Cytologic features of pleomorphic xanthoastrocytoma,WHO grade II. A comparative study with glioblastoma

Pleomorphic xanthoastrocytoma (PXA) is a WHO grade II astrocytic tumor of children and young adults. It is characterized by pleomorphic, atypical astrocytes. Atypia is so remarkable, that PXA can be easily misdiagnosed as malignant glioma. If confused with a high‐grade glioma the neurosurgeon may not proceed with a complete resection. Therefore, a specific recognition during intraoperative consultation is particularly important. We describe four cases of PXA evaluated during intraoperative procedures. Findings were compared with those of 22 glioblastomas. PXA smears were moderately cellular and showed a variable population of pleomorphic cells and fibrillary fragments with vessels. Tumoral cells were of intermediate size with a less frequent population of large, atypical cells. Some showed bi/trinucleation with bizarre nuclei. In two cases, tumoral cells with microvacuolization resembling xanthic astrocytes were present. No necrosis, mitotic activity, phagocytic macrophages or apoptotic fragments were seen. Smears from glioblastoma were more cellular than those of PXA with numerous neoplastic cells, branching vessels and myxoid substance. Cellular atypia was evident and mitoses were seen in all cases. Most cases showed an abundant population of accompanying macrophages and cellular debris. Differences between PXA and glioblastoma were related to cell turnover rather than cytomorphologic features. Glioblastoma shows features of high cellular replication showing a dirty background with necrosis and phagocytic macrophages as well as mitotic figures and apoptosis. On the other hand, smears from PXA have a clean background with no necrosis, cellular fragments or relevant mitotic activity. Diagn. Cytopathol. 2017;45:339–344. © 2016 Wiley Periodicals, Inc.     

Recurrent copy number alterations in low‐grade and anaplastic pleomorphic xanthoastrocytoma with and without BRAF V600E mutation

Pleomorphic xanthoastrocytoma (PXA) is a rare localized glioma characterized by frequent BRAF V600E mutation and CDKN2A/B deletion. We explored the association of copy‐number variants (CNVs) with BRAF mutations, tumor grade, and patient survival in a cohort of 41 PXA patients using OncoScan chromosomal microarray. Primary resection specimens were available in 38 cases, including 24 PXA and 14 anaplastic PXA (A‐PXA), 23 BRAF V600E mutant tumors (61%). CNVs were identified in all cases and most frequently involved chromosome 9 with homozygous CDKN2A/B deletion (n = 33, 87%), a higher proportion than previously detected by comparative genomic hybridization (50%–60%) (37). CDKN2A/B deletion was present in similar proportion of PXA (83%), A‐PXA (93%), BRAF V600E (87%), and wild‐type (87%) tumors. Whole chromosome gains/losses were frequent, including gains +7 (n = 15), +2 (n = 11), +5 (n = 10), +21 (n = 10), +20 (n = 9), +12 (n = 8), +15 (n = 8), and losses −22 (n = 11), −14 (n = 7), −13 (n = 5). Losses and copy‐neutral loss of heterozygosity were significantly more common in A‐PXA, involving chromosomes 22 (P = 0.009) and 14 (P = 0.03). Amplification of 8p and 12q was identified in a single tumor. Histologic grade was a robust predictor of overall survival (P = 0.003), while other copy‐number changes, including CDKN2A/B deletion, did not show significant association with survival. Distinct histologic patterns of anaplasia included increased mitotic activity in an otherwise classic PXA or associated with small cell, fibrillary, or epithelioid morphology, with loss of SMARCB1 expression in one case. In 10 cases, matched specimens were compared, including A‐PXA with areas of distinct low‐ and high‐grade morphology (n = 2), matched primary/tumor recurrence (n = 7), or both (n = 1). Copy‐number changes on recurrence/anaplastic transformation were complex and highly variable, from nearly identical profiles to numerous copy‐number changes. Overall, we confirm CDKN2A/B deletion as key a feature of PXA not associated with tumor grade or BRAF mutation, but central to the underlying genetics of PXA.     

