Cutaneous metastasectomy: Is there a role in breast cancer? A systematic review and overview of current treatment modalities.

Cutaneous metastases (CM) are neoplastic lesions involving the dermis or subcutaneous tissues, originating from another primary tumor. Breast cancer is commonest primary solid tumor, representing 24%-50% of CM patients. There is no "standard of care" on management. In particular, the role of surgery in the treatment of cutaneous metastases from breast carcinoma (CMBC) remains controversial. This systematic review evaluates the role of cutaneous metastasectomy in breast cancer and provides an overview of existing treatment types.

Oesophageal and pulmonary invasive aspergillosis in a patient with multiple myeloma.

Invasive aspergillosis (IA) is a serious fungal infection that primarily affects patients with prolonged and profound neutropenia, and compromised cell-mediated immunity. Aspergillosis of the oesophagus and gastrointestinal tract is uncommon but seen in advanced cases of disseminated IA. However, it is difficult to diagnose antemortem due to the poor specificity of the symptoms and the absence of characteristic imaging findings. Therefore, the reported cases of gastrointestinal aspergillosis have been associated with high morbidity and mortality, and frequently diagnosed postmortem. Here we present a successful outcome in a patient with relapsed and refractory multiple myeloma who had presented with febrile neutropenia, cough and dysphagia, and was diagnosed with disseminated IA comprising of pulmonary and oesophageal involvement. This case highlights the need for a high index of suspicion and the importance of invasive procedures for histopathology and molecular diagnostics to ensure an early diagnosis and therapeutic intervention.

Genomic Analysis of Cutaneous CD30-Positive Lymphoproliferative Disorders.

Primary cutaneous CD30+ T-cell lymphoproliferative disorders are the second most common cutaneous lymphomas. According to the World Health Organization, CD30+ T-cell lymphoproliferative disorders include primary cutaneous anaplastic large cell lymphoma (C-ALCL) and lymphomatoid papulosis (LyP) as well as borderline lesions. C-ALCL and LyP are thought to represent two ends of a spectrum of diseases that have different clinical presentations, clinical courses, and prognoses in their classic forms but share the same histology of medium to large CD30+ atypical lymphoid cell infiltrates. Because the behavior of these entities is different clinically and prognostically, we aim to search for oncogenic genomic variants using whole-exome sequencing that drive the development of LyP and C-ALCL. Clinical information, pathology, immunohistochemistry, and T-cell rearrangements on six cases of LyP and five cases of C-ALCL were reviewed to confirm the rendered diagnosis before whole-exome sequencing of all specimens. Both LyP and C-ALCL had recurrent alterations in epigenetic modifying genes affecting histone methylation and acetylation (SETD2, KMT2A, KMT2D, and CREBBP). However, they also harbor unique differences with mutations in signal transducer and activator of transcription gene STAT3 of the Jak/signal transducer and activator of transcription pathway and EOMES, a transcription factor involved in lymphocyte development, only noted in C-ALCL specimens. Genomic characterization of LyP and C-ALCL in this series confirms the role of multiple pathways involved in the biology and development of these lymphomatous processes. The identification of similar aberrations within the epigenetic modifying genes emphasizes common potential development mechanisms of lymphomagenesis within lymphoproliferative disorders being shared between LyP and C-ALCL; however, the presence of differences may account for the differences in clinical course.

Pathologic complete response with radiation and vismodegib in a patient with advanced basal cell carcinoma: A case report.

In locally advanced basal cell carcinoma (BCC) patients who are not surgical candidates and where radiation therapy (RT) alone would offer lower control rates, the combination of vismodegib and RT delivered concurrently may potentially improve outcomes compared to single modality treatment. The current study presents a case of very advanced, multifocal BCC who received concurrent vismodegib and RT. The patient initially came in with four large primary areas of disease including the left preauriculum, right shoulder, chest wall and right lateral ankle. All sites achieved a clinical complete response, with a pathologic complete response at the right shoulder. The ankle lesion did not require RT and continues to have a clinical complete response. The findings from our case report support several other cases with similar efficacy when vismodegib and RT are combined.

Locally advanced anal small cell carcinoma with durable complete response to chemoradiation followed by consolidation chemotherapy: case report and literature review.

