Pigmented Epidermotropic Breast Carcinoma: A Diagnostic Pitfall Mimicking Melanoma A Case Report and Literature Review.

We report the clinical and pathologic features of a patient with breast carcinoma, who developed clinically visible pigmented skin lesions during the course of the disease. The combination of clinical pigmentation, histological pagetoid epidermal spread, and considerable melanin pigment within tumour cells lead to a misdiagnosis of melanoma. This case provides a striking example of the ability of epidermotropic breast carcinoma to mimic melanoma. A literature review is also reported.

Correction: The Meaning of Lymphadenopathies During Adjuvant Durvalumab After Chemoradiotherapy for Lung Cancer: Thinking Beyond Disease Progression.

[This corrects the article DOI: 10.7759/cureus.26729.].

Case report: Using DNA short tandem repeats to confirm nongestational origin of pulmonary choriocarcinoma.

Gestational trophoblastic neoplasias (GTN) are malignant neoplasms that occur in pregnant or recently pregnant women. Choriocarcinoma (CCA) is a highly aggressive and rare GTN, and cases outside the female genital tract are commonly seen as secondary manifestations of gynecologic disease. In this paper, we describe the case of a 40 years-old female patient with a primary pulmonary CCA who was surgically treated and for whom the confirmation of the primary origin of the tumor was possible using a DNA short tandem repeat genotyping. Distinction between gestational and non-gestational trophoblastic neoplasia is crucial as they require different therapeutic approach and have different prognoses.

The Meaning of Lymphadenopathies During Adjuvant Durvalumab After Chemoradiotherapy for Lung Cancer: Thinking Beyond Disease Progression.

Immune-checkpoint inhibitors (ICIs) have become the mainstay of treatment for many malignancies. With this new strategy, relevant immune-related adverse events (irAEs) have been reported, some of which can be mistaken for disease progression. To better illustrate the current challenges in diagnosing and managing a patient under adjuvant ICI treatment, we present the case of a 67-year-old female patient with stage IIIB unresectable, epidermal growth factor receptor (EGFR)-mutated, non-small-cell lung cancer who was initially treated with chemoradiotherapy, followed by immunotherapy with durvalumab. During the course of immunotherapy, the patient presented with madarosis and erythematous and endured skin lesions, in addition to lymphadenopathies and pulmonary infiltrates. She was started on first-line palliative treatment with an EGFR tyrosine kinase inhibitor. After reviewing the case, a multidisciplinary team meeting suggested diagnostic procedures, including a transbronchial needle aspiration from mediastinal lymph nodes. The histologic examination showed chronic systemic inflammation and non-caseating granulomas of the sarcoid type. In this case, palliative treatment was suspended and systemic therapy with prednisolone was initiated. The patient became asymptomatic and the previously observed radiologic abnormalities resolved. This case highlights the importance of early recognition and appropriate treatment of irAEs, mainly because these conditions remain poorly understood and are probably underdiagnosed. Considering differential diagnosis is paramount to guide clinical management, despite curative or palliative treatment intent.

Phenotype-Genotype Correlation in Colorectal Cancer: A Real-Life Study.

BACKGROUND AND AIMS: Colorectal cancer (CRC) is a heterogeneous disease with distinctive genetic pathways, such as chromosomal instability, microsatellite instability and methylator pathway. Our aim was to correlate clinical and genetic characteristics of CRC patients in order to understand clinical implications of tumour genotype. METHODS: Single-institution retrospective cohort of patients who underwent curative surgery for CRC, from 2012 to 2014. RAS and BRAF mutations were evaluated with the real-time PCR technique Idylla®. Mismatch repair deficiency (dMMR) was characterized by absence of MLH1, MSH6, MSH2 and/or PMS2 expression, evaluated by tissue microarrays. Overall survival (OS) and disease-free survival (DFS) were assessed using survival analysis. RESULTS: Overall, 242 patients were included (males 57.4%, age 69.3 ± 12.9 years; median follow-up 49 months). RAS-mutated tumours were associated with reduced DFS (p = 0.02) and OS (p = 0.045) in stage I-III CRC. BRAF-mutated tumours were more predominant in females and in the right colon, similarly to dMMR tumours. BRAF status did not influence OS (4 years)/DFS (3.5 years) in stage I-III disease. However, after relapse, length of survival was 3.5 months in BRAF-mutated tumours in contrast to 18.6 months in BRAF wild-type tumours (p = NS). No germline mutations in mismatch repair genes were so far identified in the patients with dMMR tumours. Molecular phenotype (RAS, BRAF and MMR) did not influence OS in metastatic patients. Our small sample size may be a limitation of the study. CONCLUSION: In our cohort, RAS-mutated tumours were associated with worse DFS and OS in early-stage CRC, whereas the remaining molecular variables had no prognostic influence.