Pleomorphic xanthoastrocytoma: a comparative pathological study between conventional and anaplastic types

Aims:  To facilitate the understanding and correct diagnosis of the anaplastic variant of pleomorphic xanthoastrocytoma (PXA).
Methods and results:  Twelve cases of PXA were divided into six conventional and six anaplastic types. Three anaplastic PXAs developed in recurrent tumours and three occurred as the primary tumour. Anaplastic PXAs were microscopically characterized by monotonous proliferation of atypical cells, increased mitotic activity, necrosis and microvascular proliferation. Characteristic features of conventional PXA are also variously included in all anaplastic PXAs. No remarkable differences were detected in the immunohistochemical profiles including the neuronal phenotype between the conventional and anaplastic types. Ki67 labelling indices of the anaplastic type were significantly higher than those of the conventional type, whereas p53 showed no difference. Immunohistochemical and fluorescence in situ hybridization analyses on epidermal growth factor receptor did not demonstrate overexpression or gene amplification.
Conclusions:  The anaplastic PXA, which occurs de novo or through recurrence, should be distinguished from glioblastoma by identifying the salient microscopic features of conventional PXA even in the anaplastic areas; and by demonstrating the expression of neuronal markers, in that the former is expected to have longer survival.     

Pleomorphic xanthoastrocytoma: report of a case with light and electron microscopy

A case of pleomorphic xanthoastrocytoma is reported with light and electron microscopic findings. This unusual tumor arose in a 15-year-old male. The tumor consisted predominantly of nests of xanthomatous cells and plump spindle cells surrounded by a prominent reticulin network. There was considerable cellular pleomorphism with abundant bizarre giant cells and multinucleated cells. Occasional mitoses were present. Electron microscopy and immunoperoxidase localization of glial fibrillary acidic protein (GFAP) confirmed the glial nature of the tumor. Recognition of this tumor is important. Despite its “malignant” appearance, the tumor characteristically has a relatively good prognosis and should not be confused with highgrade gliomas or meningeal sarcomas, which require aggressive therapy.     

脑多形性黄色瘤型星形细胞瘤的临床病理观察

目的 探讨多形性黄色瘤型星形细胞瘤（PXA）的临床病理特征、诊断及鉴别诊断、治疗及预后。方法 对南京军区南京总医院1980-2004年间6287例中枢神经系统肿瘤中的15例PXA（0．2％）,以及2例会诊病例,进行临床病理学观察,免疫组织化学SP法检测8种抗体的表达：胶质纤维酸性蛋白、波形蛋白、S-100、上皮细胞膜抗原、突触素、神经微丝、CD68及CD34,获得其中10例的随访资料。结果 患者年龄12～55岁,平均30．8岁,男6例,女11例。主要症状为癫痫发作、头痛、头晕等。肿瘤发生于幕上者16例,占94．1％,其中发生于颞叶者7例,占41．2％。肿瘤大小2—7cm,平均4．3cm,9例有囊性变。除2例会诊病例外,全切除12例,次全切除3例。随访10例,生存8例,生存时间10个月- 13年7个月,平均生存6年,生存10年以上者2例。组织学特征为：单核或多核巨怪瘤细胞、梭形细胞和泡沫样瘤细胞混合而成,肿瘤中有丰富的网状纤维及淋巴细胞浸润,缺乏坏死,核分裂象无或少。胶质纤维酸性蛋白、波形蛋白及S-100蛋白免疫组织化学染色均呈弥散阳性表达,CD34阳性率为77％。1例伴有间变特征的PXA,有较多核分裂象（≥5个／10HPF）。2例有脑实质及血管周围间隙的浸润。1例影像学检查提示肿瘤复发及脑膜播散。结论 PXA属WHOII级肿瘤,肿瘤全切除及组织学为典型性PXA者预后较好,少数PXA可复发及间变。瘤细胞巨大、怪异,容易误诊为WHOⅣ级的巨细胞胶质母细胞瘤,两者的鉴别要点在于PXA部分可见泡沫样瘤细胞,核分裂象无或少,缺乏坏死。瘤细胞CD34的阳性表达有助于PXA的诊断。     

