Inflammatory Rhabdomyoblastic Tumor: Clinicopathologic and Molecular Analysis of 13 Cases.

Inflammatory rhabdomyoblastic tumors (IRMTs) are newly recognized skeletal muscle tumors with uncertain malignant potential. We investigated 13 IRMTs using clinicopathologic, genetic, and epigenetic methods. The cohort included 7 men and 6 women, aged 23 to 80 years (median, 50 years), of whom 2 had neurofibromatosis type 1. Most tumors occurred in the deep soft tissues of the lower limbs, head/neck, trunk wall, and retroperitoneum/pelvis. Two tumors involved the hypopharyngeal submucosa as polypoid masses. Eight tumors showed conventional histology of predominantly spindled cells with nuclear atypia, low mitotic activity, and massive inflammatory infiltrates. Three tumors showed atypical histology, including uniform epithelioid or plump cells and mitotically active histiocytes. The remaining 2 tumors demonstrated malignant progression to rhabdomyosarcoma; one had additional IRMT histology and the other was a pure sarcoma. All 11 IRMTs without malignant progression exhibited indolent behavior at a median follow-up of 43 months. One of the 2 patients with IRMTs with malignant progression died of lung metastases. All IRMTs were positive for desmin and PAX7, whereas myogenin and MyoD1 were expressed in a subset of cases. Targeted next-generation sequencing identified pathogenic mutations in NF1 (5/8) and TP53 (4/8). All TP53 mutations co-occurred with NF1 mutations. TP53 variant allele frequency was much lower than that of NF1 in 2 cases. These tumors showed geographic (subclonal) strong p53 immunoreactivity, suggesting the secondary emergence of a TP53-mutant clone. DNA methylation-based copy number analysis conducted in 11 tumors revealed characteristic flat patterns with relative gains, including chromosomes 5, 18, 20, 21, and/or 22 in most cases. Widespread loss of heterozygosity with retained biparental copies of these chromosomes was confirmed in 4 tumors analyzed via allele-specific profiling. Based on unsupervised DNA methylation analysis, none of the 11 tumors tested clustered with existing reference entities but formed a coherent group, although its specificity warrants further study.

Usefulness of SynCAM3 and cyclin D1 immunohistochemistry in distinguishing superficial CD34-positive fibroblastic tumor from its histological mimics.

Superficial CD34-positive fibroblastic tumor (SCPFT) is a fibroblastic/myofibroblastic soft tissue tumor of rarely metastasizing intermediate malignancy. Some recent studies have described a relationship between SCPFT and PRDM10-rearranged soft tissue tumor (PRT) based on SynCAM3 and PRDM10 expression on immunohistochemistry. We performed CD34, cytokeratin AE1/AE3, SynCAM3, and PRDM10 immunohistochemistry in SCPFT and its histological mimics, including myxoinflammatory fibroblastic sarcoma (MIFS), superficially localized myxofibrosarcoma (MFS), and undifferentiated pleomorphic sarcoma. We also examined cyclin D1 expression because it is expressed in MIFS and MFS. We conducted fluorescence in situ hybridization (FISH) of PRDM10 rearrangement in SCPFT cases. On immunohistochemistry, only SCPFT showed strong and diffuse SynCAM3 expression. SCPFT also exhibited strong nuclear and weak cytoplasmic cyclin D1 expression, which was similar to that observed in MIFS. Two of five SCPFT cases exhibited nuclear PRDM10 expression. FISH revealed PRDM10 split signals in 44% and 24% of tumor cells in two SCPFT cases showing nuclear PRDM10 expression on immunohistochemistry, respectively. A minority of non-SCPFT cases showed focal SynCAM3 expression, but a combination of SynCAM3 and cyclin D1 in addition to CD34 and cytokeratin AE1/AE3 may be useful for the differential diagnosis of SCPFT and its histological mimics.

Prognostic usefulness of a modified risk model for solitary fibrous tumor that includes the Ki-67 labeling index.

