosis was diagnosed and initially interpreted as tumor progression. Sarcoidosis has always remained asymptomatic. After progression in the thorax and supraclavicular lymph nodes, steroid therapy with prednisone was instituted with total remission of the signs of disease. The targeted therapy has never been interrupted, and the patient still shows a complete response. This clinical case suggests that rare immune-mediated events, such as pulmonary sarcoidosis, should be considered during targeted therapy for metastatic melanoma and not only during treatment with immune checkpoint inhibitors. It also suggests that the interruption of targeted treatment should be accurately considered based on the expected risks or benefits since such immune-mediated events may have low clinical impact.

Connective tissue panniculitis and vitiligo in a patient with stage IV melanoma achieving complete response to dabrafenib and trametinib combination therapy.

The combination of BRAF and MEK inhibitors, such as dabrafenib and trametinib, respectively, is an established treatment option for patients with advanced BRAFV600-mutated melanoma. With the wide adoption of these therapies, a range of cutaneous adverse effects has been reported. We describe the case of a 47-year-old woman with BRAFV600E-mutated stage IV melanoma treated with dabrafenib and trametinib for 30 months who presented to our attention for painful skin lesions that had been present on her limbs since the start of targeted therapy. We also observed vitiligo-like lesions on the extensor surface of both legs. Despite achieving a complete oncological response, the patient had to discontinue the treatment because of persisting fever, nausea and painful skin nodules that significantly impaired her quality of life. The recognition of cutaneous signs of efficacy of such drugs for advanced melanoma is of primary importance in order to identify patients with potential long-term clinical benefits.

Small lymphocytic lymphoma in true trilineage hematopoietic tissue within heterotopic ossification in an enucleated blind painful eye: a case report.

BACKGROUND: The finding of hematological malignancies within bone marrow in heterotopic ossification has been reported only a handful of times previously in the literature. We described a case of true trilineage hematopoiesis in an excised area of heterotopic ossification from an enucleated blind painful eye. CASE PRESENTATION: A 70-year-old Caucasian man, positive for asymptomatic lymphoplasmacytic lymphoma, presented with a blind painful right eye in our ophthalmology department to evaluate enucleation bulbi. After enucleation, a histopathologic examination revealed the presence of intertrabecular infiltration in the metaplastic bone marrow of non-Hodgkin B lymphoma, with small lymphocytes, with similar characteristics to the already known disease. CONCLUSION: This uncommon case reveals the possibility of the localization of malignant cells within bone metaplasia of intraocular ossification in an enucleated blind painful eye. From a practical point of view, a careful systematic histopathological examination of all resected tissues in patients with a history of malignant neoplastic pathology is necessary to confirm the diagnosis and exclude occult malignancies.