An immunohistochemical study of bizarre neoplastic cells in pleomorphic adenoma: its cytological nature and proliferative activity

The cytological nature and proliferative activity of bizarre neoplastic cells, widely scattered in pleomorphic adenomas of salivary gland origin were studied. Pleomorphic adenomas containing numerous bizarre neoplastic cells were found in four cases, and were equal to 2.9% of all pleomorphic adenomas examined. All four cases presented as well-circumscribed, firm masses measuring less than 1.5 cm in size, located in the palate, and were of 7 months to 4 years duration. Histopathologically, these pleomorphic adenomas were cell rich type, and were well demarcated from surrounding tissues, although their fibrous capsules were partially defective. In addition to characteristic histopathological findings of pleomorphic adenoma, numerous neoplastic cells with bizarre appearance were scattered throughout the lesion, excepting for tubuloductal structures. These bizarre neoplastic cells had irregular-shaped and large nuclei with or without hyperchromatism, although their nucleoli were small and mitotic figures were few. Furthermore, there were many multinucleated giant cells, some of which showed multilobulated nuclei. Neither necrosis nor infarct was seen in the tumors. Immunohistochemically, bizarre neoplastic cells scattered in solid-proliferating areas and myxoid areas were neoplastic myoepithelial cells in nature. There was no statistical significance of MIB-1 labeling indices between pleomorphic adenomas with bizarre neoplastic cells and usual pleomorphic adenomas. The p53 labeling indices were quite low. Although the benign nature of pleomorphic adenomas with numerous bizarre neoplastic cells and hypercellularity, distinguishing such pleomorphic adenomas from various stages of malignant transformation in pleomorphic adenomas and other carcinomas should be made by histological section of submitted biopsy specimen or aspirated content for cytological diagnosis. The present paper suggests that the term 'bizarre cell pleomorphic adenoma' is an appropriate name for this neoplasm, in that it is distinguished from the usual benign pleomorphic adenoma which is easily diagnosed by routinely prepared histological or cytological stainings.     

Cerebellar pleomorphic xanthoastrocytoma in a patient with neurofibromatosis type 1: a case report and literature review

Pleomorphic xanthoastrocytoma (PXA) is an uncommon tumor of young adults that typically occurs supratentorially. It is generally considered to be a low-grade, circumscribed tumor that when treated by surgical resection has a relatively favorable outcome. Cases of cerebellar PXA are rare, and those associated with neurofibromatosis type 1 (NF1) are even less common, with only 2 cases reported to date. We present herein a third case of PXA-NF1 with unusual features. A 33-year-old woman presented with a history of headache. Her medical and family history was significant for NF1. Brain MRI revealed a 3.4 cm ill-defined lesion with a gyriform enhancing pattern in the left cerebellum, superficially mimicking Lhermitte-Duclos disease. The patient underwent a gross total resection of the lesion and had an unremarkable postoperative course. While the lesion had histological features typical of “pure” PXA (WHO grade II) it had an unusual growth pattern with thickening of the superficial cerebellar folia and predominant leptomeningeal involvement. No BRAF, IDH-1, or IDH-2 mutation was identified. Three months after surgery, local recurrence was detected, and the patient was treated with radiation therapy. One year after the first surgery, she underwent surgical resection of the recurrent/residual tumor. Histologically, the recurrent tumor showed very similar features to the initially resected tumor, with no anaplastic features. Most cerebellar PXAs have an indolent clinical behavior as do most cerebral PXAs. Whether co-existence of NF1 was a factor in altering the clinical course and biologic behavior of this patient’s tumor is currently unknown.     

