Masatomo Doi

A Primary Pulmonary Glomus Tumor: A Case Report and Review of the Literature

A case of a glomus tumor originating from the lung is reported. A 43-year-old female had undergone resection of a right lung tumor following a clinical diagnosis of carcinoid, sclerosing hemangioma, or other sarcoma. Histologically, the tumor comprised uniform small round to oval cells with centrally located nucleus, a clear cytoplasm, and apparent cell borders. The tumor also showed a focally hemangiopericytomatous pattern with irregularly branching or dilated vessels. Electron microscopy revealed smooth muscle differentiation of the tumor cells. Immunostaining further revealed that the tumor cells expressed smooth muscle actin, h-caldesmon, muscle specific actin (HHF-35), but not cytokeratin, epithelial membrane antigen, synaptophysin, or chromogranin A. Based on these findings, a diagnosis of primary pulmonary glomus tumor was established. Glomus tumors of the lung are very rare and only 21 cases have been reported to date. The histological features of the present tumor and the relevant literature are discussed.

Clonality analysis of nodular fasciitis by HUMARA‐methylation‐specific PCR

Sir: Nodular fasciitis is a benign proliferation of fibroblasts and myofibroblasts in subcutaneous tissue. Most of the lesions grow rapidly but are generally small and solitary and have a preoperative duration of 1 month or less. They can arise almost anywhere on the body and their rapid growth, abundant cellularity, and mitotic activity frequently cause misdiagnosis of these lesions as sarcomas. Nodular fasciitis is generally defined as a pseudosarcomatous, self-limiting reactive process. However, case studies by Toker previously reported a more aggressive course for this disease in two cases, one of which displayed destructive invasion to bone and the other which resulted in the death of the patient. Furthermore, recent cytogenetic studies have demonstrated clonal chromosomal aberrations in some nodular fasciitis cases. These results raise the possibility that some cases of nodular fasciitis may be indeed neoplastic in origin. We therefore examined the pattern of clonality in nodular fasciitis using a recently developedmethylationspecific PCR (MSP)-based approach, which analysed the DNAmethylation status near a CAG trinucleotide repeat polymorphism of the human androgen receptor gene (HUMARA) on the X-chromosome. We studied surgical specimens from 24 female patients with nodular fasciitis (aged between 21 and 78 years). The lesions occurred most commonly in the upper and lower extremities, followed by the trunk and head and neck. The dimensions of the nodules never measured more than 20 mm. The lesions were subclassified according to the predominant histological subtypes [myxoid (two cases), cellular (six cases), or fibromatous (16 cases)] (Figure 1). As has been previously found, red blood cell extravasation (microhaemorrhage) was a consistent, if occasionally focal, finding in these cases of nodular fasciitis. An ovarian adenocarcinoma was also analysed as a control neoplasm. Sections from archival formalinfixed and paraffin-embedded tissue were mounted on glass slides, followed by microdissection of the lesional areas with a CRI-337 LCM system (Cell Robotics Inc., Albuquerque, NM, USA). DNA was extracted from the tissues by proteinase K digestion, followed by treatment with sodium bisulfite as described previously. MSP was then carried out using AR-M and AR-U primer sets as described by Kubota et al. The PCR products were analysed on an automated sequencer (310 ABI genetic analyser, Applied Biosystems, Foster City, CA, USA) using GeneScan version 3.7 software. The MSP assay showed homozygosity for the HUMARA polymorphism in three patients (one cellular and two fibromatous types) and therefore further analysis would have been uninformative. The remaining 21 patients all showed random X-chromosome inactivation (a polyclonal pattern, Figure 2a), while the control tumour DNA exhibited nonrandom inactivation (a monoclonal pattern, Figure 2b). A PCR-based method for clonal analysis, which examines the HUMARA locus using methylationsensitive restriction enzymes, has been widely used to study the nature of various diseases, though this Figure 1. Photomicrographs of nodular fasciitis. a, Cellular type nodule composed of proliferating fibroblasts and showing mitoses (inset). H&E. b, Fibromatous nodule with an irregular extension into the adjacent fat. H&E.