Extrapulmonary small cell carcinoma (EPSCC) is a rare and aggressive clinical entity that can involve a variety of anatomic locations, including the gastrointestinal tract. Involvement of the gastrointestinal tract is associated with a particularly poor prognosis with patients often presenting with widespread dissemination on initial clinical presentation or rapidly progressing to systemic disease from locoregional involvement. Primary small cell carcinoma of the anal canal is extremely rare, with limited published case reports in the literature. As a result, management of this disease is not well defined, and outcomes are poor with high rates of disease relapse. We report a patient with locally advanced anal small cell carcinoma after presenting with irregular bowel movements, changes in stool caliber, and rectal bleeding for two months and achieved a durable complete response to concurrent chemoradiation with cisplatin and etoposide followed by consolidation chemotherapy and discuss our current understanding of this disease. Specifically, we review the epidemiology, risk factors, clinical course, the treatment strategies over the past two decades, and prognosis for EPSCC. Finally, we conclude our discussion by reviewing the rationale of our treatment regimen and the potential role and benefit of consolidation therapy in the management of this rare and aggressive disease.

Whole-Exome and Transcriptome Analysis of UV-Exposed Epidermis and Carcinoma In Situ Reveals Early Drivers of Carcinogenesis.

Squamous cell carcinoma in situ (SCCIS) is a prevalent precancerous lesion that can progress to cutaneous squamous cell carcinoma. Although SCCIS is common, its pathogenesis remains poorly understood. To better understand SCCIS development, we performed laser captured microdissection of human SCCIS and the adjacent epidermis to isolate genomic DNA and RNA for next-generation sequencing. Whole-exome sequencing identified UV-signature mutations in multiple genes, including NOTCH1-3 in the epidermis and SCCIS and oncogenic TP53 mutations in SCCIS. Gene families, including SLFN genes, contained UV/oxidative-signature disruptive epidermal mutations that manifested positive selection in SCCIS. The frequency and distribution of NOTCH and TP53 mutations indicate that NOTCH mutations may precede TP53 mutations. RNA sequencing identified 1,166 differentially expressed genes; the top five enriched gene ontology biological processes included (i) immune response, (ii) epidermal development, (iii) protein phosphorylation, (iv) regulation of catalytic activity, and (v) cytoskeletal regulation. The NEURL1 ubiquitin ligase, which targets Notch ligands for degradation, was upregulated in SCCIS. NEURL1 protein was found to be elevated in SCCIS suggesting that increased levels could represent a mechanism for downregulating Notch during UV-induced carcinogenesis. The data from DNA and RNA sequencing of epidermis and SCCIS provide insights regarding SCCIS formation.

Multidisciplinary Care for Melanoma of Unknown Primary: Experience in the Era of Molecular Profiling.

BACKGROUND: Melanoma of unknown primary (MUP) accounts for approximately 3% of melanoma diagnoses. This study sought to evaluate treatment and outcomes for a modern MUP cohort. METHODS: A retrospective review of MUP was performed at a tertiary referral cancer center. RESULTS: Of 815 melanoma patients, 67 (8.2%) had MUP. Men were more likely to have MUP than women (67% vs. 55%; p = 0.04). The most common sites of MUP were lymph nodes (28%), visceral solid organs (25%), brain (16%), and skin/subcutaneous tissues (10%). Of the patients who underwent tumor genomic profiling, 52% harbored pathogenic BRAF mutations. Of the 24 patients who underwent multi-gene panel testing, all had pathogenic mutations and 21 (88%) had mutations in addition to or exclusive of BRAF, including 11 patients (46%) with telomerase reverse transcriptase promoter mutations. Checkpoint inhibitors (39%) and BRAF-MEK inhibitors (7%) were the most common first-line treatments. Upfront surgical resection was used for 25% of the MUP patients, and 12 of these resections were for curative intent. During a median follow-up period of 22.1 months, the median overall survival (OS) was not met for the patients with MUP isolated to lymph nodes. At 56.8 months, 75% of these patients were alive. The median OS was 37.4 months for skin/soft tissue MUP, 33.3 months for single solid organ viscera MUP, and 29.8 months for metastatic brain MUP. CONCLUSION: Multigene panel testing identified pathogenic mutations in all tested MUP patients and frequently identified targets outside BRAF. Despite advanced stage, aggressive multimodal therapy for MUP can be associated with 5-year OS and should be pursued for appropriate candidates.

