Atypical skin conditions of the neck and back as a dermal manifestation of anti-HMGCR antibody-positive myopathy.

BACKGROUND: Immune-mediated necrotizing myopathy (IMNM) is an idiopathic inflammatory myopathy (IIM). Though patients with IMNM were not considered to show skin rash, several reports have showed atypical skin conditions in patients with anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibody-positive IMNM (HMGCR-IMNM). The incidence and phenotype of skin conditions in patients with HMGCR-IMNM are not fully known. RESULTS: Among the 100 IIM patients diagnosed from April 2015 through August 2022, 34 (34%) presented some form of skin condition, with 27 having typical skin rashes; this included 13 patients with dermatomyositis (DM), 8 with anti-synthetase syndrome (ASS), and 6 with IMNM. Meanwhile, 8 of 19 patients with HMGCR-IMNM (42%) presented atypical skin lesions, but no patients with other IIMs did (p < 0.001). Skin eruption with ash-like scales was observed in four HMGCR-IMNM patients, and non-scaly red patches and lumps in the other four patients; accordingly, their skin manifestations were considered as other dermal diseases except for IIM. However, skin and muscle biopsies revealed the atypical skin conditions of patients with HMGCR-IMNM to have the same pathological background, formed by Bcl-2-positive lymphocyte infiltrations. CONCLUSIONS: HMGCR-IMNM patients frequently have atypical skin conditions of the neck and back. Skin biopsy specimens from these lesions showed the same Bcl-2-positive lymphocytic infiltrations as muscle biopsy specimens regardless of the different gross dermal findings. Thus, such atypical skin conditions may be suggestive for HMGCR-IMNM.

Lupus Erythematosus Tumidus as a Distinct Uncommon Subtype of Cutaneous Lupus Erythematosus: A Case Report and Review.

Lupus erythematosus tumidus (LET) is an uncommon but distinct photosensitive subtype of cutaneous lupus erythematosus (CLE). It differs from discoid and subacute cutaneous lupus erythematosus (SCLE) clinically and pathologically. LET is marked by extreme photosensitivity and carries a much lower risk of progression to systemic disease. The differential diagnosis of LET includes polymorphic light eruption (PMLE) and Jessner's lymphocytic infiltration of the skin (JLIS) because of subtle alterations in the histopathology and the paucity of immunopathologic markers in LET. We report herein a case of LET with positive immunoglobulin (Ig) deposits on direct immunofluorescence (DIF) testing. LET resolved completely with strict sun avoidance and treatment with topical corticosteroids, without the sequelae of atrophy, scarring, or dyspigmentation.

The Underestimated Impact of Hashimoto Thyroiditis on Thyroid Papillary Carcinoma.

It is stated that Hashimoto's Thyroiditis (HT) is a risk factor for the development of Papillary Thyroid Cancer (PTC). However, the effect of HT on the coexistence of HT and PTC is still controversial. In this study, our aim is to investigate the effect of the presence of HT on clinicopathological data in patients with PTC. All 356 patients whose pathology was reported as PTC who were operated between 2015 and 2023 were included in the study. PTC patients were divided into 2 groups as those with and without HT. The effect of HT association on clinicopathological features was investigated. In 356 PTC patients, the rate of HT was 31.2%. PTC patients with HT had less multifocality (p < 0.05), more lymph node metastases (LNM) (p < 0.01) compared to PTC patients without HT. The presence of HT did not affect the bilaterality of the tumor, tumor diameter, lymphovascular invasion, or capsule invasion. While multifocality was observed less frequently in PTC patients with HT, lymph node metastasis rates were higher.

Mimicking Rosacea? Jessner's Lymphocytic Infiltration of the Skin: A Case Report.