BACKGROUND: Predicting the prognosis of patients with solitary fibrous tumor (SFT) is often difficult. The prognostic risk models developed by Demicco et al. are now the standard for evaluating the risk of SFT metastasis in the current World Health Organization classification of soft tissue and bone tumors. METHODS: In this study, we examined the prognostic usefulness of a modified version of the Demicco risk models that replaces the mitotic count with the Ki-67 labeling index. We compared the three-variable and four-variable Demicco risk models with our modified risk models using Kaplan-Meier curves based on data for 43 patients with SFT. RESULTS: We found a significant difference in metastasis-free survival when patients were classified into low-risk and intermediate/high-risk groups using the three-variable (P = 0.022) and four-variable (P = 0.046) Demicco models. There was also a significant difference in metastasis-free survival between the low-risk and intermediate/high-risk groups when the modified three-variable (P = 0.006) and four-variable (P = 0.022) models were used. CONCLUSION: Modified risk models that include the Ki-67 labeling index are effective for prediction of the prognosis in patients with SFT.

Atypical spindle cell/pleomorphic lipomatous tumor with a sarcomatous component showing high mitotic activity and Ki-67 labeling index: report of a unique case mimicking dedifferentiated liposarcoma.

Atypical spindle cell/pleomorphic lipomatous tumor (ASPLT) is a new entity of benign adipocytic tumor that spans a wide spectrum of histology from adipocytic to spindle cell/pleomorphic tumors. The latter non-adipocytic component rarely shows sarcomatous features although ASPLTs are not thought to dedifferentiate. A 78-year-old woman with ASPLT in the left thigh had a sarcomatous component with high mitotic activity and Ki-67 labeling index (LI) mimicking dedifferentiated liposarcoma. The adipocytic component consisted of various-sized adipocytic cells with few lipoblasts. The sarcomatous component consisted of a fascicular proliferation of atypical spindle cells with scattered large bizarre and multinucleated giant cells. Mitotic figures including atypical mitoses were frequently observed. Immunohistochemically, the tumor cells were positive for cluster of differentiation 34 but not mouse double minute 2 homolog (MDM2), cyclin-dependent kinase 4 (CDK4), or retinoblastoma (Rb) protein. Ki-67 LI in the sarcomatous component reached 40%. MDM2 and CDK4 genes were not amplified and 13q14 including the RB1 locus was deleted according to fluorescence in situ hybridization. The patient is alive with no evidence of local recurrence or distant metastasis 3.5 years after surgery. As ASPLT may exhibit morphological variation, it is important to rule out dedifferentiated liposarcoma with careful pathological examination.

Identification of characteristic subepithelial surface granulomatosis in immune-related adverse event-associated enterocolitis.

Immune checkpoint inhibitors (ICIs) have provided an additional treatment option for various types of human cancers. However, ICIs often induce various immune-related adverse events (irAEs). Enterocolitis is a major irAE with poorly understood histopathological characteristics. In this study, we retrospectively investigated the histopathology of colon tissue samples from 17 patients treated with ICIs. There were two major histological patterns of colitis: an ulcerative colitis-like pattern and a graft vs host disease-like pattern. Although these two patterns of colitis were mutually exclusive, both patterns often showed a characteristic that we call "subepithelial surface granulomatosis" (SSG), which has not been reported in other types of colitis. SSG was found even in colon tissue without symptoms or endoscopic findings of colitis. Given the increasing reports of sarcoid reaction or exacerbation of tuberculosis after treatment with ICIs, granuloma formation could be a histological hallmark of systemic immune activation by ICIs. Although statistical significance was not obtained, probably because of the small sample size, SSG may be a surrogate biomarker of systemic anticancer immune activation. We propose that a prospective study with larger sample size be performed.

Myoepithelioma of soft tissue and bone, and myoepithelioma-like tumors of the vulvar region: Clinicopathological study of 15 cases by PLAG1 immunohistochemistry.