Primary Cutaneous CD30+ Lymphoproliferative Disorders: a Comprehensive Review.

PURPOSE OF REVIEW: Primary cutaneous CD30+ T-cell lymphoproliferative disorders (CD30+ LPDs) are the second most common cutaneous lymphomas after mycosis fungoides and Sezary syndrome. They include primary cutaneous anaplastic large cell lymphoma (pcALCL), lymphomatoid papulosis (LyP), and borderline lesions. The purpose of this literature review is to consolidate the available evidence on the primary cutaneous CD30+ LPD in order to define the tools for correct diagnosis and appropriate treatment. RECENT FINDINGS: The current body of knowledge regarding the clinical features, histopathologic changes, recently described genetic alterations, and therapeutic options will be covered in this comprehensive review. Primary cutaneous CD30+ LPD represent rare cutaneous lymphomas that have significant histologic overlap within the defined group as well as with other neoplastic and reactive entities. The importance of differentiating these entities is crucial, as each one has a different clinical course and prognosis.

Primary cutaneous marginal zone lymphoma treated with doxycycline in a pediatric patient.

We present the third reported case of a primary cutaneous marginal zone lymphoma (PCMZL) treated with doxycycline in a pediatric patient with negative serology for Borrelia burgdorferi. A 14-year-old boy presented with multiple asymptomatic erythematous papules and nodules on his extremities and trunk which biopsy confirmed to be PCMZL. He was started on doxycycline and experienced a near-complete response. Given the favorable side effect profile of doxycycline and the indolent nature of PCMZL, we believe doxycycline is a possible therapy for PCMZL pediatric patients who have widely disseminated cutaneous disease.

NRAS Q61R and BRAF G466A mutations in atypical melanocytic lesions newly arising in advanced melanoma patients treated with vemurafenib.

BACKGROUND: BRAF inhibition has improved overall survival in patients with BRAF mutant melanoma, but this is associated with a range of known and predictable cutaneous side effects, including squamous cell carcinomas associated with RAS mutations. METHODS: We identified three severely dysplastic nevi, one atypical intraepidermal melanocytic proliferation, and four melanoma in situ lesions, newly arising in four patients undergoing treatment with vemurafenib. To characterize mutations in these atypical melanocytic lesions, we used a custom iPlex panel detecting 74 mutations in 13 genes known to play a role in melanoma pathogenesis. RESULTS: We identified an NRAS mutation at codon 61 (Q61R) and a rare BRAF exon 11 mutation (G466A) in atypical melanocytic lesions that arose in patients treated with vemurafenib. CONCLUSION: There appears to be development or accelerated growth of atypical melanocytic lesions in the setting of BRAF inhibition. Our results underscore the need for careful surveillance for melanocytic lesions in patients on BRAF inhibitor therapy and shed light on potential mechanisms for melanoma pathogenesis in the context of BRAF pathway blockade. Further studies are warranted to show a causal relationship.

Biochemical and Epigenetic Insights into L-2-Hydroxyglutarate, a Potential Therapeutic Target in Renal Cancer.

PURPOSE: Elevation of L-2-hydroxylgutarate (L-2-HG) in renal cell carcinoma (RCC) is due in part to reduced expression of L-2-HG dehydrogenase (L2HGDH). However, the contribution of L-2-HG to renal carcinogenesis and insight into the biochemistry and targets of this small molecule remains to be elucidated. EXPERIMENTAL DESIGN: Genetic and pharmacologic approaches to modulate L-2-HG levels were assessed for effects on in vitro and in vivo phenotypes. Metabolomics was used to dissect the biochemical mechanisms that promote L-2-HG accumulation in RCC cells. Transcriptomic analysis was utilized to identify relevant targets of L-2-HG. Finally, bioinformatic and metabolomic analyses were used to assess the L-2-HG/L2HGDH axis as a function of patient outcome and cancer progression. RESULTS: L2HGDH suppresses both in vitro cell migration and in vivo tumor growth and these effects are mediated by L2HGDH's catalytic activity. Biochemical studies indicate that glutamine is the predominant carbon source for L-2-HG via the activity of malate dehydrogenase 2 (MDH2). Inhibition of the glutamine-MDH2 axis suppresses in vitro phenotypes in an L-2-HG-dependent manner. Moreover, in vivo growth of RCC cells with basal elevation of L-2-HG is suppressed by glutaminase inhibition. Transcriptomic and functional analyses demonstrate that the histone demethylase KDM6A is a target of L-2-HG in RCC. Finally, increased L-2-HG levels, L2HGDH copy loss, and lower L2HGDH expression are associated with tumor progression and/or worsened prognosis in patients with RCC. CONCLUSIONS: Collectively, our studies provide biochemical and mechanistic insight into the biology of this small molecule and provide new opportunities for treating L-2-HG-driven kidney cancers.

