Immunohistochemical and molecular profiles of heterogeneous components of metaplastic breast cancer: a squamous cell carcinomatous component was distinct from a spindle cell carcinomatous component.

Metaplastic breast carcinoma (MBC), a category of breast cancer, includes different histological types, which are occasionally mixed and heterogeneous. Considering the heterogeneity of cancer cells in a tumour mass has become highly significant, not only from a biological aspect but also for clinical management of recurrence. This study aimed to analyse the immunohistochemical and molecular profiles of each MBC component of a tumour mass. Twenty-five MBC tumours were histologically evaluated, and the most frequent MBC component (c) was squamous cell carcinoma (SCC), followed by spindle cell carcinoma (SpCC). A total of 69 components of MBC and non-MBC in formalin-fixed paraffin-embedded sections were examined for 7 markers by immunohistochemistry. SCC(c) were significantly PTEN negative and CK14 positive, and SpCC(c) were significantly E-cadherin negative and vimentin positive. Multivariate analyses revealed that immunohistochemical profiles of normal/intraductal (IC)(c), no special type (NST)(c), and MBC(c) differed; moreover, SCC(c) and SpCC(c) were distinctly grouped. PTEN gene mutation was detected only in SCC(c) (2/7), but not in SpCC(c). Next-generation sequence analyses for 2 cases with tumours containing SCC(c) demonstrated that PTEN gene mutation increased progressively from IC(c) to NST(c) to SCC(c). In conclusion, the immunohistochemical and molecular profiles of the SCC(c) of MBC are distinct from those of the SpCC(c).

AKR1C3-negative high-risk metastatic castration-sensitive prostate cancer has long-term response to first-line treatment with abiraterone: Four case reports.

We experienced four cases of high-risk metastatic castration-sensitive prostate cancer (mCSPC) in which first-line treatment with abiraterone showed a sustained long-term response of over 5 years. We conducted immunohistochemical staining of aldo-keto reductase family 1 member C3 (AKR1C3) expression, which associate with poor prognosis of metastatic castration-resistant prostate cancer (mCRPC), and all prostate cancer tissue from four cases showed negative. These results suggested that AKR1C3-negative high-risk mCSPC cases may respond well to first-line treatment with abiraterone. This is the first report describing association of high-risk mCSPC and negative AKR1C3.

Brain metastasis in a patient with BRCA2-mutated treatment-related neuroendocrine prostate carcinoma and long-term response to radiotherapy and Olaparib: A case report and literature review.

BACKGROUND: A new subtype of prostate cancer called treatment-related neuroendocrine prostate carcinoma (t-NEPC) was added to the revised World Health Organization classification of prostate cancer in 2022. t-NEPC cases are increasing, and there is no established standard treatment. METHODS: A 49-year-old male patient was referred to our department for dysuria. A rectal examination and a prostate biopsy revealed stony hardness and prostate adenocarcinoma, respectively. Imaging studies confirmed the presence of multiple bone and lymph node metastases. The patient was started on upfront treatment with androgen deprivation therapy and an androgen receptor signaling inhibitor, which resulted in a significant (>90%) decrease in prostate-specific antigen (PSA) levels. The patient experienced postrenal failure 6 months later, attributable to local disease progression. Concurrently, there was an elevation in neuron-specific enolase (NSE) levels and an enlargement of pelvic lymph node metastases, without PSA progression. RESULTS: Biopsy specimen for cancer genome profiling revealed deletion of BRCA 2 and PTEN, AR amplification, and the presence of the TMPRSS2-ERG fusion gene. Based on increased NSE and BRCA2 mutations, a diagnosis of t-NEPC with BRCA2 mutation was eventually made. The patient received docetaxel chemotherapy and pelvic radiotherapy. Subsequently, he was treated with olaparib. His NSE levels decreased, and he achieved a complete response (CR). However, 18 months following the olaparib administration, brain metastases appeared despite the absence of pelvic tumor relapse, and the patient's PSA levels remained low. Consequently, the patient underwent resection of the brain metastases using gamma knife and whole-brain radiotherapy but died approximately 3 months later. CONCLUSION SUBSECTIONS: Platinum-based chemotherapy is often administered for the treatment of t-NEPC, but there are few reports on the effectiveness of olaparib in patients with BRCA2 mutations. In a literature review, this case demonstrated the longest duration of effectiveness with olaparib alone without platinum-based chemotherapy. Additionally, the occurrence of relatively rare, fatal brain metastases in prostate cancer after a long period of CR suggests the necessity of regular brain imaging examinations.