Glycogen-rich pleomorphic xanthoastrocytoma with clear-cell features: confirmatory report of a rare variant with implications for differential diagnosis

Central nervous system space-occupying lesions with clear-cell features encompass a nosologically heterogeneous array, ranging from reactive histiocytic proliferations to neuroepithelial or meningothelial neoplasms of various grades and to metastases. In the face of such differential diagnostic breadth, recognizing cytoplasmic lucency as part of the morphological spectrum of some low grade gliomas will directly have an impact on patient care. We describe a prevailing clear-cell change in an epileptogenic left temporal pleomorphic xanthoastrocytoma surgically resected from a 36-year-old man. Mostly subarachnoid and focally calcified, the tumor was composed of fascicles of moderately atypical spindle cells with optically lucent cytoplasm that tended to intermingle with a desmoplastic mesh of reticulin fibers. Immunohistochemically, coexpression of S100 protein, vimentin, GFAP, and CD34 was noted. Conversely, neither punctate staining for EMA nor positivity for CD68 was seen. Mitotic activity was absent, and the MIB1 labeling index was 2-3% on average. Diastase-sensitive PAS-positive granula indicated clear-cell change to proceed from glycogen storage. Electron microscopy showed tumor cell cytoplasm to be largely obliterated by non-lysosomal-bound pools of glycogen, while hardly any fat vacuole was encountered. Neither ependymal-derived organelles nor annular lamellae suggesting oligodendroglial differentiation were detected. The latter differential diagnosis was further invalidated by lack of codeletion of chromosomal regions 1p36 and 19q13 on molecular genetic testing. By significantly interfering with pattern recognition as an implicit approach in histopathology, clear-cell change in pleomorphic xanthoastrocytoma is likely to suspend its status as a “classic”, and to prompt more deductive differential diagnostic strategies to exclude look-alikes, especially clear-cell ependymoma and oligodendroglioma.     

Carcinoma ex pleomorphic adenoma with special reference to the prognostic significance of histological progression: a clinicopathological investigation of 41 cases

Weiler C, Zengel P, van der Wal J E, Guntinas‐Lichius O, Schwarz S, Harrison J D, Kirchner T & Ihrler S
(2011) Histopathology 59 , 741–750 Carcinoma ex pleomorphic adenoma with special reference to the prognostic significance of histological progression: a clinicopathological investigation of 41 cases Aims: To investigate a large series of cases of carcinoma ex pleomorphic adenoma (CEPA) to determine prognostic factors. Methods and results: Thirty cases of CEPA associated with primary pleomorphic adenoma (PA) and 11 cases of CEPA associated with recurrent PA were investigated. The median follow‐up was 57.7 months, and ranged from 4 to 156 months. Purely intraductal carcinoma was found in 15 cases. Intraductal and extraductal intracapsular carcinoma together was found in one case. Extracapsular carcinoma was found in 25 cases. Prognosis was good for CEPA that was purely intraductal, extraductal intracapsular, or up to 5 mm extracapsular, and poor for CEPA that was 8 mm or more extracapsular. There were relatively more cases of CEPA with extracapsular invasion of 8 mm or more from recurrent PA than from primary PA, and the prognosis for CEPA associated with recurrent PA was worse than that for CEPA associated with primary PA. Conclusions: The threshold for distinguishing minor extracapsular invasion with good prognosis from wide extracapsular invasion with poor prognosis is 5 mm. The worse prognosis for CEPA associated with recurrent PA indicates the necessity for close surveillance of patients with recurrent PA.     