We report a case of rash in a 35-year-old female presenting with erythematous papules and infiltrative plaques on the nose and upper jaw resembling rosacea. The patient had been experiencing these symptoms for one year. A pathological biopsy revealed an inflammatory infiltrate consisting of dense perivascular lymphocytes surrounding hair follicles and sweat glands in the dermis. Immunohistochemistry demonstrated a predominance of CD4+ T cells compared to CD8+ T cells. Based on the clinical manifestations, histopathology, and immunohistochemistry, the patient was diagnosed with Jessner's Lymphocytic infiltration of the skin (JLIS). The patient was treated with oral Minocycline, 100mg twice daily. After 4 weeks, the dosage was reduced by half and the treatment continued for 2 months, resulting in complete resolution of the rash. The clinical presentation resembled rosacea, and this particular manifestation of JLIS has not been previously reported. Treatment with minocycline yielded satisfactory efficacy, and no recurrence has been observed for 5 year.

A rare cause of testicular torsion: Lymphocytic infiltration in an adolescent with recently diagnosed B-ALL.

Testicular torsion is a commonly encountered medical emergency in children. A 10-year-old boy with diagnostically confirmed leukemia presented with new onset testis swelling. Scrotal ultrasound showed absent blood flow on the left, consistent with acute testicular torsion. The patient underwent left orchiectomy due to the testis being unsalvageable. Later pathology confirmed lymphoblastic infiltrates. A malignancy of the testicles is rarely associated with torsion and, in the setting of leukemia, suggests widespread disease. Due to the risk of scrotal violation, an inguinal approach is preferable for surgical exploration of the testicles in patients with a history of leukemia.

Case report: Vitiligo-like toxicity due to ribociclib during first-line treatment of metastatic breast cancer: two cases of premature interruption of therapy and exceptional response.

Cancer treatment-related adverse events (AEs) are sometimes associated with outcomes for cancer patients, especially with the newest therapies such as target therapy and immunotherapy. A few years ago, the first-line therapy for hormone-receptor-positive metastatic breast cancer (mBC) patients has been deeply changed by the introduction of cyclin-dependent kinase (CDK) 4/6 inhibitors, and now, we are improving our knowledge about their AEs and significance in clinical practice. Here, we report our experience with two cases of vitiligo-like lesions that occur early during treatment with ribociclib. We tried to change the CDK4/6 inhibitor for one patient, but the skin reaction persisted. Both patients retained only the endocrine therapy alone and had an unexpected durable progression-free survival (PFS). Some data on skin toxicities, including vitiligo-like lesions by CDK4/6 inhibitors, have recently been reported in the literature, but for the first time, we highlight a possible correlation with improved survival outcomes of patients. Uncovering the etiology of this toxicity, verifying the involvement of the immune system, and demonstrating a possible positive impact in survival represent an intriguing research objective for the near future.

Pathologic Characteristics of Digestive Tract and Liver in Patients with Coronavirus Disease 2019.

With the high prevalence of coronavirus disease-2019 (COVID-19), there has been increasing understanding of the pathologic changes associated with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This review summarizes the pathologic changes in the digestive system and liver associated with COVID-19, including the injuries induced by SARS-CoV2 infection of GI epithelial cells and the systemic immune responses. The common digestive manifestations associated with COVID-19 include anorexia, nausea, vomiting, and diarrhea; the clearance of the viruses in COVID-19 patients with digestive symptoms is usually delayed. COVID-19-associated gastrointestinal histopathology is characterized by mucosal damage and lymphocytic infiltration. The most common hepatic changes are steatosis, mild lobular and portal inflammation, congestion/sinusoidal dilatation, lobular necrosis, and cholestasis.

Patterns of Lymphocytic Infiltrates Can Differentiate Feline Hepatic Lymphoma from Lymphocytic Portal Hepatitis.