Cutaneous Squamous Cell Carcinoma.

Cutaneous squamous cell carcinoma (cSCC) is a malignant neoplasm of the skin characterized by an aberrant proliferation of keratinocytes. Cutaneous SCC is the second most common malignancy globally, and usually arises in the chronically sun-damaged skin of elderly white individuals. From a pathologist's perspective, it is important to differentiate cSCC from the benign and reactive squamoproliferative lesions and identify the high-risk features associated with aggressive tumor behavior. In this article, we provide an up-to-date overview of cSCC along with its precursor lesions and important histologic variants, with a particular emphasis on the histopathologic features and molecular pathogenesis.

Invasive Renal Angiomyolipoma With Cytologic Atypia.

Renal angiomyolipoma (AML) is a benign neoplasm of the kidney arising sporadically in an idiopathic manner, or syndromically as a component of tuberous sclerosis complex. Although the classic AML has no malignant potential, and is the most common mesenchymal tumor of the kidney, variant AML cases with epithelioid morphology have demonstrated aggressive or invasive behavior. Classic AML, on the other hand, can occasionally display focal histology concerning for sarcomatous transformation, but in the absence of invasive features, it is easy to distinguish from a malignancy. In this article, we describe a remarkable case of classic AML that harbored areas histologically mimicking liposarcoma and invaded into the renal vein and extended up to inferior vena cava, thereby presenting a unique diagnostic conundrum. However, the tumor is negative for a CPM gene amplification, arguing against a liposarcomatous transformation. In addition, the patient does not have any sign of recurrence and metastasis clinically after 2 years of follow-up, also favoring a benign diagnosis of this tumor.

Mammary Analogue Secretory Carcinoma.

Mammary analogue secretory carcinoma (MASC) is a recently described salivary gland tumor that shares the same histologic appearance and ETV6 gene (12p13) rearrangement as secretory carcinoma of the breast. Prior to its recognition, MASC cases were commonly labeled acinic cell carcinoma and adenocarcinoma, not otherwise specified. Despite distinctive histologic features, MASC may be difficult to distinguish from other salivary gland tumors, in particular zymogen-poor acinic cell carcinoma and low-grade salivary duct carcinoma. Although characteristic morphologic and immunohistochemical features form the basis of a diagnosis of MASC, the presence of an ETV6-NTRK3 gene fusion is confirmatory. Given its recent recognition the true prognostic import of MASC is not yet clearly defined.

Posterior Mediastinal Adenomatoid Tumor: A Case Report and Review of the Literature.

Adenomatoid tumor is an uncommon benign neoplasm of mesothelial differentiation that distinctively arises in and around the genital organs. In rare instances, it has been described in extragenital locations. There have been only two reports documenting its occurrence in the anterior mediastinum, and no reports documenting its occurrence in the posterior mediastinum. We report the first case of posterior mediastinal adenomatoid tumor. A 37-year-old Caucasian woman presented with symptoms of bronchitis. Imaging studies identified a 2.0 cm posterior mediastinal mass abutting the T9 vertebral body, clinically and radiologically most consistent with schwannoma. Histologic sections revealed a lesion composed of epithelioid cells arranged in cords and luminal profiles embedded in a fibrotic to loose stroma and surrounded by a fibrous pseudocapsule. Lesional cells showed vacuolated eosinophilic cytoplasm and peripherally displaced nuclei with prominent nucleoli. There was focal cytologic atypia but no mitotic figures or necrosis was identified. The lesional cells expressed cytokeratin, calretinin, and nuclear WT1 but were negative for PAX8, TTF1, p53, chromogranin, CD31, and CD34, and Ki67 showed <2% proliferation rate, diagnostic of adenomatoid tumor. Three years after resection, the patient is in good health without tumor recurrence. Thus, our encounter effectively expands the differential diagnosis of posterior mediastinal neoplastic entities.