ABCG2 Expression as a Potential Survival Predictor in Human Gliomas.

Gliomas are notably challenging to treat due to their invasive nature and resistance to conventional therapies. The ABCG2 protein has attracted attention for its role in multidrug resistance, complicating treatment effectiveness. This study scrutinized the relationship between ABCG2 expression and glioma grade and the role of ABCG2 in the process of glioma progression, aiming to evaluate ABCG2 expression as a predictive factor of tumor progression and patient survival. Conducted at Dubrava University Hospital, Zagreb, Croatia, the study analyzed 152 glioma specimens from 2013 to 2022, assessing ABCG2 expression alongside standard clinical markers. A significant association was found between patients' survival and the ABCG2 profile (p = 0.003, r = 0.24), separately for patients who underwent chemotherapy (p = 0.0004, r = 0.32) and radiotherapy (p = 0.003, r = 0.29). Furthermore, the ABCG2 profile was significantly associated with disease progression (p = 0.007, r = 0.23), tumor grade (p = 0.0002, r = 0.31), and Ki67 expression (p = 0.0004, r = 0.31). ABCG2-positive tumor cells only showed association with Ki67 expression (p = 0.002, r = 0.28). The ABCG2 profile was found to affect the overall patient survival (p = 0.02) and represent a moderate indicator of tumor progression (p = 0.01), unlike the percentage of ABCG2-positive tumor cells. ABCG2 may serve as a marker of angiogenesis and vascular abnormalities within tumors, predicting glioma progression and treatment response. Targeting ABCG2 could enhance chemoradiotherapy efficacy and improve patient outcomes, which highlights its value in assessing tumor aggressiveness and designing treatment strategies.

Merkel Cell Carcinoma of Unknown Primary Origin.

Merkel cell carcinoma (MCC) is a rare and highly aggressive primary cutaneous neuroendocrine carcinoma most often occurring in the elderly. Risk factors include chronic sun exposure and immunosuppression (1). MCC is associated with frequent recurrences and a high metastatic potential and mortality rate (1). It is the second most common cause of skin-cancer-related death after melanoma. At primary diagnosis with an apparent cutaneous tumor, loco-regional metastases are present in up to 30% of patients, and 6-12% have distant metastatic disease (2-3). Up to 5% of cases present with unknown primary origin (4). Five-year overall survival for patients with advanced or metastatic disease is 13-18% (4). We report two cases of MCC presenting without primary cutaneous involvement; first at an unusual location in the adipose tissue of the right breast, and the second one with only a clinically positive left inguinal lymph node. In October 2018, a 78-year-old woman presented with a 15-week history of a painless solitary mass in the upper outer quadrant (UOQ) of the right breast with no visible cutaneous involvement. Her medical history included hypertension, dyslipidemia, and plaque psoriasis. She underwent ultrasound guided biopsy, and histopathology confirmed the diagnosis of metastatic MCC (mMCC). Positron emission tomography/computed tomography (PET/CT) scans showed increased standardized uptake values in the mass in the UOQ and an additional mass in the lower inner quadrant (Figure 1A). The patient underwent mastectomy and lymph node dissection of the right axilla. Histopathology confirmed mMCC and negative axillary lymph nodes. Regular follow-up (clinical examination, PET/CT scan, ultrasound, mammography) every 6 months revealed no disease recurrence during this 4-year period (Figure 1B). In September 2021, a 66-year-old man was referred to our Clinic with clinically detectable painful left inguinal lymphadenopathy. Excisional biopsy was performed, and histopathology confirmed the diagnosis of mMCC (Figure 2). After an extensive clinical and imaging evaluation (PET/CT scan), which confirmed disseminated disease (Figure 3A), initial treatment with the programmed cell death ligand 1 inhibitor (anti PD-L1) avelumab was proposed. The first cycle consisting of seven intravenous applications, and was applied in October 2021. After one year and completion of the third cycle of therapy, imaging assessment (PET-CT scan) detected a solitary lesion in the pancreas. Fine needle aspiration biopsy confirmed a distant metastasis of MCC that was later treated with stereotactic radiosurgery. The fourth cycle of immunotherapy was completed in March 2023. No treatment-related adverse events were noted during these 18 months of follow-up. Recent PET/CT scans demonstrated scaring tissue in the pancreas with no signs of locoregional or distant metastatic disease (Figure 3B). Management of MCC should be individualized based on the specific pattern of disease presentation. The presence of nodal disease is one of the most powerful predictors of overall survival and risk for developing distant metastatic disease (3-4). Multidisciplinary tumor board discussions are mandatory for the management of advanced MCC. New emerging treatment options have once again returned focus to this rare and highly-aggressive entity. Until recent years, mMCC was managed with extensive surgery, radiotherapy, or chemotherapy, but responses were not durable (1). Based on new clinical trials, immunotherapy has now become a rational and promising treatment option and is considered as first-line treatment in patients with advanced MCC (5). The management of patients with MCC of unknown primary origin should adhere to that for patients with an identifiable primary tumour (6). Although cutaneous manifestations are the hallmark of MCC, only a minority of cases have been reported in the literature without any cutaneous involvement (7-10). Our cases highlight this unusual presentation of MCC that could be misleading and contribute to delayed diagnosis. We therefore emphasize the importance of considering rare forms of malignancies such as MCC even in the absence of a primary cutaneous lesion.