Hepatic lymphoma is poorly characterized in cats and differentiating between inflammation and lymphomas is often difficult. The diagnosis of hepatic lymphoma in humans relies on recognition of specific patterns of lymphocytic infiltrates and clonality testing of antigen receptors. Herein, we defined similar patterns of lymphocytic infiltrates in hepatic biopsies of cats and correlated them with clonality to determine which patterns are predictive of lymphoma. A retrospective study was performed on surgical biopsies from 44 cats. The immunophenotype was characterized using CD3 and CD20 on all 44 samples. All 44 samples were tested using PCR for T-cell receptor gamma-gene rearrangements. PCR for immunoglobulin heavy chain gene rearrangements was performed on 24 of these cats. Four patterns of lymphocytic infiltrates were characterized: (1) tightly periportal, (2) periportal and centrilobular, (3) nodular, and (4) periportal with sinusoidal extension. Other histomorphologic features (fibrosis, biliary hyperplasia, bile ductopenia, bile duct targeting, hepatic hematopoiesis, lipogranulomas, lymphonodular aggregates, other inflammatory cells) were also evaluated. The sensitivity and specificity of the lymphocytic patterns to diagnose lymphomas were determined using Bayesian Hui-Walter analysis (BLCM) against clonality results. Lymphocytic patterns 2, 3, and 4 accurately diagnosed hepatic lymphomas with a sensitivity and specificity of 82% (CI 95%: 0.65, 0.96) and 77% (CI 95%: 0.54, 1.00), respectively. None of the other microscopic features evaluated were predictive of a lymphoma or inflammation. Our study identified specific patterns of lymphocytic infiltration that differentiate feline hepatic lymphoma from inflammation while other histologic features were not associated with an accurate diagnosis.

The number of the intraepithelial T cells correlate with the proliferation index in human bulbourethral gland epithelium.

Background: Our study has immunohistochemically examined T cells localization and number as well as proliferative activity level for the bulbourethral gland epithelium in men of different ages, using monoclonal antibodies against CD45RO and proliferating cell nuclear antigen (PCNA). Results: We have found that the T cells have been localized mainly in excretory ducts epithelium of the glands in any age group, meanwhile their relative number varies with age. The excretory ducts epithelium has shown a high proliferative activity when in acini the PCNA index has been low. Postnatal dynamics of the epithelium proliferative activity positively correlates with age-related density fluctuations in lymphocytic infiltration of the glands. Conclusions: We consider that intraepithelial T cells may contribute to the regulation of epithelial cells proliferation in the bulbourethral glands.

To Identify Adenomatous Polyposis Coli Gene Mutation as a Predictive Marker of Endometrial Cancer Immunotherapy.

The adenomatous polyposis coli (APC) gene is the chromatin-remodeling-related gene and a typical tumor suppressor. Patients with a high expression of programmed death-ligand 1 (PD-L1) or a high level of tumor mutational burden (TMB) may benefit from immunotherapy in endometrial cancer (EC). This study aimed to demonstrate the role of APC in the diagnosis and immunotherapy treatment of EC. We performed an integrative analysis of a commercial panel including 520 cancer-related genes on 99 tumors from an endometrial cancer cohort in China and DNA-seq data from The Cancer Genome Atlas (TCGA) to identify new gene mutations as endometrial cancer immunotherapy markers. We found that the significant mutant genes that correlated with the PD-L1 expression and TMB were related to the chromatin state and generated a discovery set having 12 mutated genes, including the APC gene, which was identified as a new marker for immunotherapy. Further analysis revealed that tumors with the APC mutation had high TMB, increased expression of PD-L1, and increased lymphocytic infiltration. Next, we verified that APC has an inactive mutation in EC, which may affect the immune response, including PD-L1 expression, microsatellite instability, and lymphocytic infiltrate. Furthermore, patients with the APC mutation had longer overall survival. Our study demonstrates that APC could play an important role in enhancing the response to endometrial cancer treatment, particularly immunotherapy.

Case report: Radiotherapy plus pneumococcal conjugate vaccine stimulates abscopal immune response in a patient with ALK+ NSCLC.