We demonstrated the clinicopathological findings of 13 myoepitheliomas of soft tissue and bone (MESTBs) and two myoepithelioma-like tumors of the vulvar region (MELTVRs), focusing on the association between nuclear atypia and clinical course, and the utility of immunohistochemistry (IHC) of pleomorphic adenoma gene 1 (PLAG1) for the pathological diagnosis of these tumors. Of the 13 MESTBs, eight, one and four cases exhibited mild, moderate and severe nuclear atypia, respectively. Two cases with venous invasion showed severe nuclear atypia and both died of advanced disease. Two MELTVR cases showed moderate nuclear atypia and had no evidence of disease after surgery. On IHC, 12 of 13 (92.3%) MESTBs showed PLAG1 immunoreactivity and none of the MELTVRs expressed PLAG1. In addition, MELTVRs showed loss of INI1 expression. In contrast, all MESTBs retained INI1 expression. Fluorescence in situ hybridization detected EWSR1, FUS and PLAG1 rearrangement in 5 (38.5%), 0 (0%) and 2 (15.4%) of the 13 MESTBs, respectively. No EWSR1, FUS and PLAG1 rearrangement were observed in the METLVRs. In conclusion, MESTBs with both severe nuclear atypia and venous invasion would be indicative of malignant potential. PLAG1 might be a useful IHC marker in MESTB diagnosis.

Pathological evaluation of the accuracy of a fluorescence spectroscopy system for detecting parathyroid glands.

PURPOSE: A fluorescence-based technique for the detection of parathyroid glands (PGs) intraoperatively was previously reported. The technique was based on the phenomenon in which PGs emit autofluorescence when exposed to near-infrared light and we undertook an evaluation to consider the pathological accuracy of the method. METHODS: The study comprised 17 patients (18 specimens) who underwent thyroid surgery at Kushiro City General Hospital between November 2018 and June 2019. We searched for PGs intraoperatively using a fluorescence spectroscopy system and evaluated the pathological accuracy of the system. We statistically evaluated the clinical factors associated with the accuracy of the system, including age, gender, body mass index, laterality, disease state, renal function, and comorbidity. RESULTS: Eighteen specimens were evaluated pathologically, with 13 specimens confirmed as PGs. These were evaluated as "true positive," giving a positive predictive value of 72.2% (13/18). Among the false-negative cases, one specimen was a metastatic lymph node in a patient with papillary thyroid carcinoma. There was a significant difference in the true-positive rates between malignant (25%) and benign (85.7%) disease (P = 0.044). CONCLUSION: We consider that this technique is useful, however, we have to exercise care in malignant cases as the true-positive rate may be low.

Does the extension of the type of hysterectomy contribute to the local control of endometrial cancer?

OBJECTIVE: To examine the necessity and sufficiency of different types of hysterectomy for the surgical treatment of endometrial cancer. METHODS: This was a multicenter collaborative study conducted by 11 institutions. Among patients with stage I-III endometrial cancer who underwent surgery as the initial treatment (only chemotherapy was provided if adjuvant therapy was needed) from 2001 to 2012, we retrospectively examined the type of hysterectomy, clinicopathological factors, recurrence rate over a maximum period of 5 years, and the site of recurrence. The local recurrence rate was examined by univariate and multivariate analyses. RESULTS: Among 1335 patients, 982 (73.6%) underwent simple hysterectomy (SH) and 353 (26.4%) underwent modified radical hysterectomy (mRH) and were observed for a mean duration of 51.8 months. No significant difference was observed in the rate of local recurrence between the SH and mRH groups (p = 0.928). In multivariate analysis, clinicopathological factors independently associated with localized recurrence included postmenopausal status [hazard ratio (HR) 5.036, 95% confidence interval (CI) 1.506-16.841, p = 0.009], with stages II (HR 3.337, 95% CI 1.701-6.547, p < 0.001) and III (HR 2.445, 95% CI 1.280-4.668, p = 0.007), vs stage I and histological type 2 (HR 1.610, 95% CI 0.938-2.762, p = 0.001). CONCLUSIONS: For endometrial cancer patients requiring surgery, the selection of a more extensive type of hysterectomy did not reduce the rate of local recurrence. Therefore, there is little significance in performing mRH in such cases.

Image analysis is an excellent tool for quantifying Ki-67 to predict the prognosis of gastrointestinal stromal tumor patients.

