Melanoma Metastases to the Adrenal Gland Are Highly Resistant to Immune Checkpoint Inhibitors.

BACKGROUND: Adrenal gland metastases (AGMs) are common in advanced-stage melanoma, occurring in up to 50% of patients. The introduction of immune checkpoint inhibitors (ICIs) has markedly altered the outcome of patients with melanoma. However, despite significant successes, anecdotal evidence has suggested that treatment responses in AGMs are significantly lower than in other metastatic sites. We sought to investigate whether having an AGM is associated with altered outcomes and whether ICI responses are dampened in the adrenal glands. PATIENTS AND METHODS: We retrospectively compared ICI responses and overall survival (OS) in 68 patients with melanoma who were diagnosed with an AGM and a control group of 100 patients without AGMs at a single institution. Response was determined using RECIST 1.1. OS was calculated from time of ICI initiation, anti-PD-1 initiation, initial melanoma diagnosis, and stage IV disease diagnosis. Tumor-infiltrating immune cells were characterized in 9 resected AGMs using immunohistochemical analysis. RESULTS: Response rates of AGMs were significantly lower compared with other metastatic sites in patients with AGMs (16% vs 22%) and compared with those without AGMs (55%). Patients with AGMs also had significantly lower median OS compared with those without AGMs (3.1 years vs not reached, respectively). We further observed that despite this, AGMs exhibited high levels of tumor-infiltrating immune cells. CONCLUSIONS: In this cohort of patients with melanoma, those diagnosed with an AGM had lower ICI response rates and OS. These results suggest that tissue-specific microenvironments of AGMs present unique challenges that may require novel, adrenal gland-directed therapies or surgical resection.

Cutaneous foreign body microemboli-induced occlusive vasculopathy: A complication of illicit intravenous injection of oral opioid tablets.

Occlusive nonvasculitic vasculopathy is a process characterized clinically by retiform purpura and potential ulceration and necrosis of affected areas, secondary to blockage of small vessels without associated inflammatory vasculitis. Intravascular injection of foreign material is known to cause distal ischemia and necrosis due to thrombosis, local vasoconstriction, or microemboli formation. A 27-year-old male presented with retiform purpura and worsening distal fingertip necrosis of the right upper extremity accompanied by suspicious intravascular polarizable foreign material identified on skin, muscle, and vascular biopsies. We report a case that highlights concerning complications and dermatopathologic findings of intravascular injection of oral opioid tablets.

Diverse clinical and histopathologic features of cutaneous post-transplant lymphoproliferative disorders: A presentation of two cases.

Heterogeneous lymphoproliferative disorders occurring in the post-transplant setting are considered together as post-transplant lymphoproliferative disorders and can rarely present as primary cutaneous lesions. These disorders are often Epstein-Barr virus-driven and in some cases need only be treated with reduction in immune suppressive medications. We present two cases of monomorphic post-transplant lymphoproliferative disorder, a plasmablastic lymphoma and a diffuse large B-cell lymphoma, and summarise common reported clinical and histopathological features.

High-Velocity Paint Gun Injuries.

Cutaneous injuries due to industrial high-pressure paint guns are well-documented in the literature; however, the histologic characteristics are uncommonly described, and facial involvement has not been previously reported. Histopathologic features of paint gun injuries vary depending on the time since injection and type of material. Early lesions display an acute neutrophilic infiltrate, edema, and thrombosis, with varying degrees of skin, fat, and muscle necrosis. More developed lesions (120-192 hours after injury) have prominent histiocytes and fibrosis around necrotic foci, possibly with the pitfall of muscle regenerative giant cells that could be mistaken for sarcoma. Continuing inflammation, swelling, and resultant vascular compression could explain ongoing necrosis months after the accident. The histopathologic differential diagnosis in the absence of clinical history includes paint in an abrasion, foreign body reaction to tattoo, giant cell tumor of tendon sheath, and various neoplasms. If available, radiologic studies can substitute for clinical photographs to indicate the extent of injury. The radiologic differential, uninformed by history, may include calcific periarthritis, gouty tophus, and tumoral calcinosis. Seven cases of injury due to high-velocity paint guns are presented with 4 additional cases mimicking paint gun injury and with review of the literature.

