Metastatic papillary thyroid cancer to cerebellum with incidental medullary microcarcinoma.

Thyroid cancer is the most common endocrine cancer, with papillary thyroid carcinoma (PTC) accounting for the majority of these cases. Cerebellar metastasis is rarely the presenting feature and confers poor prognosis. Genetic mutations in this setting are most commonly TERTp, in contrast to BRAF V600E in the majority of PTC. We report the case of an 82 year-old male who presented with a symptomatic right cerebellar lesion and underwent surgical resection to demonstrate metastatic PTC. Extensive workup with computed tomography, neck ultrasound and FDG-PET was suggestive of a left thyroid primary lesion, with FNA confirming PTC. However, total thyroidectomy demonstrated incidental microMTC (medullary thyroid microcarcinoma, defined as tumour <10mm) without any evidence of PTC, whereas the left level VI neck dissection demonstrated a 30mm nodule of PTC without identifiable normal thyroid or lymph node tissue.

Mass Forming Basement Membrane Material Secondary to Adnexal Adenocarcinoma - a Case Report.

We report a 77-year-old male with biopsy proven adnexal adenocarcinoma where there was only mass deposit of basement membrane material in the therapeutic excision. To our knowledge, this finding is extremely rare and has not been previously described in the literature and necessitates distinction from other conditions which cause eosinophilic hyaline deposits within the dermis.

Merkel cell carcinoma in situ: A systematic review of prognosis and management.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare primary cutaneous neuroendocrine tumour. While dermally invasive MCC is known to have a five-year survival of only 30-40%, the prognosis and management of MCC in situ (MCCis) is not widely reported. OBJECTIVE: We present a systematic review to elucidate the prognosis and management of MCCis. METHODS: We performed a systematic review, searching three databases to 01 June 2021. Case reports, cohort studies, clinical trials and literature reviews were considered for inclusion. RESULTS: We identified 26 cases of MCCis published in the literature with a median age of 74 years and involving 19 males and 7 females. Most cases were on the face and neck (n = 17), followed by upper limb (n = 8) and lower limb (n = 1). Sentinel lymph node biopsy was performed in three patients, and all were negative. One subject underwent adjuvant radiotherapy. No MCCis-associated deaths were reported. CONCLUSION: This review suggests that MCCis has an excellent prognosis with minimal, if any, risk of mortality and a very low risk of dermal invasion and recurrence when treated with wide local excision alone. Sentinel lymph node biopsy is unlikely to be useful for MCCis.

Interobserver concordance in visual assessment of Ki67 immunohistochemistry in surgical excision specimens from patients with lymph node-negative breast cancer.

PURPOSE: This study aimed to determine the interobserver concordance of two methods for proliferation assessment in breast cancer using Ki67 immunohistochemistry. METHODS: Ki67 was independently assessed in randomly selected tumour samples from patients with lymph node-negative breast cancer using two different methods: either cell counting or visual estimation of hot spot areas. For hot spot cell counting, positive and negative cell numbers were recorded for total cell counts of 300-500, 500-800 and 800-1000 cells. Visual estimation involved allocation of a score from 1 to 5 using a visual scale to estimate percentage positivity. Interobserver agreement for hot spot counting was calculated using a two-way fixed effects intraclass correlation model, and by using Cohen's kappa measure for visual assessment. Prognostic concordance between the two methods was also calculated using Cohen's kappa. RESULTS: Samples from 96 patients were included in this analysis. Interobserver agreement for hot spot cell counting was excellent (> 0.75) across all three cell count ranges, with correlation coefficients of 0.88 (95% CI 0.84-0.92), 0.87 (95% CI 0.82-0.91) and 0.89 (95% CI 0.85-0.92), respectively. Interobserver agreement with visual estimation was greatest for hot spots compared with areas of intermediate or low proliferation, with kappa scores of 0.49, 0.42 and 0.40, respectively. Both assessment methods demonstrated excellent prognostic agreement. CONCLUSIONS: Interobserver and prognostic concordance in Ki67 immunohistochemistry assessments was high using either hot spot cell counting or visual estimation, further supporting the utility and reproducibility of these cost-efficient methods to assess proliferation.

Paraneoplastic bullous pemphigoid - A sign of clear cell renal carcinoma.