Higher Expressions of SHH and AR Are Associated with a Positive Receptor Status and Have Impact on Survival in a Cohort of Croatian Breast Cancer Patients.

Breast cancers (BC) are usually classified into four molecular subtypes according to the expression of estrogen (ER), progesterone (PR), and human epidermal growth factor 2 (HER2) receptors and proliferation marker Ki-67. Despite available anti-hormonal therapies and due to the inherent propensity of some subtypes to develop metastasis, there is a permanent need to discover new prognostic and predictive biomarkers, as well as therapeutic targets for BC. In this study, we used immunohistochemical staining to determine the expression of androgen receptor (AR) and sonic hedgehog protein (SHH), the main ligand of the Hedgehog-GLI (HH-GLI) signaling pathway, in 185 archival primary BC tissue samples and correlated it with clinicopathological characteristics, molecular subtypes, receptors statuses, and survival in a cohort of Croatian BC patients. Results showed that higher SHH and AR expressions were associated with positive receptor status, but increased SHH expression had a negative impact on survival in receptor-negative BCs. On the contrary, higher AR expression was mostly protective. However, multivariate analysis showed that only higher AR expression could be considered as an independent prognostic biomarker for poorer overall survival in triple-negative breast cancer patients (TNBC) (HR 10.9, 95% CI 1.43-83.67; p = 0.021), what could be Croatian population-related. SHH could be a potential target for treating TNBCs and HER2-enriched BCs, in cases where HH-GLI signaling is canonical (SHH-dependent).

Giant Cell Tumor of the Distal Ulna: Multimodal Radiological Investigation of a Very Rare Location.

BACKGROUND Giant cell tumor is a rare tumor of mesenchymal origin. According to World Health Organization classification, it is considered a benign tumor with locally aggressive characteristics and the capacity to metastasize. The tumor typically occurs in the epiphyseal regions, most often of long bones after the completion of bone growth. The disease is characterized by severe pain and swelling of the affected area. Tumor growth is expansive but relatively slow. The tumor rarely metastasizes, but when it does, the lungs are primarily affected. CASE REPORT A 28-year-old man, otherwise healthy, presented with pain in the right wrist joint, limited range of motion, and spindle-shaped thickening/swelling in the same area, which he had noticed several months earlier. After a comprehensive diagnostic evaluation (wrist X-ray, computed tomography, magnetic resonance imaging, ultrasound-guided biopsy, and histopathological analysis), he was diagnosed with giant cell tumor of the right ulna. The tumor was surgically removed with good recovery, and the patient continued to be seen thereafter in regular followup. CONCLUSIONS The wide range of benign and malignant differential diagnostic entities requires a detailed diagnostic approach and comprehensive assessment, using different radiological modalities, as was done in this case. The final diagnosis was confirmed by histopathological analysis of core biopsy material.