Trastuzumab deruxtecan for human epidermal growth factor receptor 2-low advanced or metastatic breast cancer: recommendations from the Japanese Breast Cancer Society Clinical Practice Guidelines.

The Japanese Breast Cancer Society Clinical Practice Guidelines are published as timely guidance on clinical issues in breast cancer treatment in Japan. In the recent edition of these guidelines, we addressed a new clinical question 34 (CQ 34, systemic treatment part) "Is trastuzumab deruxtecan recommended for patients with unresectable or metastatic HER2-low breast cancer?" and a new future research question 7 (FRQ 7, pathological diagnosis part) "How is HER2-low breast cancer diagnosed for the indication of trastuzumab deruxtecan?". These questions address use of trastuzumab deruxtecan in patients with unresectable or metastatic HER2-low breast cancer who have previously received chemotherapy for metastatic disease. The strengths of evidence and recommendation were determined through a quantitative and qualitative systematic review using multiple outcomes, including efficacy and safety. We conclude that trastuzumab deruxtecan is recommended for this patient population (strength of recommendation: 1; strength of evidence: moderate; CQ34) and that HER2-low expression for the indication of trastuzumab deruxtecan should be diagnosed using companion diagnostics based on appropriate criteria (FRQ7).

Correlation between pathology and quantitative ultrasonographic evaluation of pancreatic fat with ultrasonographic classification.

PURPOSE: No studies of the relationship between grayscale sonographic findings and pancreatic fat content have been reported to date. This study aimed to investigate the correlation between echogenicity and fat content of resected specimens using quantitative analysis. METHODS: Forty-two consecutive patients who underwent pancreatoduodenectomy or distal pancreatectomy for pancreatic tumors were enrolled in this study. Ultrasonographic images were compared with quantitative pathological analysis. Subjective evaluation of echogenicity was classified as hypoechoic, isoechoic, hyperechoic, and super hyperechoic. The total and intralobular fat areas were measured. RESULTS: The mean, median, modal, minimum, and maximum ultrasound gray values correlated with the proportion of total fat area (r = 0.349; 0.357, 0.486, 0.466, and 0.347; p = 0.024, 0.020, 0.014, 0.019, and 0.089, respectively), but did not correlate with the proportion of intralobular fat area. Subjective classification was correlated with median gray value (p < 0.001), intralobular fat area (p = 0.118), and total fat area (p = 0.011). Cases were classified as hypoechoic (n = 3), isoechoic (n = 7), hyperechoic (n = 30), and super hyperechoic (n = 2). The subjective classification was correlated with the median gray value (p < 0.001) and total fat area (p = 0.005), and not correlated with the intralobular fat area (p = 0.118). Hyperechoic or super hyperechoic pancreatic parenchyma contains over 19.7% fat. Computed tomography values correlated with the proportion of intralobular fat area (r = - 0.479, p = 0.004) and total fat area (r = - 0.541, p < 0.001). CONCLUSION: Echogenicity classified based on subjective evaluation and image analysis were correlated with the proportion of fat in the pancreas.

A comparison of diagnostic utility of new endoscopic scraper combined cell block method and conventional brush catheter for biliary tract cancer.