Paraneoplastic bullous pemphigoid is a rare paraneoplastic syndrome. Rash is pruritic, with erythematous eruption of large subepidermal bullae over skin and often mucosal surfaces. We present an 84y woman with a three week history of erythematous rash, and 48hrs of bullae. A left clear cell renal cell carcinoma was identified on CT imaging during the presentation. Subsequent removal of the tumour resulted in resolution of bullous pemphigoid symptoms. This first-of-kind case and successful result strengthens the association between renal cell carcinoma and paraneoplastic bullous pemphigoid, arguing for a high degree of clinical suspicion in unexplained presentations of bullous pemphigoid.

Survival and prognosis of individuals receiving programmed cell death 1 inhibitor with and without immunologic cutaneous adverse events.

BACKGROUND: The treatment response to new immunotherapy in advanced melanoma patients remains varied between individuals. Immune-related cutaneous side effects might have prognostic value. OBJECTIVE: To determine whether development of ≥1 of the 3 immune-mediated cutaneous events (eczema, lichenoid reaction, or vitiligo-like depigmentation) is associated with improved progression-free survival. METHODS: A cohort study of adults with stage IIIC-IV melanoma treated with pembrolizumab or nivolumab during May 1, 2012-February 1, 2018, at Westmead Hospital, Sydney, Australia. Treatment response was based on iRECIST version 1.1. RESULTS: In total, 82 patients of an average age of 59.9 years were included. Median follow-up was 40.7 months; 33 patients had ≥1 target skin reaction. Skin reactions developed in one-third of individuals by 6 months. At any given time, the instantaneous risk of disease progression and death was lower for individuals who had ≥1 cutaneous adverse event (CAE) develop. Compared with individuals with no CAE, the hazard ratio for disease progression and death for individuals who had ≥1 CAE develop was 0.46 (95% confidence interval 0.23-0.91; P = .025) by the time-dependent Cox proportional hazards model. LIMITATIONS: Single-center study. CONCLUSION: This study demonstrates an association between the development of ≥1 of 3 CAEs and improved progression-free survival in this cohort of patients.

Cutaneous adverse events of anti-programmed death 1 antibodies combined with anti-cytotoxic T-lymphocyte-associated protein 4 therapy use in patients with metastatic melanoma.

To date, cutaneous toxicities of combination therapies of anti-programmed death-1 (anti-PD1) and ipilimumab are poorly described. Understanding cutaneous presentations will aid clinicians with early diagnoses and treatments. We aim to describe and compare the cutaneous toxicities between the combination therapies and anti-PD1 monotherapy. This is a cohort study comparing previously published data on 82 patients with metastatic melanoma on anti-PD1 monotherapy, with a new group of 25 patients with metastatic melanoma receiving combined ipilimumab and pembrolizumab between January 2015 to February 2016. A single institution, internal referrals were received from medical oncology teams from May 2012 to February 2015 for the anti-PD1 monotherapy group and from January 2015 to February 2016 for combination group. All patients who were treated with either anti-PD1 therapy or combination therapies during the timeframe within the institution were included in the study. Kaplan-Meier curves were used to illustrate the time taken to develop cutaneous toxicities in the monotherapy and combination groups. Of the 25 patients, 88% developed new cutaneous lesions since the treatment. Immune-related lesions; lichenoid reaction (64%) and vitiligo (28%) were the most frequent. The incidence of lichenoid reaction increased rapidly in the early phase of treatment. Approximately one-third developed their first lichenoid reaction within 12 days of commencing treatment in combination group compared to 14 months in the anti-PD1 monotherapy. The rate of incidence of vitiligo was comparable in both groups. There was no statistical significance in the development of cutaneous toxicities and the treatment response between the two groups. The time taken to develop immune-related cutaneous toxicities was shorter for those on combination therapy versus anti-PD1 monotherapy.

Anti-programmed cell death-1 therapy-associated bullous disorders: a systematic review of the literature.