Comparison of Androgen Receptor, VEGF, HIF-1, Ki67 and MMP9 Expression between Non-Metastatic and Metastatic Stages in Stromal and Tumor Cells of Oral Squamous Cell Carcinoma.

OBJECTIVES: Oral squamous cell carcinoma (OSCC) is the most common oral malignancy with low survival as it is very often diagnosed at an advanced stage, which is why the accurate profiling of the tumor is essential. The aim of this study was to, for the first time, compare in OSCC the frequency of AR, VEGF, MMP9, HiF1beta and Ki67 between the non-metastatic and metastatic disease. MATERIALS AND METHODS: In the study, 96 non-metastatic and 91 metastatic OSCC patients were analysed for AR, VEGF, MMP9, HiF1beta and Ki67 levels by immunohistochemistry. RESULTS: All of the tested biomarkers significantly differed between non-metastatic and metastatic disease. A significant association was found between >/=20% AR positive epithelium cells in cytoplasm, Ki67 and VEGF in cancer stroma. Ki67, HiF1beta, VEGF and MMP9 were significantly associated with TNM stages. CONCLUSION: Our results show for the first time an interplay between AR, VEGF, MMP9, HiF1beta and Ki67 in OSCC which may contribute to better diagnostics and therapy selection.

SONOELASTOGRAPHIC FEATURES OF HIGH-RISK BREAST LESIONS AND DUCTAL CARCINOMA IN SITU - A PILOT STUDY.

The aim of this study was to evaluate the quantitative sonoelastographic values recorded on shear-wave sonoelastography (SWE) of high-risk breast lesions and ductal carcinoma in situ (DCIS). We retrospectively analyzed histopathologic and SWE data (quantitative maximum, minimum and mean stiffness, lesion-to-fat ratio (E-ratio), lesion size) of 228 women referred to our Department for core needle breast biopsy during a four-year period. Among 230 lesions, histopathologic findings showed 34 high-risk breast lesions and 29 DCIS, which were compared with 167 ductal invasive carcinomas. High-risk lesions had lower values of all sonoelastographic features than ductal in situ and invasive carcinoma, however, only E-ratio showed a statistically significant difference in comparison to DCIS (3.7 vs. 6, p<0.001). All sonoelastographic features showed significant difference between in situ and invasive carcinoma. There was a significant correlation between lesion size and stiffness (r=0.36; p<0.001). Stiffness measured by SWE is an effective predictor of the histopathologic severity of sonographically detectable breast lesions. Elasticity values of high-risk lesions are significantly lower than those of malignant lesions. Furthermore, we showed that along with the sonographic appearance, which in most cases shows typical microcalcifications, DCIS had significantly different elasticity parameters than invasive carcinoma.

Androgen Receptor as a Biomarker of Oral Squamous Cell Carcinoma Progression Risk.

BACKGROUND/AIM: Oral squamous cell carcinoma (OSCC) is a cancer with poor prognosis due to therapy resistance, locoregional recurrences, and distant metastases. There is on increased interest in profiling the androgen receptor (AR) in cancer biology. The aim of this study was to compare AR and Ki-67 levels in the neoplastic epithelium and stroma between non-metastatic and metastatic stages of OSCC. PATIENTS AND METHODS: Tissue specimens of 101 non-metastatic and 95 metastatic OSCC patients were analyzed by immunohistochemistry. RESULTS: More than 20% of AR-positive cytoplasmic staining of OSCC epithelium was significantly associated with nuclear AR levels in the epithelium and increased AR levels in the stroma. In metastatic OSCC patients, Ki-67 was significantly higher than in non-metastatic OSCC patients. CONCLUSION: More than 20% of AR-positive cytoplasmic staining in neoplastic OSSC epithelium is a significant predictor of OSCC progression risk.