Background/Aims: The sensitivities of endoscopic trans-papillary pathologic diagnosis of biliary tract cancer (BTC) are unsatisfactory. Recently, the diagnostic utility of the endoscopic scraper device, Trefle for biliary stricture has been reported. The Trefle can be guided to the target biliary stricture over the guidewire and is as easy to use as the conventional brush catheter (CBC). This study evaluated the efficacy and safety of Trefle-assisted tissue acquisition combined cell block method and CBC cytology for biliary strictures due to BTCs. Methods: We retrospectively reviewed consecutive patients with biliary strictures in whom CBC cytology or Trefle-assisted tissue acquisition under endoscopic retrograde cholangiopancreatography was performed for suspected BTCs from January 2015 to June 2022 at our institution. Results: 173 patients (CBC group; n = 55, Trefle group; n = 118) were enrolled in this study. The sensitivity, specificity, and accuracy of CBC cytology for BTC were 68.3%/100%/76.4%. On the other hand, the sensitivity, specificity, and accuracy of Trefle-assisted tissue acquisition for BTC were 93.7%/95.7%/94.1%, showing superior sensitivity (p < 0.001) and accuracy (p = 0.002) compared to that of CBC. Conclusions: Compared to CBC cytology, Trefle-assisted tissue acquisition has superior diagnostic performance while maintaining procedural simplicity and is considered useful for diagnosing malignant biliary stricture.

Different effects of crizotinib treatment in two non-small cell lung cancer patients with SDC4::ROS1 fusion variants.

The possibility of stratifying patients according to differences in ROS proto-oncogene 1 (ROS1) fusion partners has been discussed. This study aimed to clarify the clinicopathological differences between two SDC4::ROS1 positive NSCLC cases who had different responses to crizotinib. Cytology and pathology samples from two NSCLC cases with SDC4::ROS1 who were diagnosed and treated with crizotinib at Nihon University Itabashi Hospital were obtained. Case 1 has been well-controlled with crizotinib for over 5 years, but case 2 was worse and overall survival was 19 months. Sequencing analysis of ROS1 fusion genes was performed by reverse-transcription-PCR and Sanger's sequencing methods. In addition, thyroid transcription factor (TTF)-1, ROS-1, Ki67, and phosphorylated extracellular signal-regulated kinase (pERK)1/2 expression were investigated using immunohistochemistry. Sequencing analysis showed SDC4 exon2::ROS1 exon 32 (exon33 deleted) in case 1, and coexistence of SDC4 exon2::ROS1 exon 34 and SDC4 exon2::ROS1 exon35 in case 2. The Ki67 index was not different, but ROS1 and pERK1/2 expression levels tended to be higher in the tumor cells of case 2 than in case 1. Therapeutic response to crizotinib and patients' prognosis in ROS1 rearranged NSCLC may be related to the activation of ROS1 signaling, depending on ROS1 and pERK1/2 overexpression status, even if the ROS1 fusion partner is the same.

Pulmonary interstitial glycogenosis in Birt-Hogg-Dubé syndrome-associated lung cysts: A new insight into the pathogenesis?

Multiple lung cysts are one of the major features of Birt-Hogg-Dubé syndrome (BHD), but little is known about their nature and pathogenesis. We report a case of a woman diagnosed with BHD lung cysts who exhibited pulmonary interstitial glycogenosis (PIG), a mesenchymal abnormality hitherto undescribed in this disease, in specimens resected at 14 and 29 years of age. Histopathologically, oval to spindle clear cells were seen in the subepithelial interstitial tissue of septal structures and the walls of the cysts. They had abundant periodic acid-Schiff-positive cytoplasmic glycogen. Immunohistochemically, these cells were positive for a few markers of mesenchymal stem cell-like lineage, including vimentin, CD44, and CD10, and negative for markers of epithelial or specific mesenchymal differentiation; these results were consistent with the reported immunophenotype of PIG cells. These PIG cells were more abundant in her specimen at age 14 years than in the second specimen from adulthood. The present case suggests that BHD lung cysts belong to a group of pulmonary developmental disorders characterized by combined PIG and alveolar simplification/cystic change. Disorders with PIG may persist until adulthood and may be of clinical and pathological significance.