Most patients with anaplastic lymphoma kinase-positive (ALK+) non-small-cell lung cancer (NSCLC) could benefit from the treatment with selected tyrosine kinase inhibitors (TKIs) for a period of time, but almost inevitably progress due to drug resistance. It was reported that these patients were generally unresponsive to immune-based therapies. Here, we reported that stereotactic body radiotherapy (SBRT) combined with pneumococcal conjugate vaccine (PCV) produced excellent therapeutic outcomes in a patient after multiple lines of TKI treatment. The patient's metastasis lesion experienced regression after SBRT for lumbar spine. Unexpectedly, the patient also experienced an abscopal complete pathological response (CPR) just after combination use of SBRT and PCV. Biopsy analysis indicated that the primary lung lesion was map-like necrotic and infiltrated by tumor-infiltrating lymphocytes (TILs), and multifocal granulomas and early tertiary lymphoid structures (TLS) were formed. Our case reported that radiotherapy plus PCV could specifically stimulate immune response and remodel the tumor immune microenvironment in TKI-resistant NSCLC, which may provide a new perspective for future immunotherapy in this challenging clinical situation.

Effects of high-fat diet on thyroid autoimmunity in the female rat.

BACKGROUND: While contributions of dyslipidemia to autoimmune diseases have been described, its impact on thyroid autoimmunity (TA) is less clear. Programmed cell death 1(PD-1)/PD-ligand 1 (PD-L1) immune checkpoint is crucial in preventing autoimmune attack while its blockade exacerbates TA. We thus unveiled the effect of high-fat diet (HFD) on TA, focusing on the contribution of PD-1/PD-L1. METHODS: Female Sprague Dawley (SD) rats were randomly fed with a regular diet or HFD (60% calories from fat) for 24 weeks. Then, thyroid ultrasonography was performed and samples were collected for lipid and thyroid-related parameter measure. RESULTS: HFD rats exhibited hyperlipemia and abnormal biosynthesis of the unsaturated fatty acid in serum detected by lipidomics. These rats displayed a relatively lower echogenicity and increased inflammatory infiltration in thyroid accompanied by rising serum thyroid autoantibody levels and hypothyroidism, mimicking human Hashimoto's thyroiditis. These alterations were concurrent with decreased mRNA and immunostaining of intrathyroidal PD-1 and also serum PD-1 levels but not the PD-L1 expression, suggesting a role of a PD-1 pathway. Meanwhile, the infiltration of B and T cell, a key cellular event inhibited by the PD-1 signals, was enhanced in the thyroid of HFD rats, along with thyroid fibrosis and apoptosis. CONCLUSIONS: Our data suggest that HFD triggers TA through a mechanism possibly involving downregulation of PD-1-related immunosuppression, providing a novel insight into the link between dyslipidemia and autoimmune toxicities.

Histopathological Evidence of Thyroid Dermopathy and its Correlation with Thyroid-Associated Orbitopathy in Patients with Graves' Disease having Normally Appearing Pretibial Skin: A Case-Control Study.

Objective: Thyroid dermopathy (TD), reportedly encountered in less than 5% of patients with Graves' disease (GD), is supposed to coexist only with thyroid-associated orbitopathy (TAO). However, clinically inapparent TD, detected non-invasively by thermal imaging or ultrasonography, seems to be present in a larger proportion of GD. Histopathological examination (HPE), though considered as gold standard for detecting TD, has not been performed widely to identify subclinical TD in GD. Materials and Methods: In this single-centre, cross-sectional, case-control study, 50 patients with GD (cases) and normal appearing pretibial skin were compared with 45 age- and sex-matched individuals (39 healthy volunteers, 3 with toxic multinodular goitre and 3 with solitary toxic nodule) (control). All patients were evaluated clinically for presence of TAO. Punch biopsy specimens were obtained from the pretibial skin in all 95 participants. Tissue sections were examined under light microscopy for mucin deposition, splitting of collagen fibrils and perivascular lymphocytic infiltration. Results: Sixty per cent of patients with GD demonstrated at least one of the above three histological features, while 52% had any combination of two features and 46% harboured all the three features. Mucin deposition, splitting of collagen fibrils and lymphocytic infiltration were found overall in 52%, 54% and 52% of GD, respectively; 4.4-11.1% of controls also had some evidence of TD on HPE. Subclinical TD was not related to age, duration of disease and TAO in our study. Conclusions: TD, particularly in its subclinical form, Seems to be widely prevalent in GD (46-60%) and exists even in absence of TAO. HPE, though more sensitive than the various non-invasive tests, is not specific (ranges from 89% to 95%) for TD. However, HPE can accurately diagnose TD in appropriate clinical background.