Clinicopathological correlation and prognostic significance of sonic hedgehog protein overexpression in human gastric cancer

Objectives: This study investigated the expression of Sonic Hedgehog (Shh) protein in gastric cancer, and correlated it with clinicopathological parameters. The prognostic significance of Shh protein was analyzed. Methods: Shh protein expression was evaluated in 113 cases of gastric cancer and 60 cases of normal gastric mucosa. The immunoreactivity was scored semi quantitatively as: 0 = absent; 1 = weak; 2 = moderate; and 3 = strong. All cases were further classified into two groups, namely non-overexpression group with score 0 or 1, and overexpression group with score 2 or 3. The overexpression of Shh protein was correlated with clinicopathological parameters. Survival analysis was then performed to determine the Shh protein prognostic significance in gastric cancer. Results: In immunohistochemistry study, nineteen (31.7%) normal gastric mucosa revealed Shh protein overexpression, while eighty-one (71.7%) gastric cancer revealed overexpression. The expression of Shh protein were significantly higher in gastric cancer tissues than in normal gastric mucosa (P < 0.001), which was statistically correlated with age (P = 0.006), tumor differentiation (P < 0.001), depth of invasion (P = 0.042), pathologic staging (P = 0.017), and nodal metastasis (P = 0.019). We found no significant difference in both overall and disease free survival rates between Shh overexpression and non-expression groups P = 0.168 and 0.071). However, Shh overexpression emerged as a significant independent prognostic factor in multivariate Cox regression analysis (hazard ratio 1.187, P = 0.041). Conclusions: Shh protein expression is upregulated and is statistically correlated with age, tumor differentiation, depth of invasion, pathologic staging, and nodal metastasis. The Shh protein overexpression is a significant independent prognostic factor in multivariate Cox regression analysis in gastric cancer.     

Expression of E-cadherin,b-catenin,and Ki-67 in goblet cell carcinoids of the appendix: an immunohistochemical study with clinical correlation

Goblet cell carcinoid (GCC) of the appendix is a rare entity, of which both the histogenesis and biologic behavior remain controversial, and prognostic tools and therapeutic strategies for this unusual tumor have yet to be defined. The aim of this study was to analyze expression of E-cadherin and β-catenin in GCCs of the appendix with long-term follow-up data as related to the expression of Ki-67 proliferation marker to provide a rationale for treatment guidelines. We analyzed the expression of E-cadherin, β-catenin, and Ki-67 in 11 GCCs of the appendix and control groups of typical carcinoids of the large intestine (n=29), well to moderately differentiated adenocarcinomas of the colon (n=10), poorly differentiated adenocarcinomas of the colon (n=12), and normal appendiceal tissues (n=10). There was no significant difference between the GCCs and normal appendiceal tissues regarding the expression of E-cadherin or β-catenin (p=0.297 and 0.103, respectively). The percentage of positive GCC cells ranged between 0.52 and 10.35% (4.27 ± 0.80), and only one case had a score > 10%. Metastatic tumor spread and death were found in high MIB-1 labeling index (LI) cases of GCC (>3%). Our findings suggest that the behavior of the majority of GCCs might be indolent and different from adenocarcinomas because of the preserved expression of E-cadherin and β-catenin and relatively low MIB-1 LI. However, some of these tumors act aggressively and MIB-1 LI might be a good parameter to determine the therapeutic procedure.     

Renal cell carcinoma with rhabdoid features: an aggressive neoplasm

AIMS: Only a few reports on renal cell carcinoma with rhabdoid features have been published. This study was performed to investigate the clinicopathological characteristics of renal cell carcinomas with rhabdoid features. METHODS AND RESULTS: Among 253 cases of renal cell carcinoma in adults, eight cases with rhabdoid features were detected. Rhabdoid areas ranged from 10% to 90% of each of the cases. Seven of the eight cases were TNM stage III or IV, and four of the eight cases died within 8 months of surgery. Immunohistochemically, the rhabdoid areas were positive for CAM 5.2 (4/8), AE1/AE3 (6/8), epithelial membrane antigen (6/8) and vimentin (8/8), and negative for myogenetic markers (0/8). The mean MIB-1 labelling index in the rhabdoid areas was higher than that in the definite carcinomatous areas. Ultrastructurally, perinuclear whorls of intermediate filaments were demonstrated in three of the eight cases using paraffin-embedded blocks. CONCLUSIONS: The rhabdoid areas in renal cell carcinoma have histological, immunohistochemical and ultrastructural similarities to malignant rhabdoid tumours. Renal cell carcinoma with rhabdoid features is a highly aggressive neoplasm and its malignant behaviour may be due to the high cell-proliferative activity of the rhabdoid areas. Rhabdoid features in renal cell carcinoma may represent the endpoint of clonal evolution of renal cell carcinoma (especially in clear cell type cases).     