Bullous disorders are rare adverse events associated with anti-programmed cell death-1 (anti-PD1) therapy. This paper presents two new cases of bullous disorders under anti-PD1 therapy and systematically reviewed the literature to foster a better understanding of the presentation and pathogenesis of bullous disorders under anti-PD1. A systematic review of the literature was completed using MEDLINE, Embase, PubMed and LILACS databases. We identified 29 cases of bullous disorders under anti-PD1 therapy, including our two new cases. This includes 18 cases of bullous pemphigoid (BP), five cases of toxic epidermal necrolysis (TEN)/Stevens-Johnson syndrome (SJS) spectrum, one case of erythema multiforme (EM), four cases of bullous lichenoid reactions and one case of vesiculobullous eczema. In BP, blistering occurred by a median of 23 weeks after anti-PD1 therapy initiation and is often preceded by a prodrome, which lasts for a median of 9.5 weeks. Limbs and trunk were the most frequently involved body sites. Most cases (76%) achieved remission. In TEN/SJS/EM, blistering was usually preceded by a prodrome of interface dermatitis that lasted for a median of 1.5 weeks. Most cases (80%) died from either TEN/SJS or disease progression. Bullous disorders under anti-PD1 may be classified clinically as BP, SJS/TEN/EM, bullous lichenoid reactions and vesiculobullous eczema and histologically by intraepidermal splitting and subepidermal splitting. BP is usually preceded by a pruritic eruption and has a relatively good prognosis. SJS/TEN is usually preceded by a maculopapular eruption and has a very poor prognosis.

Incidence of Basal Cell Carcinoma and Squamous Cell Carcinoma in Patients on Antiprogrammed Cell Death-1 Therapy for Metastatic Melanoma.

Systemic melanoma therapies have the potential to affect basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cuSCC) development. In this study, we aim to compare the incidence of BCC and cuSCC in patients with metastatic melanoma treated with antiprogrammed cell death-1 (anti-PD1), BRAF inhibitor (BRAFi) monotherapy or dabrafenib and trametinib combination therapy (CombiDT) with a group of control patients having similar risk factors. We reviewed the records of melanoma patients on anti-PD1, BRAFi, or CombiDT, and patients from the High-Risk Melanoma Clinic, Westmead Hospital. We also performed an immunohistochemical analysis of BCCs under anti-PD1 compared with controls using PD1, PD-L1, CD3, CD8, and CD20 stains. For the results, in all, 340 patients were included; 82 on anti-PD1, 134 on BRAFi, 69 on CombiDT, and 55 controls. BRAFi had the highest incidence of BCC (12.7%), followed by CombiDT (10.1%) and anti-PD1 (2.4%). The incidence of BCC was significantly lower in patients on anti-PD1 (2.4% vs. 19.4%; P<0.001) compared with controls. Patients on anti-PD1 were 8.54 times less likely to develop BCC than the controls [hazard ratio, 0.117 (95% confidence interval, 0.026-0.526), P=0.005]. BRAFi and CombiDT showed no significant differences in BCC incidence compared with controls. BRAFi had the highest cuSCC incidence (23.9%), followed by anti-PD1 (7.3%) and CombiDT (2.9%). The incidence of cuSCC was significantly higher in patients on BRAFi (23.9% vs. 3.5%; P<0.001) compared with controls, but anti-PD1 and CombiDT showed no differences in cuSCC incidence compared with controls. Immunohistochemistry analysis of 10 BCC from under anti-PD1 and 8 BCC from controls patients showed that while all BCC had negative PD-L1 staining, the percentage of PD1 staining in anti-PD1 group is significantly lower than that of the control group (independent t test, 8% vs. 26%; P<0.001). In conclusion, our study suggests that anti-PD1 therapy decreases the incidence of BCC, as a result of the PD1/PD-L1 blockade. Future studies investigating the role of anti-PD1 in suppressing or treating BCC may be warranted.

Intracorneal pustular drug eruption, a novel cutaneous adverse event in anti-programmed cell death-1 patients that highlights the effect of anti-programmed cell death-1 in neutrophils.

The introduction of anti-programmed cell death-1 (anti-PD1) monoclonal antibodies has revolutionized the treatment of various advanced malignancies. Despite its efficacy, anti-PD1 therapy is accompanied by a variety of cutaneous adverse events. A 79-year-old man developed erythematous scaly plaques and pustules of the forehead, legs and arms after four cycles of nivolumab infusions every 2 weeks. Histology showed intracorneal pustules with dermal neutrophils and eosinophils. He was treated successfully with topical corticosteroids without discontinuation of nivolumab. We report subcorneal pustular eruption as a novel cutaneous adverse event in patients on anti-PD1 therapy. Other neutrophilic eruptions (psoriasis, Sweet's syndrome, acute generalized pustulosis) have been reported in patients on anti-PD1 treatments, suggesting the neutrophil as another cell type modulated by anti-PD1 antibodies.