We investigated the quantification of Ki-67 staining using digital image analysis (IA) as a complementary prognostic factor to the modified National Institutes of Health (NIH) classification in patients with gastrointestinal stromal tumor (GIST). We examined 92 patients, focusing on the correlation between age, sex, primary tumor site, tumor size, predominant histologic type, mitotic index, modified NIH classification (low/intermediate vs high), Ki-67 quantitation, and recurrence-free survival (RFS). We compared two IA processes for whole slide imaging (WSI) and manually captured image (MCI) methods. A Ki-67 quantitation cutoff was determined by receiver operator characteristics curve analysis. In the survival analysis, the high-risk group of a modified NIH classification, a mitotic count >5 per 20 high-powered fields, and Ki-67 cutoffs of ≥6% and ≥8% obtained by IA of the WSI and MCI methods, respectively, had an adverse impact on RFS. On multivariate analysis, each Ki-67 quantitation method strongly predicted prognosis, more strongly than the modified NIH classification. In addition, Ki-67 quantitation using IA of the MCI method could stratify low or intermediate risk and high risk GIST patients. Thus, IA is an excellent tool for quantifying Ki-67 to predict the prognosis of GIST patients, and this semiautomated approach may be preferable for patient care.

Diagnostic utility of automated SureFISH (Dako Omnis) in the diagnosis of musculoskeletal translocation-related sarcomas.

Fluorescence in situ hybridization (FISH) is an essential tool for genetic diagnosis in daily pathological work. Almost full automation of FISH can be achieved with the recently released automated SureFISH platform (Dako Omnis, Agilent Technologies, Santa Clara, CA, USA). Its utility has been reported in HER2 amplification of breast and gastric carcinoma and ALK-rearranged lung cancer. Here, we examined the utility of automated SureFISH for the identification of rearrangement signals in translocation-related sarcomas (TRSs), including 11 EWSR1-rearranged and 10 synovial sarcoma cases, compared with non-automated conventional FISH using the same specimens. The percentages of EWSR1 or SS18 split signals were higher in automated SureFISH than in conventional FISH in 13 of the 21 cases. On the other hand, 8 of the 21 cases showed the same or lower percentage of split signals in automated SureFISH. Both FISH approaches detected EWSR1 and SS18 split signals in more than 10% of tumor cells in all cases. The strongest advantage of automated SureFISH is its ability to reduce running time without sacrificing quality. Other advantages include improved signal sharpness with oligo probes and reduced ecological toxicity by avoiding formamide use. Automated SureFISH is an excellent tool for the genetic diagnosis of TRSs and contributes to their rapid definitive diagnosis.

A rare case of resection of a mucinous cystic neoplasm originating from the extrahepatic bile duct with cholangioscopic imaging.

A 29-year-old woman was admitted to our hospital for examination of obstructive jaundice and an extrahepatic bile duct lesion. Contrast-enhanced computed tomography revealed a 20 mm cystic lesion with a thin external capsule in the common hepatic duct. Cholangioscopy revealed translucent oval masses with capillary vessels attached to the bile duct walls. The surface was mostly smooth yet partially irregular with redness, suggesting that the masses were epithelial neoplasms. Histological findings of cholangioscopy-guided targeted biopsies of the mass showed subepithelial spindle cell proliferation with no atypical epithelium. The patient underwent an extrahepatic bile duct resection to confirm the pathological diagnosis. Immunohistochemistry of surgical specimens revealed that the spindle cells were positive for estrogen and progesterone receptors. Finally, the cystic lesion with ovarian-like stroma was diagnosed as a mucinous cystic neoplasm with low-grade intraepithelial neoplasia. This is the first report of cholangioscopic imaging of a biliary mucinous cyctic neoplasm. Cholangioscopic imaging can be helpful in the differential diagnosis of biliary neoplasms and in the determination of treatment strategies.

Usefulness of cell block examination for the cytological diagnosis of thoracic SMARCA4-deficient undifferentiated tumor: A case report.