Grape seed extract and resveratrol prevent 4-nitroquinoline 1-oxide induced oral tumorigenesis in mice by modulating AMPK activation and associated biological responses.

Preventive measures against oral carcinogenesis are urgently warranted to lower the high morbidity and mortality associated with this malignancy worldwide. Here, we investigated the chemopreventive efficacy of grape seed extract (GSE) and resveratrol (Res) in 4-nitroquinoline-1-oxide (4NQO)-induced tongue tumorigenesis in C57BL/6 mice. Following 8 weeks of 4NQO exposure (100 µg/ml in drinking water), mice were fed with either control AIN-76A diet or diet containing 0.2% GSE (w/w) or 0.25% Res (w/w) for 8 subsequent weeks, while continued on 4NQO. Upon termination of the study at 16 weeks, tongue tissues were histologically evaluated for hyperplasia, dysplasia, and papillary lesions, and then analyzed for molecular targets by immunohistochemistry. GSE and Res feeding for 8 weeks, moderately decreased the incidence, but significantly prevented the multiplicity and severity of 4NQO-induced preneoplastic and neoplastic lesions, without any apparent toxicity. In tongue tissues, both 4NQO + GSE and 4NQO + Res treatment correlated with a decreased proliferation (BrdU labeling index) but increased apoptotic death (TUNEL-positive cells) as compared to the 4NQO group. Furthermore, tongue tissues from both the 4NQO + GSE and 4NQO + Res groups showed an increase in activated metabolic regulator phospho-AMPK (Thr172) and decreased autophagy flux marker p62. Together, these findings suggest that GSE and Res could effectively prevent 4NQO-induced oral tumorigenesis through modulating AMPK activation, and thereby, inhibiting proliferation and inducing apoptosis and autophagy, as mechanisms of their efficacy.

Patient-derived luminal breast cancer xenografts retain hormone receptor heterogeneity and help define unique estrogen-dependent gene signatures.

Bypassing estrogen receptor (ER) signaling during development of endocrine resistance remains the most common cause of disease progression and mortality in breast cancer patients. To date, the majority of molecular research on ER action in breast cancer has occurred in cell line models derived from late stage disease. Here we describe patient-derived ER+ luminal breast tumor models for the study of intratumoral hormone and receptor action. Human breast tumor samples obtained from patients post surgery were immediately transplanted into NOD/SCID or NOD/SCID/ILIIrg(-/-) mice under estrogen supplementation. Five transplantable patient-derived ER+ breast cancer xenografts were established, derived from both primary and metastatic cases. These were assessed for estrogen dependency, steroid receptor expression, cancer stem cell content, and endocrine therapy response. Gene expression patterns were determined in select tumors ±estrogen and ±endocrine therapy. Xenografts morphologically resembled the patient tumors of origin, and expressed similar levels of ER (5-99 %), and progesterone and androgen receptors, over multiple passages. Four of the tumor xenografts were estrogen dependent, and tamoxifen or estrogen withdrawal (EWD) treatment abrogated estrogen-dependent growth and/or tumor morphology. Analysis of the ER transcriptome in select tumors revealed notable differences in ER mechanism of action, and downstream activated signaling networks, in addition to identifying a small set of common estrogen-regulated genes. Treatment of a naïve tumor with tamoxifen or EWD showed similar phenotypic responses, but relatively few similarities in estrogen-dependent transcription, and affected signaling pathways. Several core estrogen centric genes were shared with traditional cell line models. However, novel tumor-specific estrogen-regulated potential target genes, such as cancer/testis antigen 45, were uncovered. These results evoke the importance of mapping both conserved and tumor-unique ER programs in breast cancers. Furthermore, they underscore the importance of primary xenografts for improved understanding of ER+ breast cancer heterogeneity and development of personalized therapies.

Cutaneous decidualized endometriosis in a nonpregnant female: a potential pseudomalignancy.

Endometriosis is a disease process characterized by ectopic endometrial tissue. Involvement most commonly occurs in the lower pelvis, outside the uterine cavity, but can occur elsewhere, including the skin. Cutaneous endometriosis is a rare manifestation of this disease, with decidualization occurring in a very small minority of cases, almost always seen in pregnant females. Cutaneous involvement of endometriosis may present a diagnostic problem for the pathologist, particularly in the event of decidualization. Decidualization may mimic a malignancy and as a result may result in unnecessary diagnostic studies for the patient. We present a case of a nonpregnant patient with decidualized cutaneous endometriosis, discuss the histopathologic and immunohistochemical features of this entity, and review the pertinent literature on this subject. To our knowledge, this is the second reported case of cutaneous decidualized endometriosis in a nonpregnant female.