Primary dural lymphoma mimicking meningioma: a clinical and surgical case report.

INTRODUCTION: Primary central nervous system lymphoma and its subtype, primary dural lymphoma, are types of non-Hodgkin's lymphoma that only occur in the central nervous system without any dissemination. They are extremely rare cases of extra nodal lymphomas accounting for 1--5% of intracranial tumors. CASE REPORT: We present a patient diagnosed with primary dural lymphoma in right frontal brain region who underwent surgical resection. Histopathological analysis revealed diffuse B-type large cell non-Hodgkin lymphoma. Patient underwent four cycles of R-CHOP and intrathecal methotrexate protocol. Six months postoperative, no signs of newly onset infiltration were present. DISCUSSION: Primary dural lymphoma most likely presents with unusual radiological signs, which can easily be mistaken for meningioma, the main differential diagnosis. A thorough immunological, histopathological and clinical patients profile should be conducted in order to establish the certainty of diagnosis. Although there are few treatment options: surgery, radiotherapy or chemotherapy, there is no established treatment protocol.

Significance of stroma in biology of oral squamous cell carcinoma.

The worldwide annual incidence of oral squamous cell carcinoma (OSCC) is over 300,000 cases with a mortality rate of 48%. This cancer type accounts for 90% of all oral cancers, with the highest incidence in men over 50 years of age. A significantly increased risk of developing OSCC exists among smokers and people who consume alcohol daily. OSCC is an aggressive cancer that metastasizes rapidly. Despite the development of new therapies in the treatment of OSCC, no significant increase in 5-year survival has been recorded in the past decades. The latest research suggests focus should be put on examining tumor stroma activation within OSCC, as the stroma may contain cells that can produce signal molecules and a microenvironment crucial for the development of metastases. The aim of this review is to provide an insight into the factors that activate OSCC stroma and hence faciliate neoplastic progression. It is based on the currently available data on the role and interaction between metalloproteinases, cytokines, growth factors, hypoxia factor and extracellular adhesion proteins in the stroma of OSCC and neoplastic cells. Their interplay is additionally presented using the Systems Biology Graphical Notation in order to sublimate the collected knowledge and enable the more efficient recognition of possible new biomarkers in the diagnostics and follow-up of OSCC or in finding new therapeutic targets.

The case of synchronous occurrence of primary adenocarcinoma and squamous cell carcinoma in the same lobe of the lung.

Synchronous occurrence of multiple lung cancers in the same lobe of the lung is very rare. Most of the tumors diagnosed in this way have the same histologic type. With imaging methods it is difficult to determine if the multiple lung lesions present hematogenous spread of lung cancer (or cancer from other origin) or these lesions present the second primary lung cancer. We report a rare and unusual case of synchronous occurrence of primary adenocarcinoma and squamous cell carcinoma in the same lobe of the lung. Our case demonstrates that in case of synchronous occurrence of multiple lung lesions each lesion should be sampled and histologic type of every lesion should be determined so the further treatment can be planned accordingly.

Canonical Wnt/ß-Catenin Signaling Pathway Is Dysregulated in Patients With Primary and Secondary Myelofibrosis.