Tumoral and Parenchymal Morphological Assessment in Liver Metastases of Colorectal Carcinoma: Micrometastasis, Peritumoral Lymphocytes, Tumor Budding and Differentiation are Potential Prognostic Factors.

Introduction: Various potential prognostic histopathologic factors for colorectal carcinoma liver metastasis have been proposed. However, there is still no consensus on pathological reporting of colorectal carcinoma liver metastasis resection materials. The aim of this study was to investigate the relation between selected tumoral and parenchymal histopathologic features and prognostic factors for better characterization and prognostic prediction of the patients with colorectal carcinoma liver metastasis. Methods: Hematoxylin-eosin stained slides from 100 patients who underwent hepatic resection were evaluated. Pathologic characteristics; including number of tumor nodules, largest tumor size, status of surgical margin, tumor distance to closest margin, tumor necrosis, the presence of tumor capsule, tumor differentiation, perineural and lymphovascular invasion, micrometastasis, tumor budding, peritumoral lymphocytic infiltrate and parenchymal features including steatosis, steatohepatitis, lobular inflammation, confluent necrosis, hepatocyte ballooning, portal inflammation were assessed. For 49 patients who were treated with preoperative chemotherapy, tumor regression grade and chemotherapy-related parenchymal changes such as sinusoidal damage, venous obstruction, nodular regenerative hyperplasia, steatosis and steatohepatitis were also evaluated. Results: The presence of lymphovascular invasion (p < 0.001), micrometastasis (p=0.004), absent or mild peritumoral lymphocytic infiltration (p =0.013), high tumor budding score (p=0.033) and moderate/poor differentiation (p=0.022) were significantly associated with shorter overall survival. Lymphovascular invasion (p < 0.001) was an independent predictor of mortality in multivariate analysis. Conclusions: We conclude that tumor differentiation, lymphovascular invasion, micrometastasis, peritumoral lymphocytic reaction and tumor budding score are potential prognostic histopathological features and candidates for inclusion in pathology reports of colorectal carcinoma liver metastasis resections.

T-Cell Large Granular Lymphocytic Leukemia: A First Case Report Diagnosed by Flow Cytometry in Vietnam.

T-cell large granular lymphocytic leukemia (T-LGL leukemia) is a rare, chronic lymphoproliferative disorder in the peripheral blood. This is characterized by peripheral blood and bone marrow (BM) lymphocytic infiltration with clonal large granular lymphocytes (LGLs). The neoplastic cells of this disease display a mature T-cell immunophenotype, with the majority of cases showing a CD4-/CD8+ T-cell, T-cell receptor (TCR) subset immunophenotype versus other permutations of those markers.

Three Cases of Lymphocytic Infiltration of the Eyelid.