A "high-risk" epithelioid hemangioendothelioma presenting as a solitary, ulcerated, subcutaneous tumor.

So-called "high-risk" epithelioid hemangioendotheliomas are uncommon neoplasms that demonstrate classic histopathologic features of epithelioid hemangioendotheliomas and a size larger than 3 cm or >3 mitotic figures per 50 high power fields. These neoplasms show an increased rate of metastasis (25% of cases) and are associated with a poor 5-year survival (59%). They may pose a diagnostic challenge for dermatopathologists as they mimic metastatic carcinoma, malignant mixed tumor, melanocytic neoplasms, epithelioid sarcoma, and epithelioid angiosarcoma. High-risk epithelioid hemangioendothelioma has not been previously reported as a solitary ulcerated mass in the skin. Here, we describe one such lesion that developed as a rapidly growing ulcerative skin tumor in a 33-year-old African American man with a remote history of Burkitt lymphoma. We also review the evolution and controversies in the understanding and classification of this neoplasm.

CD20, AIF-1, and TGF-beta in graft-versus-host disease: a study of mRNA expression in histologically matched skin biopsies.

Graft-versus-host disease is the leading cause of non-relapse mortality after allogeneic bone marrow transplantation. The cell-mediated immune mechanisms that underlie the pathogenesis of graft-versus-host disease remain unclear. In this study, 47 skin biopsies representing graft-versus-host disease grades 0-III, lichenoid, and sclerodermoid were included from 31 allogeneic bone marrow transplantation recipients. RNA from paraffin-embedded tissue was harvested. Transcript levels of the following markers were assessed and correlated with grade and survival: CD3, CD20, FoxP3, IL-17, gamma-interferon (IFN-gamma), transforming growth factor-beta (TGF-beta), IL-6, connective tissue growth factor (CTGF), allograft inflammatory factor-1(AIF-1), and IL-13. Levels of three markers significantly correlated with the length of survival (TGF-beta, correlation coefficient -20.8, P=0.016; AIF-1, 13.2, P=0.016; and CD20, 66, P=0.027). CD20 expression was limited to lichenoid cases. Levels of TGF-beta, AIF-1, and IFN-gamma appeared to correlate with histological progression, but did not reach statistical significance. Expression of FoxP3 correlated with worse survival, and approached statistical significance (P=0.053). Two potential mechanistic pathways were identified: the 'scleroderma' group (AIF-1 and TGF-beta) and the 'B-cell' group (CD20). Transcript levels of these markers were implicated in the progression from acute to chronic disease, and also correlated significantly with the duration of survival. Identification of these three markers may direct therapy selection with targeted agents, including the use of rituximab when B-lymphocytes are implicated.

Dermatitis Artefacta, a Form of Factitial Disorder Imposed on Self, Misdiagnosed as Pyoderma Gangrenosum for Eight Years.

Dermatitis artefacta is a rare psychological disorder in which patients self-inflict cutaneous lesions to satisfy an emotional need. Due to the nature of this disease, patients can present with a wide array of sometimes very severe skin lesions. Here, we describe a case of dermatitis artefacta initially misdiagnosed as pyoderma gangrenosum and treated as such for eight years. The patient reported a long history of cutaneous ulcers on her extremities and trunk, with resultant extensive scarring. Upon presentation, she displayed rapidly progressing necrotizing skin lesions on her bilateral distal lower extremities. Both the skin manifestations and histologic sections were extremely atypical for pyoderma gangrenosum leading to extensive medical records review and subsequent diagnosis of dermatitis artefacta. This case represents the importance of the timely recognition and treatment of dermatitis artifacta to prevent its progression to severe harm and even death.

Multi-visceral resection of pancreatic VIPoma in a patient with sinistral portal hypertension.