INTRODUCTION: ß-Catenin is a central effector molecule of the canonical wingless-related integration site (Wnt) signaling pathway. It is important for maintenance of stem cell homeostasis and its aberrant activation has been implicated in a wide array of malignant hematological disorders. There are few reports suggesting its dysregulation in Philadelphia chromosome-negative (Ph-) myeloproliferative neoplasms (MPNs). PATIENTS AND METHODS: We analyzed ß-catenin mRNA expression in bone marrow (BM) aspirates of 29 patients with primary (PMF) and 4 patients with secondary, post Ph- MPN, myelofibrosis (SMF) using quantitative real-time polymerase chain reaction (qRT PCR). The control group consisted of 16 BM aspirates from patients with limited-stage aggressive non-Hodgkin lymphoma without BM involvement. We compared relative gene expression with clinical and hematological parameters. RESULTS: Relative expression of ß-catenin differed significantly among groups (P = .0002), it was significantly higher in patients with PMF and SMF than in the control group, but did not differ between patients with PMF and SMF. A negative correlation was found regarding hemoglobin level in PMF (P = .017). No association according to Janus kinase 2 (JAK2) V617F mutational status or JAK2 V617F allele burden was detected. CONCLUSION: Our results show for the first time that ß-catenin mRNA expression is increased in patients with PMF and SMF and its upregulation might potentiate anemia. A number of inflammatory cytokines associated with PMF are capable of mediating their effects through increased ß-catenin expression. Accordingly, ß-catenin can induce expression of a number of genes implicated in processes of cell cycle control, fibrosis, and angiogenesis, which are central to the PMF pathogenesis. Therefore, ß-catenin might represent an interesting new therapeutic target in these diseases.

Shear-wave sonoelastographic features of invasive lobular breast cancers.

AIM: To evaluate shear-wave elastographic (SWE) and related gray-scale features of pure invasive lobular breast carcinoma (ILC) and compare them with invasive ductal breast cancers (IDC). METHODS: Quantitative SWE features of mean (El-mean), maximum (El-max), minimum (El-min) elasticity values of the stiffest portion of the mass, and lesion-to-fat elasticity ratio (E-ratio) were measured in 40 patients with pure ILC and compared with 75 patients with IDC. Qualitative gray-scale features of lesion size, echogenicity, orientation, and presence of distal shadowing were determined and compared between the groups. RESULTS: ILC were significantly larger than IDC (P=0.008) and exhibited significantly higher El-max (P=0.015) and higher El-mean (P=0.008) than IDC. ILC were significantly more often horizontally oriented, while IDC were significantly more often vertically oriented (P<0.001); ILC were significantly more often hyperechoic than IDC (P<0.001). Differences in stiffness between ILC and IDC determined by quantitative SWE parameters were present only in small tumors (≤1.5 cm in size), ie, small ILC had significantly higher El-max (P=0.030), El-mean (P=0.014), and El-min (P=0.045) than small IDC, while tumors larger than 1.5 cm had almost equal stiffness, without significant differences between the groups. CONCLUSION: Specific histopathologic features of ILC are translated into their qualitative sonographic and quantitative sonoelastographic appearance, with higher stiffness of small ILC compared to small IDC. Gray-scale and sonoelastographic features may help in diagnosing ILC.

Simultaneous presentation of oral and skin anaplastic large T-cell lymphoma.

We present case of oral and skin anaplastic T-cell lymphoma in a 68-year-old woman. The patient presented with extensive ulcerations and necrotic tissue on the left mandibular gingiva. Orthopantomogram finding showed extensive necrolytic lesions of the adjacent mandible. Biopsy finding of oral lesions and subsequently of the skin confirmed the diagnosis of anaplastic T-cell lymphoma. The bridge on the teeth 35-37 was taken out. After three cycles of chemotherapy, oral lesions subsided, unlike skin lesions. Dentists should be aware that differential diagnosis when dealing with oral ulcerations might be the result of certain malignant hematologic diseases.

Renal cell carcinoma with concurrent urothelial carcinoma of urinary bladder and non-Hodgkin lymphoma.

We report a case of a 71-year-old male with multiple primary malignancies involving kidney and urinary bladder, combined with synchronous lymphoma. The patient was admitted to the hospital because of painless gross hematuria. Examination revealed tumor of the right kidney and papillary tumor in the urinary bladder and enlarged lymph nodes along aorta and inferior vena cava. Transurethral resection of bladder tumor (TUR), radical nephrectomy of the right kidney and retroperitoneal lymphadenectomy were performed. Pathohistologic evaluation, together with immunohistochemistry, gave the patient the final diagnosis of renal cell carcinoma (RCC), urothelial carcinoma of the urinary bladder and B- small cell Non-Hodgkin lymphoma (B-CLL).