Correlations between class I glucose transporter expression patterns and clinical outcomes in non-small cell lung cancer.

BACKGROUND: Glucose transporters (GLUTs) are highly expressed in various cancers. However, the implications of these variable expression patterns are unclear. This study aimed to clarify the correlation between class I GLUT expression patterns and clinical outcomes in non-small cell lung cancer (NSCLC), including their potential role in inflammatory signaling. METHODS: Biopsy tissues from 132 patients with NSCLC (92 adenocarcinomas [ADC] and 40 squamous cell carcinomas [SQCC]) were analyzed. mRNA expression levels of class I GLUTs (solute carrier 2A [SLC2A]1, SLC2A2, SLC2A3, and SLC2A4) and inflammation-related molecules (toll-like receptors TLR4, RelA/p65, and interleukins IL8 and IL6) were measured. Cellular localization of GLUT3 and GLUT4 was investigated using immunofluorescence. RESULTS: Single, combined, and negative GLUT (SLC2A) expression were observed in 27/92 (29.3%), 27/92 (29.3%), and 38/92 (41.3%, p < 0.001) of ADC and 8/40 (20.0%), 29/40 (72.5%, p < 0.001), and 3/40 (7.5%) of SQCC, respectively. In ADC, the single SLC2A3-expressed group had a significantly poorer prognosis, whereas the single SLC2A4-expressed group had a significantly better prognosis. The combined expression groups showed no significant difference. SLC2A expression was not correlated with SQCC prognosis. SLC2A4 expression correlated with lower IL8 expression. GLUT3 and GLUT4 expressions were localized in the tumor cytoplasm. CONCLUSIONS: In lung ADC, single SLC2A3 expression correlated with poor prognosis, whereas single SLC2A4 expression correlated with better prognosis and lower IL8 expression. GLUT3 expression, which is increased by IL8 overexpression, may be suppressed by increasing the expression of GLUT4 through decreased IL8 expression.

Human epidermal growth factor 2 overexpressed alpha-fetoprotein-producing-gastric cancer.

PURPOSE: This study aimed to elucidate the clinicopathological characteristics of α-fetoprotein (AFP)-producing gastric carcinoma (AFP-GC) with human epidermal growth factor receptor (HER)2 overexpression to extend the treatment strategy for AFP-GC. METHODS: We analyzed 41 patients with AFP-GC who underwent surgical resection or chemotherapy from 1989 to 2019, and who had over 20ng/mL of serum AFP or positive immunohistochemical AFP expression. HER2 expression status was investigated by immunohistochemistry (IHC) for all patients and by fluorescence in situ hybridization (FISH) for cases with an IHC score of 2+. AFP-GC with an IHC score of 3 + or 2 + and FISH positivity was defined as HER2 overexpressed AFP-GC. The correlation between HER2 status and clinicopathological characteristics and prognosis in AFP-GC was analyzed. RESULTS: HER2 overexpression was detected in 17.1% of AFP-GC patients. The prognosis of the patients with HER2 overexpressed AFP-GC was not significantly different compared to HER2 non-overexpressed AFP-GC. HER2 overexpressed AFP-GC consisted of heterogeneous histology with a higher proportion of mixed-type tumors (p = 0.002). The clinical outcome of AFP-GC with mixed-type of histology tended to be better than other intestinal or diffuse types (p = 0.05). CONCLUSION: HER2 overexpressed AFP-GC consisted of a mixed type of histology, which showed a better prognosis. The results presented that HER2 status in AFP-GC is one of the molecular candidates to improve the prognosis.

Sudden death of a child associated with invasive non-typeable Haemophilus influenzae infection with underlying IgG2 subclass deficiency.