Lymphocytic infiltration of the skin (LIS), first reported by Jessner and Kanof in 1953, is a disease of unknown etiology characterized by erythematous papules and plaques on the head, neck, and upper back and histopathological findings of a normal epidermis with underlying lymphocytic infiltration of the reticular dermis without mucin deposition. A 69-year-old man and a 21-year-old woman presented with edematous indurative erythema of the left upper eyelid. Lymphocytic infiltration of the dermis with CD4+ T cell predominance was noted on biopsy. A 68-year-old man presented with a four-year history of recurrent edematous indurative erythema of the right upper eyelid that extended up to the right cheek. Predominantly dermal infiltration of CD8+ T lymphocytes was found on biopsy. We treated all three patients with 8-16 mg of methylprednisolone daily, and the erythema and induration improved. CD4+ T cells were predominant in the acute phase (patients 1 and 2), whereas CD8+ T cells were predominant in the chronic phase (patient 3). CD8+ T cells may be involved in LIS recurrence. Lymphocytic infiltration of the eyelid may be associated with isolated circumscribed, edematous, indurative, colorless lesions that are responsive to daily low-to-middle doses of oral methylprednisolone.

Neutrophilic Dermatosis of the Hands with Palmar Involvement and Predominant Lymphomononuclear Cell Infiltration.

Neutrophilic dermatosis of the hands (NDH) is a rare localized acral variant of Sweet syndrome. NDH predominantly involves the dorsal hands with characteristic dense dermal neutrophilic infiltrate with an upper dermal edema observed on histopathology. Unusual findings like palmar involvement and predominant lymphomononuclear dermal infiltration in our case with NDH, makes it an interesting read.

Radiologically Undetectable Latent Pulmonary Lymphocyte Infiltration Suggesting the Need for Early Glucocorticoid Therapy: An Autopsy Case of Rapidly Progressive COVID-19 Pneumonia with Lymphopenia.

We herein report a fatal case of coronavirus disease 2019 (COVID-19) pneumonia with rapid progression of respiratory failure and lymphopenia. Excessive recruitment and sequestration of lymphocytes in the lung were suggested as the pathophysiology underlying COVID-19-associated lymphopenia. Interestingly, the autopsy in this case revealed lymphocytic infiltration in the lungs even at sites that appeared normal on autopsy imaging. These findings suggest that in COVID-19 cases with risk factors of severe exacerbation, early glucocorticoid administration should be considered, especially if lymphopenia is present, even if the imaging findings show only mild abnormalities.

A Comparison of Methods for Studying the Tumor Microenvironment's Spatial Heterogeneity in Digital Pathology Specimens.

BACKGROUND: The tumor microenvironment is highly heterogeneous, and it is understood to affect tumor progression and patient outcome. A number of studies have reported the prognostic significance of tumor-infiltrating lymphocytes and tumor budding in colorectal cancer (CRC). However, the significance of the intratumoral heterogeneity present in the spatial distribution of these features within the tumor immune microenvironment (TIME) has not been previously reported. Evaluating this intratumoral heterogeneity may aid the understanding of the TIME's effect on patient prognosis as well as identify novel aggressive phenotypes which can be further investigated as potential targets for new treatment. METHODS: In this study, we propose and apply two spatial statistical methodologies for the evaluation of the intratumor heterogeneity present in the distribution of CD3 + and CD8 + lymphocytes and tumor buds (TB) in 232 Stage II CRC cases. Getis-Ord hotspot analysis was applied to quantify the cold and hotspots, defined as regions with a significantly low or high number of each feature of interest, respectively. A novel spatial heatmap methodology for the quantification of the cold and hotspots of each feature of interest, which took into account both the interpatient heterogeneity and the intratumor heterogeneity, was further developed. RESULTS: Resultant data from each analysis, characterizing the spatial intratumor heterogeneity of lymphocytes and TBs were used for the development of two new highly prognostic risk models. CONCLUSIONS: Our results highlight the value of applying spatial statistics for the assessment of the intratumor heterogeneity. Both Getis-Ord hotspot and our proposed spatial heatmap analysis are broadly applicable across other tissue types as well as other features of interest. AVAILABILITY: The code underpinning this publication can be accessed at https://doi.org/10.17630/c2306fe9-66e2-4442-ad89-f986220053e2.