PD-1 inhibitor-associated lichenoid inflammation with incidental suprabasilar acantholysis or vesiculation-Report of 4 cases.

BACKGROUND: Immune checkpoint agents targeting programmed cell death-1 protein (PD1) or cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) receptors are increasingly utilized in treatment of advanced malignancies. However, these immunotherapies are commonly associated with idiosyncratic cutaneous adverse reactions. Thus, recognition and awareness of these reactions are necessary. METHODS: We reviewed the skin biopsies of all patients on anti-PD1 therapy with or without ipilimumab who developed lichenoid inflammation and included those with microscopic suprabasal or intraepidermal clefts. RESULTS: Four patients presented with interface dermatitis with microscopic intraepidermal clefts. In 2 patients, the clefts were well developed and had some acantholytic cells while the other 2 appeared to be spongiosis or inflammation related. Immunofluorescence was negative in 1 patient. None of them had clinical findings in keeping with paraneoplastic pemphigus (PP) and the symptoms improved with either topical corticosteroid or withdrawal of immunotherapy. CONCLUSIONS: Lichenoid drug reaction occurring in patients receiving anti-PD1 therapy may be associated with microscopic suprabasal or intraepidermal clefting. The clinical course was similar to lichenoid drug reactions without clefting even though some lesions may resemble PP microscopically.

Acute Truncal Lymphedema Secondary to Axillary Metastatic Melanoma Presenting Like Cellulitis.

There are reported cases of diphencyprone used in treating cutaneous metastases of melanoma. Here, we report a patient with previous primary melanoma on his left back treated with surgical excision and lymphadenectomy, followed by radiotherapy for the recurrent tumor on the primary site. Despite radiotherapy and treatment with dabrafenib and trametinib, in-transit metastases have developed and topical diphencyprone was applied to these metastases. Six weeks later, the patient developed fever and a spreading erythematous tender indurated plaque covering the left side of the body including axillae, back, and flank, clinically suggestive of cellulitis. Systemic antibiotic therapy did not improve the condition and a biopsy showed sparse lymphocytic infiltrate. With the diagnosis of possible acute lymphedema, a CT scan was requested that showed significant axillary lymph node metastasis. The fever was considered secondary to dabrafenib and trametinib therapy. This case highlights that, in patients with lymphadenectomy, atypical forms of lymphedema on the body may appear. Truncal lymphedema is an infrequent event.

Histologic Assessment of Lichenoid Dermatitis Observed in Patients With Advanced Malignancies on Antiprogramed Cell Death-1 (anti-PD-1) Therapy With or Without Ipilimumab.

Lichenoid drug reaction is a common adverse reaction in patients taking immune-modulatory agents such as antiprogramed cell death (PD-1) and cytotoxic T lymphocyte antigen-4 agents. The authors describe the clinical and histologic features of lichenoid drug reaction in 20 biopsies from 15 patients on anti-PD-1 agents and 9 biopsies from 7 patients on anti-PD-1 plus ipilimumab therapy. Clinically, all except 2 patients presented with discrete, violaceous exanthematous papules to plaques. The lichenoid inflammation in the majority (18 of 29 biopsies) was florid although histology was quite heterogeneous. Nevertheless, there was frequent involvement of the superficial follicular epithelium and acrosyringium, and also a propensity to blister that occurred in approximately 20% of the biopsies. Occasional patients had disease closely resembling lichen planus, although all of these biopsies had some atypical features for lichen planus such as parakeratosis. Dermal eosinophils were common particularly in those with mild inflammation. The lichenoid reaction was responsive to topical steroid or oral systemic treatment in general, and the anti-PD-1 agent had to be ceased in only one patient.

PD-1 inhibitors induced bullous lichen planus-like reactions: a rare presentation and report of three cases.