Haemophilus influenzae can be divided into typeable and non-typeable strains. Although non-typeable Haemophilus influenzae (NTHi) is less likely to be a fatal bacterium, invasive NTHi infection has been reported to increase worldwide. This study presents a case of sudden death of a child with invasive NTHi infection and underlying immunoglobulin G2 (IgG2) deficiency. A two years seven months male child with a high fever was found unresponsive in bed, lying face down on a soft pillow. Later, the hospital declared the subject dead. An autopsy revealed that the only noteworthy finding was tissue congestion. The histopathological findings disclosed neutrophils within blood vessels of major organs. Meanwhile, the formation of the micro abscess was not visible, which indicated bacteremia. The bacterial blood culture was positive for Haemophilus Influenzae. Polymerase chain reaction assay revealed the absence of an entire capsule locus. The transmission electron microscopy showed that the colonies did not have polysaccharide capsules. Based on the above findings, the strain was identified as NTHi. Furthermore, the value of serum IgG2 was deficient, indicating the presence of IgG2 subclass deficiency. The subject eventually died from asphyxia by smothering due to a comorbid condition with a high fever brought on by NTHi-induced bacteremia and lying face down. IgG2 subclass deficiency contributed to the development of invasive NTHi infection. The invasive NTHi infection might present a risk of sudden death, particularly for immunocompromised children. As forensic pathologists and pediatricians may encounter such a problematic clinical condition, they should be aware of this.

Application of Immunohistochemistry in Clinical Practices as a Standardized Assay for Breast Cancer.

Immunohistochemistry (IHC) has become an indispensable tool in the clinical practices for breast cancer; however, to achieve its standardization, numerous issues need to be overcome. In this review, we describe the development of IHC as an important clinical tool, and the challenges in standardizing IHC results for patients. We also present ideas for resolving the remaining issues and unmet needs, along with future directions.

A neuroendocrine tumor within an anterior mediastinal mature teratoma: a case report.

BACKGROUND: Mature teratomas are benign germ cell tumors. On rare occasions, they have been associated with somatic malignancies and are termed rare germ cell tumors with a somatic-type malignancy (GCTSM). Mature teratomas commonly comprise adenocarcinomas; only seven previous cases of mature teratomas with neuroendocrine tumors have been reported to date. Here, we report a patient with a neuroendocrine tumor whithin a mature teratoma. CASE PRESENTATION: A 26-year-old man visited our department complaining of chest tightness. Contrast-enhanced computed tomography (CT) scans showed a strongly enhanced lesion within a 10-cm encapsulated cystic lesion in the anterior mediastinum. Positron emission tomography (PET) scans showed no areas of significant 18F-fluorodeoxyglucose (18F-FDG) accumulation. He underwent complete tumor resection via the transsternal approach. Histopathological examination of the specimen indicated a neuroendocrine tumor contained within a mature teratoma. CONCLUSIONS: In this case, a neuroendocrine tumor was contained within a mature teratoma. Our patient had no specific symptoms and his serum markers were within the normal range. Although PET is beneficial for diagnosing other GCTSM, it is not useful in detecting a neuroendocrine tumor. Therefore, the preoperative diagnosis of neuroendocrine tumors contained within mature teratomas remains challenging. However, GCTSM should be suspected in patients exhibiting CT findings of a mediastinal tumor, measuring ≥ 6 cm, in addition to characteristic GCTSM findings. Moreover, surgery should be performed carefully in such cases.

Clinical impact of central nervous system-directed therapies on intravascular large B-cell lymphoma: A single institution's experience.

Intravascular large B-cell lymphoma (IVLBCL) is a rare subtype of B-cell lymphoma characterized by aggressive disease progression with a high incidence of central nervous system (CNS) involvement. We retrospectively analyzed 16 patients with de novo IVLBCL treated at our hospital between 2004 and 2018 with either standard therapy plus CNS-directed therapy or standard therapy alone. CNS-directed therapy was associated with a significantly better 2-year CNS-free survival (100% vs. 63%, p = 0.0191), despite no significant effects on progression-free or overall survival. Further studies should assess CNS-focused treatment in patients with IVLBCL with or without primary CNS involvement.