Increased occurrence of caspase-dependent apoptosis in unfavorable neuroblastomas

Neuroblastoma frequently shows spontaneous regression in which two distinct types of programmed cell death, ie, caspase-dependent apoptosis and H-Ras-mediated autophagic degeneration, have been suggested to play a key role. The current study was conducted to determine which of these cell suicide pathways predominated in this tumor regression. Periodic acid-Schiff (PAS) staining and immunostaining for H-Ras and for the full-length and cleaved forms of caspase-3, poly (ADP-ribose) polymerase (PARP), and lamin A were carried out on 55 archival tumor specimens. The incidence of caspase-dependent apoptosis in each tumor was quantified by cleaved lamin A staining and compared with clinicopathologic prognostic factors. Although a recent report has shown that neuroblastic cells undergoing autophagic degeneration were readily detectable by PAS and H-Ras staining, we could not confirm this result in any of our samples with the exception of one tumor. Instead, many of our neuroblastoma samples showed nonspecific PAS and Ras staining in areas of necrosis, suggesting that autophagic “degeneration” indeed corresponds to coagulation necrosis or oncosis. Unexpectedly, the incidence of caspase-dependent apoptosis was significantly correlated with indicators of a poor prognosis in these tumors, including Shimadas unfavorable histology, MYCN amplification, and a higher mitosis-karyorrhexis index, but not with factors related to tumor regression such as clinical stage and mass screening. These results indicate that neither caspase-dependent apoptosis nor autophagic “degeneration” may be involved in spontaneous neuroblastoma regression. This suggests that other mechanisms, perhaps such as tumor maturation, may be responsible for this phenomenon.

Can synaptophysin be used as a marker of breast cancer diagnosed by core‐needle biopsy in epithelial proliferative diseases of the breast?

The differential diagnosis of epithelial proliferative disease using core needle biopsy (CNB) is problematic because it is difficult to differentiate between intraductal papilloma, ductal hyperplasia, ductal carcinoma in situ, and invasive ductal carcinoma. Many studies have reported that breast cancer lesions are positive for neuroendocrine (NE) markers, whereas only a small number of studies have reported immunopositivity for NE markers in normal mammary tissues or benign lesions. We asked whether NE factors could be used as markers of breast cancer. We determined the immunopositivity rate of synaptophysin, an NE marker, in 204 lesions excised from the breast using CNB in patients who visited a university‐affiliated comprehensive medical facility and examined whether synaptophysin is a marker of breast cancer. The specimens were classified as synaptophysin‐negative cases (56 benign, 99 malignant); equivocal cases (<1 %: 2 benign, 15 malignant); and synaptophysin‐positive cases (1 benign, 31 malignant). The sensitivity, specificity, positive predictive value, and negative predictive value for malignancy of the lesions classified as synaptophysin positive were 23.3 %, 98.2 %, 96.9 %, and 36.1 %, respectively. The respective values for lesions classified as equivocal were 11.6 %, 96.6 %, 88.2 %, and 36.1 %. Synaptophysin may provide a marker of breast cancer diagnosed by CNB.

Nuclear inverse polarity papillary lesions lacking myoepithelial cells: A report of two cases

Here, cases of a 68‐ (Case 1) and a 44‐year‐old (Case 2) female are presented. They had an abnormality in the breast, and came to our hospital for further examination and treatment. Radiologically, malignancy could not completely excluded so breast excision was performed. Histologically, both cases revealed papillary neoplastic lesions lined by fibrovascular core and nuclear inverse polarity without atypia. Loss of myoepithelial cells was observed by HE, p63, and calponin. Previous report indicate CK5/6, ER, p63 and MUC3 are important for distinguishing between papillary lesions according to the differential index (based on Allred score) of ([ER total score] + [MUC3 total score])/([CK5/6 total score] + [p63 total score] + 1). Based on this analysis, our two cases had benign lesions. However, based on immunopositivity for cell‐cycle marker Cyclin‐D1, Case 1 was negative, and Case 2 was about 70% positive. Additionally, the Ki‐67 index was <1% in both cases, and no evidence of disease was observed after a maximum 62 months of follow‐up in both cases, despite lack of additional treatment. Thus, we propose that lack of myoepithelial cells in papillary lesions do not necessarily indicate malignancy and are thought to be, at the most, uncertain malignant potential.