INTRODUÇÃO: O cancro colo-rectal (CCR) é uma doença heterogénea, com vias genéticas distintas, nomeadamente instabilidade cromossómica, instabilidade de microssatélites e via metiladora. O nosso objetivo foi correlacionar as características clínicas e genéticas dos doentes com CCR e, deste modo, conhecer as implicações na prática clínica do genótipo tumoral. MÉTODOS: Estudo de coorte retrospectivo unicêntrico de doentes diagnosticados com CCR e submetidos a cirurgia com intuito curativo, entre 2012 e 2014. As mutações RAS e BRAF foram avaliadas pela técnica de real time PCR Idylla®. A deficiência de mismatch repair (MMR) foi avaliada pela técnica de tissue microarrays e definida pela ausência de expressão de MLH1, MSH6, MSH2 e/ou PMS2. A sobrevivência global (SG) e a sobrevivência livre de doença (SLD) foram avaliadas por análise de sobrevivência. RESULTADOS: No total, foram incluídos 242 doentes (homens 57.4%, idade 69.3 ± 12.9 anos, mediana de seguimento de 49 meses). Os tumores RAS-mutados associaram-se a menor SLD (p = 0.02) e SG (p = 0.045) em doentes com CCR estadio I­III. Os tumores BRAF-mutados foram mais frequentes em mulheres e nos tumores do cólon direito, assim como os tumores com deficiência para MMR. O status BRAF não influenciou a SG (4 anos)/SLD (3.5 anos) nos estadio I­III. Contudo, após a recidiva, o tempo de sobrevivência foi de 3.5 meses nos tumores BRAF-mutados, em comparação com 18.6 meses nos tumores sem esta mutação (p = NS). Não se identificaram mutações germinativas nos genes de mismatch repair nos doentes com tumores deficientes para estas proteinas (dMMR). O perfil molecular (RAS, BRAF e MMR) não influenciou a sobrevivência global dos doentes com metástases ao diagnóstico. O tamanho da amostra pode ser uma limitação do estudo. CONCLUSÃO: Na nossa coorte, os tumores RASmutados associaram-se a pior SLD e SG nos estádios precoces de CCR. Os restantes marcadores moleculares não influenciaram o prognóstico dos doentes.

Cathepsin K is Superior to HMB45 for the Diagnosis of Pulmonary Lymphangioleiomyomatosis.

Pulmonary lymphangioleiomyomatosis (LAM) is a rare cystic lung disease affecting predominantly young women. Classified as a low-grade malignant soft tissue neoplasm from the family of perivascular epithelioid cell (PEC) tumors or PEComas, it is characterized by a proliferation of abnormal smooth muscle-like cells (LAM cells), coexpressing myogenic and melanocytic markers, with HMB45 as the gold-standard immunohistochemical diagnostic marker. Cathepsin K, a papain-like cysteine protease with high matrix degrading activity, is commonly used in the pathologic diagnosis of other PEComa tumors, but there are few data regarding its expression in pulmonary LAM. This study compares the sensitivity of cathepsin K with that of HMB45 as immunohistochemical diagnostic markers for pulmonary LAM. Twenty-one (n=21) specimens of pulmonary LAM were retrieved from the archives of the Department of Pathology of the Cleveland Clinic. All cases were evaluated for protein expression of HMB45 and cathepsin K, on consecutive sections of formalin-fixed, paraffin-embedded tissue. The intensity and the total area of the immunostaining were quantified using an Aperio Scan Scope and analyzed with imaging software (Spectrum). Statistical analysis was performed using GraphPad software. The probability of a positive stained lesion on a transbronchial biopsy for each antibody was calculated. The percentage of LAM cells expressing cathepsin K was significantly higher than for HMB45 and overall expression was statistically significantly higher (P=0.0116). Our findings conclude that cathepsin K is a significantly more sensitive immunohistochemical marker than HMB45 in diagnosing pulmonary LAM.

Flower lose, a cell fitness marker, predicts COVID-19 prognosis.