Comprehensive genetic analysis of histological components of combined small cell carcinoma.

BACKGROUND: Combined small-cell lung cancer (cSCLC) is a rare type of small-cell lung cancer (SCLC) that includes both SCLC and non-small-cell lung cancer (NSCLC). The molecular biological mechanisms underlying the heterogeneity of histological types in combined or metachronously transformed SCLC (mtSCLC) remain unclear. This study aimed to investigate the relationship between genetic alterations and each histological component heterogeneously detected in cSCLC and mtSCLC. METHODS: This study included four cSCLC cases and one mtSCLC case. Formalin-fixed and paraffin-embedded sections of each histological component of these tumors were subjected to next-generation sequencing (NGS) and quantitative reverse transcription-polymerase chain reaction to investigate the genetic mutations and expression levels of neuroendocrine cell-specific transcription factors (achaete-scute homolog-1 [ASCL1], brain-2 [BRN2] also known as POU domain class 3 transcription factor 2, nuclear factor 1 B [NF1B], insulinoma-associated protein 1 [INSM1], and thyroid transcription factor-1 [TTF-1]). RESULTS: NGS analysis revealed that SCLC and NSCLC components share the same somatic mutations detected most frequently in TP53, and also in RB1 and EGFR. Gene expression analysis showed ASCL1 expression was significantly lower in the NSCLC component than in the SCLC component. CONCLUSION: We conclude that the morphological evolution of heterogeneous histological components in cSCLC may be associated with differences in ASCL1 expression levels, but not in acquired somatic gene mutations.

Multiple Immunofluorescence Imaging Analysis Reveals Differential Expression of Disialogangliosides GD3 and GD2 in Neuroblastomas.

BACKGROUND: Peripheral neuroblastic tumors (pNTs) are the most common childhood extracranial solid tumors. There are several therapeutic strategies targeting disialoganglioside GD2. Disialoganglioside GD3 has become a potential target. However, the mechanism by which pNTs express GD3 and GD2 remains unclear. We investigated the combined expression status of GD3 and GD2 in pNTs and delineated their clinicopathological values. METHODS: GD3 and GD2 expression was examined in pNT tissue samples (n = 35) using immunohistochemistry and multiple immunofluorescence imaging. RESULTS: GD3 and GD2 expression was positive in 32/35 and 25/35 samples, respectively. Combinatorial analysis of GD3 and GD2 expression in neuroblastoma showed that both were heterogeneously expressed from cell to cell. There were higher numbers of GD3-positive and GD2-negative cells in the low-risk group than in the intermediate-risk (P = 0.014) and high-risk (P = 0.009) groups. Cases with high proportions of GD3-positive and GD2-negative cells were associated with the International Neuroblastoma Staging System stage (P = 0.004), Children's Oncology Group risk group (P = 0.001), and outcome (P = 0.019) and tended to have a higher overall survival rate. CONCLUSION: We demonstrated that neuroblastomas from low-risk patients included more GD3-positive and GD2-negative cells than those from high-risk patients. Clarifying the heterogeneity of neuroblastoma aids in better understanding the biological characteristics and clinical behavior.

Celiac Disease Diagnosed after Gastrectomy for Gastric Cancer.

Celiac disease is a systemic autoimmune disorder leading to manifestations of malabsorption syndrome. A 47-year-old Japanese man developed severe diarrhea after surgery for gastric cancer. The diarrhea persisted for seven months, leading to a state of malabsorption. Celiac disease was suspected based on small bowel capsule endoscopy findings. The duodenal findings observed during gastric cancer surgery were reassessed, and Marsh-Oberhuber classification type 3c celiac disease was diagnosed. The anti-tissue glutaminase antibody test results were positive. The patient was started on a gluten-free diet, following which the diarrhea resolved, and the nutritional status improved. Adjuvant therapy after gastric cancer surgery was initiated.