Disseminated erythema with intense and selective inflammation of sweat gland and lichenoid drug eruption during nivolumab therapy

Dear Editor, Nivolumab, a monoclonal antibody against programmed cell death 1 (PD-1), induces antitumor immune reactions and is increasingly used for treating malignant melanoma, lung cancer and other malignancies. With increasing frequency of nivolumab use, the incidences of immune-related adverse events (irAE) are also increasing. The reported cutaneous irAE include vitiligo, maculopapular rash, lichenoid dermatitis, erythematous, psoriasiform eruption, bullous reaction, pruritus, perivascular dermatitis and eczema. Here, we report a rare and distinctive cutaneous irAE seen in a patient receiving nivolumab therapy. A 70-year old Japanese man with lung cancer was treated with nivolumab (3 mg/kg per dose) every 2 weeks. After 18 courses, the patient developed disseminated faint erythema with pruritus on his trunk and upper extremities (Fig. 1a) and erythematous-to-violaceous papules with peripheral desquamative scales on the dorsa of his hands (Fig. 1b). He had no history of skin disease prior to nivolumab therapy, and there were no other suspicious medications. At the time of developing skin eruptions, his complete blood cell count revealed hemoglobin content of 8.7 g/dL; moreover, his serum chemistry was within normal limits except for creatinine level, which was 1.66 mg/mL. Biopsies were performed for both skin eruptions. The histopathology of disseminated erythema showed scattered lymphocytes mostly in the upper dermis (Fig. 1c). Strikingly, dense lymphocytic infiltration was noted, particularly around the sweat gland (Fig. 1c,d). The infiltrated lymphocytes mostly consisted of CD4 and CD8 lymphocytes, and a few CD20 lymphocytes were also seen. Erythematous-toviolaceous papules revealed histopathological characteristics of lichen planus, including hyperkeratosis, thickening of the granular layer, liquefaction degeneration of the basal layer and dense band-like lymphocytic infiltration in the upper dermis (Fig. 1e). We treated the disseminated erythema and erythematous-to-violaceous papules with a topical steroid. The disseminated erythema gradually disappeared and the erythematous-to-violaceous papules was flattened within a few months. The present case was characterized by two kinds of skin rashes: faint erythema and lichenoid drug eruption caused by nivolumab therapy. Surprisingly, the histopathology of faint erythema revealed selective lymphocytic infiltration around the sweat gland. It is well known that nivolumab causes lichenoid drug eruption. Hwang et al. reported that 17% of patients

Rhabdomyolysis in a Patient with Polyarteritis Nodosa

Polyarteritis nodosa (PAN) is a medium vessel vasculitis affecting systemic organs. Muscle involvement of PAN usually lacks elevation of creatinine kinase (CK). We herein report a case of PAN with rhabdomyolysis. A 71-year-old man was hospitalized because of muscle weakness of the lower limbs that persisted for 1 month. On a physical examination, rapidly progressive lower proximal muscle weakness and bilateral drop foot were observed. His blood test showed an elevation in the C-reactive protein (19.5 mg/dL) and CK (13,435 IU/L) levels and negativity for anti-neutrophilic cytoplasmic antibody. Computed tomographic angiography showed stenosis of the left renal artery. Electromyogram indicated mono-neuritis multiplex pattern, and enhanced magnetic resonance imaging demonstrated discretely granular hyperintensities on T2 and slow tau inversion recovery in his femoral muscles. A femoral muscle-biopsy specimen showed fibrinoid necrosis of medium-sized vessels and disruption of the elastic lamina of the vessel wall in fascia. Furthermore, muscle necrosis was localized depending on the arterial distribution, suggesting ischemic changes in the muscles. Given these findings, he was diagnosed with PAN with rhabdomyolysis and treated with methyl-prednisolone pulse therapy followed by oral prednisolone at 50 mg/day. He was additionally treated with monthly intravenous cyclophosphamide at 500 mg. Sustained remission has been obtained for two months since the treatment. Although rhabdomyolysis rarely manifests with PAN, it should be included in a differential diagnosis of febrile patients presenting with acute myalgia and weakness with CK elevation.