Risk stratification of COVID-19 patients is essential for pandemic management. Changes in the cell fitness marker, hFwe-Lose, can precede the host immune response to infection, potentially making such a biomarker an earlier triage tool. Here, we evaluate whether hFwe-Lose gene expression can outperform conventional methods in predicting outcomes (e.g., death and hospitalization) in COVID-19 patients. We performed a post-mortem examination of infected lung tissue in deceased COVID-19 patients to determine hFwe-Lose's biological role in acute lung injury. We then performed an observational study (n = 283) to evaluate whether hFwe-Lose expression (in nasopharyngeal samples) could accurately predict hospitalization or death in COVID-19 patients. In COVID-19 patients with acute lung injury, hFwe-Lose is highly expressed in the lower respiratory tract and is co-localized to areas of cell death. In patients presenting in the early phase of COVID-19 illness, hFwe-Lose expression accurately predicts subsequent hospitalization or death with positive predictive values of 87.8-100% and a negative predictive value of 64.1-93.2%. hFwe-Lose outperforms conventional inflammatory biomarkers and patient age and comorbidities, with an area under the receiver operating characteristic curve (AUROC) 0.93-0.97 in predicting hospitalization/death. Specifically, this is significantly higher than the prognostic value of combining biomarkers (serum ferritin, D-dimer, C-reactive protein, and neutrophil-lymphocyte ratio), patient age and comorbidities (AUROC of 0.67-0.92). The cell fitness marker, hFwe-Lose, accurately predicts outcomes in COVID-19 patients. This finding demonstrates how tissue fitness pathways dictate the response to infection and disease and their utility in managing the current COVID-19 pandemic.

Solitary CD8-Positive Primary Cutaneous Peripheral T-Cell Lymphoma: A Question of Classification.

ABSTRACT: Acral CD8(+) lymphoma is a provisional entity in the latest edition of the WHO Lymphoma Classification and is associated with a highly specific dot-like pattern of immunohistochemical expression of CD68. We report a case of an ulcerated solitary cutaneous lesion arising on the forehead of an adult man, which had a CD8(+) cytotoxic phenotype and areas of dot-like CD68 positivity, but with a number of features that significantly detracted from the classically described acral CD8(+) lymphoma. The nosological status of the lesion is discussed with respect to a preferred diagnosis of peripheral T-cell lymphoma, not otherwise specified.

Clinicopathologic analysis of upper urinary tract carcinoma with variant histology.

We report on the clinicopathologic features of 115 cases of high-grade urothelial carcinoma of the upper urinary tract with variant histology present in 39 (34%). Variant histology was typically seen in high pathological stage (pT2-pT4) (82%, 32 cases) patients with lower survival rate (70%, 27 cases, median survival 31 months) and consisted in urothelial with one (23%), two (3%), and three or more variants (3%); 4% of cases presented with pure variant histology. Squamous divergent differentiation was the most common variant (7%) followed by sarcomatoid (6%) and glandular (4%), followed by 3% each of micropapillary, diffuse-plasmacytoid, inverted growth, clear cell glycogenic, or lipid-rich. The pseudo-angiosarcomatous variant is seen in 2%, and 1% each of nested, giant-cell, lymphoepithelioma-like, small-cell, trophoblastic, rhabdoid, microcystic, lymphoid-rich stroma, or myxoid stroma/chordoid completed the study series. Loss of mismatch repair protein expression was identified in one case of upper urinary tract carcinoma with inverted growth variant (3.6%). Variant histology was associated to pathological stage (p = 0.007) and survival status (p = 0.039). The univariate survival analysis identified variant histology as a feature of lower recurrence-free survival (p = 0.046). Our findings suggest that variant histology is a feature of aggressiveness in urothelial carcinoma of the upper urinary tract worth it to be reported.

Eruptive Junctional Nevi Appearing During Langerhans Cell Histiocytosis Treatment.

Langerhans cell histiocytosis (LCH) is a multisystemic disorder that results from the clonal proliferation of immunophenotypically and functionally immature Langerhans cells (LC). The detection of the V600E mutation in the BRAF oncogene in LCH biopsy specimens supports previous evidence that LCH is a neoplastic disorder. This mutation is present in other cutaneous lesions including malignant melanoma and benign nevi. Single case reports of a correlation between LCH and the appearance of eruptive nevi limited to the inguinal folds after chemotherapy have previously been described in the literature. This suggested that LCH could be an additional cause of eruptive melanocytic nevi, with a specific distribution mimicking that of LCH cutaneous lesions. We present the case of a 6-year-old boy, previously treated with chemotherapy for Langerhans cell histiocytosis, with disseminated junctional nevi. Although this co-occurrence may be coincidental, the skin involvement is distinct from other previously reported clinical cases. It would be interesting to evaluate whether the BRAF mutation described in LCH cells might in fact support a genetic background for the development of nevi in these patients. LEARNING POINTS: Langerhans cell histiocytosis (LCH) is a clonal neoplastic proliferation of immature Langerhans cells, with the V600E mutation in the BRAF oncogene present in approximately 60% of cases.The V600E mutation in the BRAF oncogene is also documented in other cutaneous lesions, namely malignant melanoma and benign nevi.There are case reports of a correlation between LCH and the appearance of eruptive nevi after chemotherapy, but it is not known whether the BRAF mutation described in LCH cells supports a genetic background for the development of nevi in these patients.

An Unusual Presentation of Metastatic Breast Carcinoma.