The introduction of immunotherapy such as antiprogrammed death1 (anti-PD1) monoclonal antibodies has changed the scenario of treatment in cancer. Apart from their impressive efficacy profiles, they are better tolerated than the anticytotoxic T-lymphocyte-associated protein 4 antibodies. Dermatological adverse events such as pruritus and rash have been reported in various clinical trials. We report three cases of anti-PD1-induced bullous lichen planus (LP)-like reactions encountered in our institution. These patients developed LP-like papules and annular plaques with vesicles or crusted centres. Histology showed LP-like changes with negative immunofluorescence. Vesiculobullous lesions in patients treated with anti-PD1 therapies require a careful clinicopathological evaluation.

Bullous pemphigoid, an autoantibody-mediated disease, is a novel immune-related adverse event in patients treated with anti-programmed cell death 1 antibodies.

Anti-programmed cell death 1 (anti-PD1) antibodies such as pembrolizumab have shown improved progression-free and overall survival in patients with advanced melanoma. Of 124 patients reviewed in Westmead Hospital from May 2012 to November 2015, treated with pembrolizumab for advanced melanoma, we encountered three cases of bullous pemphigoid (BP). We have previously reported a case of BP. In two recent cases, BP was diagnosed early and treated promptly with potent topical or oral steroid. Patients on anti-PD1 antibodies are at a higher risk of developing cutaneous immune-related adverse events such as lichenoid reactions, eczema and vitiligo. No cases of BP were encountered in the previously published cohort of 260 melanoma patients treated with BRAF inhibitors; as such, it appears that BP is associated with anti-PD1 treatment rather than metastatic melanoma. BP appears to be another immune-related adverse event, and clinicians should have a low threshold for performing cutaneous biopsies and immunofluorescence studies in patients on anti-PD1 therapies.

Cutaneous adverse events (AEs) of anti-programmed cell death (PD)-1 therapy in patients with metastatic melanoma: A single-institution cohort.

BACKGROUND: Anti-programmed cell death (PD)-1 therapy is emerging as the backbone of new standard of care immunotherapy for metastatic melanoma. Immune-related cutaneous events are observed in these patients. OBJECTIVE: We sought to describe cutaneous adverse events observed in patients with metastatic melanoma on anti-PD-1 therapy. METHODS: We reviewed the clinical and histologic information of all patients treated with single-agent anti-PD-1 therapy for metastatic melanoma at Westmead Hospital, Sydney, Australia, from May 2012 to February 2015. RESULTS: Of the 82 patients included in the study, 34 had dermatology assessments. Forty (49%) developed a form of anti-PD-1-associated cutaneous adverse events. In all, 17% developed lichenoid reactions and eczema, and 15% developed vitiligo. An estimated 25% of patients were expected to develop their first lichenoid reactions within 8.3 months, and eczema and vitiligo within 10.3 months of therapy. These adverse events tend to appear together in patients on anti-PD-1 therapy. LIMITATIONS: The study was from a single center and clinical information was reviewed retrospectively in patients not referred to dermatology. CONCLUSION: Anti-PD-1 therapy is associated with the development of immune-related cutaneous events. Lichenoid reactions, eczema, and vitiligo are the 3 most prevalent lesions observed in our population. There is a tendency for lichenoid reactions and eczema to occur with vitiligo.

Predicting discordant HER2 results in ipsilateral synchronous invasive breast carcinomas: experience from a single institution.

With the emergence of multiple lines of highly effective Human Epidermal Growth Factor Receptor 2 (HER2) directed therapy, accurate identification of HER2 positive tumour has become a critical aspect in the histopathological analysis of breast cancers. Multifocal invasive breast carcinomas are relatively common, and given the aggressive inherent biology of HER2 positive disease, identification of even small tumours with HER2 positive status may be of importance for treatment planning. There are currently no clear guidelines as to whether all of these foci should be tested for HER2 status. We reviewed the results of 172 patients in whom HER2 in situ hybridisation (ISH) testing was performed on at least two ipsilateral synchronous invasive carcinomas. Discordant results in different invasive foci were relatively uncommon and occurred in only eight (5%) of the 172 patients. This showed a statistically significant correlation with similarly discordant oestrogen receptor (ER) results. In addition HER2 discordance was more likely amongst different tumour foci if these arose in distinct and separate areas of DCIS. An algorithm based on a combination of College of American Pathologists (CAP) recommendation for HER2 testing, differing ER status and background DCIS profile may be useful in detecting these discordant cases.