SMARCA4-deficient undifferentiated tumor (SMARCA4-UT) is a high-grade malignant neoplasm showing undifferentiated or rhabdoid morphology that significantly involves the thorax of adults. It has been reported as SMARCA4-deficient thoracic sarcoma or SMARCA4-deficient non-small cell lung carcinoma according to the findings of immunohistochemical and genetic studies. We report a case of thoracic SMARCA4-UT for which cell block analysis and immunohistochemical staining were useful for the final diagnosis. A 51-year-old man had a chief complaint of left back pain and visited our hospital for further examination. Cytological examination of a left pleural effusion was performed and we also made a cell block of the pleural effusion. Cytological examination revealed polyhedral to round tumor cells. The tumor cells appeared singly or formed loosely cohesive clusters. The nuclei were round to oval, enlarged, and sometimes eccentric with prominent nucleoli with irregular borders. The nuclear chromatin was unevenly distributed. The cytoplasm was vacuolar to eosinophilic. There were no characteristic structures of tumor cells. The cell block revealed many single or loosely cohesive round to epithelioid cells. Some tumor cells often exhibited eccentrically located nuclei and lightly eosinophilic cytoplasm, showing a rhabdoid morphology. On immunohistochemistry, the tumor cells were positive for SOX-2 and they demonstrated significantly reduced SMARCA4 (BRG1) expression; SMARCA2 (BRM) and SMARCB1 (INI1) expression were retained. Accordingly, we made a diagnosis of SMARCA4-UT. This case demonstrates the importance of performing histological and immunohistochemical analysis using cell blocks for immediate diagnosis.

Metastatic pulmonary pleomorphic carcinoma replaced by a granulomatous lesion after spontaneous regression and PD-1 blockade-induced regression: can epithelioid granuloma be a histological hallmark of cancer immunity?

Immune checkpoint inhibitors (ICIs) for various types of malignancy, including non-small-cell lung cancer, have improved prognosis in some cases. Granuloma formation after ICI administration suggests a tumor antigen-specific cytotoxic T cell response with abundant interferon-gamma production, which can be used to estimate the curative effect of ICIs. In this report, we present a case with a resected lung lesion, clinically suspected to be lung cancer, that consisted of a granulomatous lesion. A tumor was also found in the duodenum that was presumed to be derived from the pulmonary pleomorphic carcinoma. Duodenal tumor cells highly expressed PD-L1, suggesting PD-1/PD-L1 axis-mediated immune escape. As expected, pembrolizumab induced a complete response for the duodenal lesion. Interestingly, in histopathological analysis, the duodenal lesion was also replaced by an epithelial granuloma and multinucleated giant cells. We conclude that autoimmunity regressed the untreated primary lung lesion spontaneously, while the metastatic duodenal lesion responded to PD-1 blockade. Tumor-associated epithelioid granulomas, even before ICI administration, may be an important pathological finding indicating an immune response with interferon-gamma production by cytotoxic T cells to the tumor.

[Accuracy Evaluation of Air Kerma-area Product of Over-couch-type X-ray Fluoroscopic System].

PURPOSE: The purpose of this study was to evaluate the accuracy of incident air kerma (Ka,r) and air kerma-area product (PKA) displayed on over-couch-type X-ray fluoroscopic systems by comparing them with the measured values. METHODS: An ionizing chamber was placed at the patient entrance reference point to measure the Ka,r. The PKA was calculated by multiplying the Ka,r by the irradiation area. These measured values were compared with the displayed values. RESULTS: The differences between measured and displayed Ka,r and PKA were less than ±35%, which was the criteria of the Japanese Industrial Standards (JIS). However, the accuracy of the displayed values differed depending on the manufacturer and the device. CONCLUSION: Although no error exceeding the JIS criteria was observed, it is necessary to understand the characteristics of the X-ray fluoroscopic systems related to displayed dose and to manage the systems by performing dose measurements periodically.

Severe thrombocytopenia and anemia as an initial presentation of breast cancer: A case report.

Breast cancer patients with bone marrow metastasis (BMM) having profound thrombocytopenia and anemia are rare and there is no definitive treatment guideline. We present a case of successful initial treatment with anti-disseminated intravascular coagulation therapy and endocrine therapy, followed by chemotherapy to avoid deterioration of severe thrombocytopenia and anemia.