Cutaneous metastasis from a carcinoma is a relatively uncommon phenomenon. Prompt diagnosis is crucial, as it will have future implications, particularly regarding prognosis and treatment. Skin metastases can be suspected and recognized earlier through physical examination than metastases in other organs or systems. However, they can be a diagnostic challenge due to the variable clinical presentation. This case highlights the importance of having a high index of suspicion for cutaneous metastases, especially in patients with a previous history of cancer. LEARNING POINTS: Cutaneous metastases occur in approximately 0.7-10% of patients with invasive carcinomas and, when present, usually indicate an unfavourable outcome.Clinically, cutaneous metastasis can pose a diagnostic challenge and a high index of suspicion is mandatory for a prompt diagnosis.Skin biopsy of such lesions is important to confirm the diagnosis and, in the right clinical scenario, they can provide information on the primary origin of the tumour.

Immunoglobulin M gene association with autoantibody reactivity and type 1 diabetes.

Several lines of evidence show that autoimmune responses evolving in type 1 diabetes (T1D) patients include the generation of multi-reactive autoantibody (AutoAb) repertoires, but their role in T1D pathogenesis remains elusive. We tested the hypothesis that variants at the immunoglobulin heavy chain (IGH) locus are genetic determinants of AutoAbs against pancreatic antigens and contribute to T1D susceptibility. With this aim, two independent study designs were used: a case-control study and a family-based cohort comprising a total of 240 T1D patients, 172 first-degree relatives (mother and/or father), and 130 unrelated healthy controls living in Portugal. We found that three SNPs in the IGH locus show suggestive association with T1D with the highest nominal association at rs1950942 (in the IGHM-IGHJ gene region) in both the case-control study (P = 9.35E-03) and the family-based cohort (P = 3.08E-03). These SNPs were also associated with IgG AutoAbs against pancreatic antigens and with AutoAb multi-reactivity in T1D patients. Notably, we found that the SNP with the highest association with T1D susceptibility and IgG autoantibody reactivity (rs1950942) was also associated with anti-GAD IgM reactivity in T1D patients (P = 5.98E-03) and in non-affected parents (P = 4.17E-03). This finding implies that IGH association with autoreactive IgM is detectable irrespective of disease status.These results suggest that genetic variants at the IgM gene region of the IGH locus contribute to antibody autoreactivity and are associated with T1D. We propose that the control of autoantibody generation by IGH polymorphisms is a component of the complex architecture of T1D genetic susceptibility.

Transperineal aggressive angiomyxoma.

A 45-year-old woman with a history of total hysterectomy with adnexal preservation for uterine leiomyomas presented to our hospital with a right gluteal palpable mass, which she first noticed 6 months before and had progressively enlarged since then.Radiological studies revealed a 14 cm lesion with translevator growth that displaced rather than invaded adjacent structures, with a peculiar whorled pattern on T2-weighted MRI, which enhanced following gadolinium administration. CT-guided biopsy was performed, and in conjunction with imaging features the diagnosis of an aggressive angiomyxoma was assumed and confirmed following surgical excision.

Mid-Esophagus Columnar Metaplasia: What Is the Biopathogenic Pathway?

We report a case of metaplastic columnar epithelium in the mid-esophagus in a patient with history of caustic ingestion. A cardiac-type gastric phenotype, with early signs of intestinalization, was confirmed by immunohistochemistry studies (MUC5AC, MUC6, SOX2, and CDX2). Nonmetaplastic mucosa had histologic evidence of gastroesophageal reflux. In this case, esophageal reepithelization seems to have been modulated by acidic gastroesophageal reflux, which might activate transcription factors leading to phenotypic reprogramming of the regenerative epithelium. Most interestingly, it is a clinical example showcasing the origin of columnar metaplasia from stem cells located within the esophageal epithelium.

Mature cystic teratoma with high proportion of solid thyroid tissue: a controversial case with unusual imaging findings.

We describe a case of a mature cystic teratoma of the ovary with high proportion of solid thyroid tissue (< 50% of the entire tumor) in a childbearing woman. The patient presented with non-specific abdominal bloating. Pelvic ultrasound and magnetic resonance imaging revealed a complex cystic-solid tumor confined to the left ovary with an anterior fat-containing locus compatible with mature cystic teratoma and a posterior predominantly solid component with low signal intensity on T2-weighted images that was histopatologically diagnosed as benign thyroid tissue. Thyroglobulin levels were in normal range. Although thyroid tissue is present in up to 20% of mature cystic teratomas, with exception of struma ovarii, it is not usually macroscopically nor radiologically identified. The differential diagnosis should include T2-hypointense adnexal lesions associated with mature cystic teratoma, malignant transformation of mature teratoma, and immature teratoma.