BACKGROUND: VIPomas are rare neuroendocrine tumors poorly described in the literature. Aggressive resection of patients with advanced VIPoma neuroendocrine tumors has rarely been reported. CASE PRESENTATION: A 46 year old women presented with abdominal pain and diarrhea. A three-dimensional (3-D) pancreas protocol computed tomography scan revealed an 18 x 12 cm pancreatic VIPoma abutting the liver, stomach, spleen, left adrenal, colon that also invaded the distal duodenum - proximal jejunum at the ligament of Treitz in association with sinistral portal hypertension. Following preoperative proximal splenic artery embolization, the patient with underwent successful en bloc resection of the locally advanced VIPoma in conjunction with a diaphragmatic resection, total gastrectomy, splenectomy, left adrenalectomy, as well as small and large bowel resection. The estimated blood loss was 500 ml. All margins were negative (R0 resection). The patient is alive and disease-free. CONCLUSION: This case illustrates the role of aggressive resection of pancreatic neuroendocrine tumors and highlights several key technical points that allowed for successful resection.

Unusual presentation of ectopic extramammary Paget disease.

Extramammary Paget disease (EMPD) is a malignant tumor typically found in apocrine-rich areas of the skin, particularly in the anogenital region. Some germinative apocrine-differentiating cells might exist on the trunk, preferentially in Asian individuals. Ectopic EMPD arises in nonapocrine-bearing areas, specifically the nongerminative milk line. We present a case of a 67-year-old Thai man with a slowly progressive, pruritic, erythematous to brown plaque on the right lower back of 30 years' duration. Histopathologic examination of 2 scouting biopsies revealed a proliferation of large cells with pleomorphic nuclei, prominent nucleoli, and abundant pale to clear cytoplasm within the epidermis. In one of the biopsies, tumor cells were found in the dermis with an infiltrative growth pattern. Immunohistochemically, the tumor cells were positive for cytokeratin 7, carcinoembryonic antigen, and gross cystic disease fluid protein 15. Based on these findings, a diagnosis of ectopic EMPD was made.

Discordance Between Intraoperative Consultation by Frozen Section and Final Diagnosis.

Discrepancies between intraoperative consultations with frozen section diagnosis and the final pathology report have the potential to alter treatment decisions and affect patient care. Monitoring these correlations is a key component of laboratory quality assurance, however identifying specific areas for improvement can be difficult to attain. Our goal is to develop a standardized method utilizing root cause analysis and a modified Eindhoven classification schematic to identify the source of discrepancies and deferrals and subsequently to guide performance improvement initiatives. A retrospective review of intraoperative consultations performed at a tertiary level hospital and cancer center over a 6-month period identified deferrals and discrepancies between the intraoperative consult report and the final pathology report. We developed and applied a classification tool to identify the process errors and cognitive errors leading to discrepant results. A total of 48 (4.6%) discrepancies and 24 (2.3%) deferrals were identified from the 1042 frozen sections. Within the entire data set of frozen sections, the process errors (n = 26, 54.2%) were due to gross sampling (n = 16, 33.3%), histologic sampling (n = 8, 16.7%), and surgical sampling (n = 2, 4.2%). Interpretation errors (n = 22, 45.8%) included undercalls/false negatives (n=8, 16.7%), overcalls/false positives (n = 10, 20.8%), and misclassification errors (n = 4, 8.3%). Application of our classification tool demonstrated that the root cause of discrepancies and deferrals varied both between organ systems and by specific organs and that classification models may be utilized as a standardized method to identify focused areas for improvement.

Kinase gene fusions in defined subsets of melanoma.

Genomic rearrangements resulting in activating kinase fusions have been increasingly described in a number of cancers including malignant melanoma, but their frequency in specific melanoma subtypes has not been reported. We used break-apart fluorescence in situ hybridization (FISH) to identify genomic rearrangements in tissues from 59 patients with various types of malignant melanoma including acral lentiginous, mucosal, superficial spreading, and nodular. We identified four genomic rearrangements involving the genes BRAF, RET, and ROS1. Of these, three were confirmed by Immunohistochemistry (IHC) or sequencing and one was found to be an ARMC10-BRAF fusion that has not been previously reported in melanoma. These fusions occurred in different subtypes of melanoma but all in tumors lacking known driver mutations. Our data suggest gene fusions are more common than previously thought and should be further explored particularly in melanomas lacking known driver mutations.