The Significance of Lactate and Lipid Peaks for Predicting Primary Neuroepithelial Tumor Grade with Proton MR Spectroscopy

Purpose: 1H-MRS is a non-invasive technique used to assess the metabolic activity of brain tumors. The technique is useful for the preoperative prediction of tumor grade, which is important for treatment planning and accurate prognosis. We used 1H-MRS to study the lactate peak, which appears in various conditions, including hyperglycemia, ischemia, and hypoxia and lipid peak, which is associated with necrotic cells. The purpose of this study was to retrospectively examine the frequency and significance of lactate and lipid peaks in relation to brain tumor grade. Materials and Methods: Fifty-five patients diagnosed with neuroepithelial tumors of Grades I (3 cases), II (11 cases), III (15 cases), and IV (26 cases) were enrolled. Biopsies were excluded. Single voxel (TE = 144 ms) point resolved 1H-MRS spectroscopy sequences were retrospectively analyzed. An inverted doublet peak at 1.3 ppm was defined as lactate, a negative and positive peak was defined as combined lactate and lipid, and a clear upward peak was defined as lipid. Results: Lactate peaks were detected in all grades of brain tumors and were least common in Grade II tumors (9.1%). The frequency of combined lactate-lipid peaks was 0% (Grades I and II), 8.3% (Grade III), and 44% (Grade IV). Grade IV tumors were significantly different to the other grades. There were three cases with a lipid peak. All were glioblastoma. Conclusions: The presence of a lac peak may be useful to largely rule out the Grade II tumors, and allow the subsequent differentiation of Grade I tumors from Grade III or IV tumors by conventional imaging. The presence of a lipid peak may be associated with Grade IV tumors.

Effectiveness of computer-aided diagnosis (CADx) of breast pathology using immunohistochemistry results of core needle biopsy samples for synaptophysin, oestrogen receptor and CK14/p63 for classification of epithelial proliferative lesions of the breast

Aims The aim of this study was to develop a computer-aided diagnosis (CADx) system for identifying breast pathology. Methods Two sets of 100 consecutive core needle biopsy (CNB) specimens were collected for test and validation studies. All 200 CNB specimens were stained with antibodies targeting oestrogen receptor (ER), synaptophysin and CK14/p63. All stained slides were scanned in a whole-slide imaging system and photographed. The photographs were analysed using software to identify the proportions of tumour cells that were positive and negative for each marker. In the test study, the cut-off values for synaptophysin (negative and positive) and CK14/p63 (negative and positive) were decided using receiver operating characteristic (ROC) analysis. For ER analysis, samples were divided into groups with <10% positive or >10% positive cells and decided using receiver operating characteristic (ROC) analysis. Finally, these two groups categorised as ER-low, ER-intermediate (non-low and non-high) and ER-high groups. In the validation study, the second set of immunohistochemical slides were analysed using these cut-off values. Results The cut-off values for synaptophysin, <10% ER positive, >10% ER positive and CK14/p63 were 0.14%, 2.17%, 77.93% and 18.66%, respectively. The positive predictive value for malignancy (PPV) was 100% for synaptophysin-positive/ER-high/(CK14/p63)-any or synaptophysin-positive/ER-low/(CK14/p63)-any. The PPV was 25% for synaptophysin-positive/ER-intermediate/(CK14/p63)-positive. For synaptophysin-negative/(CK14/p63)-negative, the PPVs for ER-low, ER-intermediate and ER-high were 100%, 80.0% and 95.8%, respectively. The PPV was 4.5% for synaptophysin-negative/ER-intermediate/(CK14/p63)-positive. Conclusion The CADx system was able to analyse sufficient data for all types of epithelial proliferative lesions of the breast including invasive breast cancer. This system may be useful for pathological diagnosis of breast CNB in routine investigations.

A solitary pleural metastasis of benign giant cell tumor of bone

Giant cell tumor of bone (GCTB) usually appears as a benign tumor. We describe an extremely rare case of a metastatic pleural tumor arising from a benign GCTB. The patient had undergone radial resection of a GCTB in his left wrist. After 6 years, he was sent to us for diagnosis of a large mass detected upon routine radiographic screening. We resected the tumor, which was found to be a solitary pleural metastasis of GCTB and had evidently spread arterially. To our knowledge, this is the first report of its kind.