Diffuse skin hyperpigmentation in CD30+ lymphoproliferation.

CD30+ T-cell lymphoproliferative disorders (LD) comprise two main groups of diseases: CD30+ LD of the skin and systemic anaplastic large cell lymphoma (ALCL). The main feature of these disorders is the expression of CD30. We present a patient with an unusual clinical presentation of CD30+ lymphoproliferative disease in a 54-year old Caucasian male who presented with generalized lymphadenopathy and pronounced skin hyperpigmentation. In the lymph nodes and skin, CD30+ lymphoproliferation (ALCL) was diagnosed. The Prussian blue staining identified that the pigment responsible for the skin color was hemosiderin. Chemotherapy was started but the patient's condition progressively worsened and he died a week after the first cycle. The complete color transformation of the entire skin due to hemosiderin accumulation is, to the best of our knowledge, the first reported observation in a CD30+ lymphoproliferation/ALCL patient. We speculate that hemosiderin-loaded macrophages resulted from the paraneoplastic process by some still unknown mechanism.

Tumor and breast volume ratio as a predictive factor for axillary lymph node metastases in T1c ductal invasive breast cancer: prospective observational clinico-pathological study.

OBJECTIVE: The status of the axilla is the single most important prognostic indicator of overall survival in patients with breast cancer. Sentinel-node biopsy has false-negative rates of 5-10%. The aim of this study was to assess the importance of tumor and breast volume ratio as a predictive factor for axillary lymph node metastases in patients with T1c ductal invasive breast cancer. METHODS: This study included 136 consecutive patients with T1c ductal invasive breast cancer. Three tumor diameters were measured. Tumor volume was calculated by the formula for ellipse. Breast volume was measured preoperatively. Tumor and breast volume ratio was calculated and shown per thousand. RESULTS: Tumor and breast volume ratio is a new independent predictive factor for axillary lymph node metastase in T1c ductal invasive breast cancer. CONCLUSIONS: This predictive factor could help to define a subgroup of patients who will be at a higher risk for axillary lymph node metastase and would benefit from additional close follow up or axillary lymph node dissection.

Intraoperative imprint cytological assessment of the subareolar tissue of the nipple areola complex (NAC).

One of the criteria of selection for skin sparing mastectomy (SSM) with nipple areola complex (NAC) preservation is to exclude the neoplastic involvement of subareolar tissue (NAC base) in order to minimize the possibility of local recurrence. The most common way to assess the possible neoplastic involvement is intraoperative frozen section of the NAC base tissue. Because of its limitations, particularly the false negative results due to unsampling, we tried to use intraoperative imprint cytology for more thorough intraoperative assessment. The aim was to compare intraoperative imprint findings with the definitive histology of the NAC base, to evaluate diagnostic accuracy of this method and possibility to substitute frozen section for intraoperative assessment of NAC base. A prospective clinical study was conducted of 208 consecutive female patients who underwent open biopsy because of carcinoma. Intraoperative imprints were taken from the excised subareolar tissue which was then routinely processed for definitive histology. Imprint findings designated positive, negative, suspicious or atypia, were compared with definitive histological findings. Our results with 7.5% false negative rate, 9.8% false positive rate, sensitivity of 50% and specificity of 87.58% argue that imprint cytology might not be sufficient as an exclusive method for the intraoperative assessment of the NAC base though it should be used routinely in conjunction with frozen section examination.

Fine-needle aspiration cytology of apocrine hidradenoma.

An apocrine hidradenoma is a benign adnexal neoplasm, usually covered by intact skin, but may show superficial ulceration and serous discharge. This feature is raising the possibility of malignancy as it was in our case of macroscopically suspicious tumour. We described cytomorphologic features of cutaneous nodule that might be a lead to the cytologic diagnosis of hidradenoma, but primary or secondary malignant tumour has been ruled out first.