An intracapsular carcinoma ex pleomorphic adenoma with lung metastases composed exclusively of benign elements: Histological evidence of a continuum between metastasizing pleomorphic adenoma and carcinoma ex pleomorphic adenoma

Malignant mixed tumors of the salivary glands, encompassing carcinoma ex pleomorphic adenoma (ca ex PA), carcinosarcoma and metastasizing pleomorphic adenoma (mPA), are rare neoplasms. Ca ex PA arises in a pre-existing pleomorphic adenoma (PA). When the malignant component does not breach the capsule of the parent PA, the lesion is termed intracapsular ca ex PA, a neoplasm which is thought to have no metastatic potential. Metastatic deposits of ca ex PA are composed exclusively of malignant elements or mixed benign and malignant components. We describe the case of a 62-year-old female with an intracapsular ca ex PA of the buccal mucosa with subsequent metastases to the lung. The metastatic deposits resembled benign PA with no histological evidence of malignancy. This pattern of spread is described with mPA, an entity that caused controversy in the past regarding its exact classification as a benign or malignant tumor. The possibility that ca ex PA originates from a mPA, with intracapsular ca ex PA representing an intermediate lesion in a histological continuum, is discussed.     

Cyclin D1 and p16 expression in pleomorphic adenoma and carcinoma ex pleomorphic adenoma of the parotid gland

AIMS: To compare cyclin D1 and p16(ink4) (p16) expression in normal tissue, pleomorphic adenoma (PA) and carcinoma ex pleomorphic adenoma (CXPA) of the parotid gland. METHODS AND RESULTS: Immunohistochemistry was used to examine cyclin D1 and p16 expression in 43 parotid tumours (29 PAs and 14 CXPAs). Cyclin D1 and p16 were both significantly more likely to be expressed in the neoplastic than in the normal epithelial and stromal components of PA and CXPA (P < 0.001 and P < 0.005, respectively). Cyclin D1 was more likely to be expressed in the malignant components of CXPA than in the benign components of PA (50% versus 31% and 31%, respectively), but the trend was not statistically significant. There was no evidence of this association for p16 (corresponding positivity rates 69% versus 81% and 52%). CONCLUSIONS: Our findings provide preliminary evidence of roles for cyclin D1 and p16 in the development of PA and for cyclin D1 in the progression of PA to CXPA.     

涎腺恶性多形性腺瘤161例临床病理分析

目的分析涎腺恶性多形性腺瘤（malignant pleomorphic adenoma,MPA）的临床病理特征。方法对经病理复片诊断为MPA的161例临床病理材料进行回顾性分析。结果161例MPA中,152例为原发性肿瘤、7例为局部复发性肿瘤、2例为肿瘤颈淋巴结转移灶。152例原发MPA中发生于腮腺85例、腭部39例、颌下腺21例、颊部3例、唇部2例、磨牙后区1例、上颌骨1例;男性95例,女性57例,男女比为1．7：1;发病年龄为27～92岁,平均59岁。恶性成分的组织学类型包括肌上皮癌62例、非特异性腺癌59例、腺样囊性癌8例、黏液表皮样癌7例、导管癌3例、腺鳞癌3例、上皮-肌上皮癌3例、癌肉瘤3例、未分化癌2例、腺泡细胞癌1例、黏液腺癌1例。组织学高、中、低度恶性的分别为45、69、38例。同一肿瘤中恶性成分≤50％的为21例,〉50％的为131例。侵袭性、微侵袭性、非侵袭性癌分别为106、10、33例。侵袭性癌、组织学分级与肿瘤发生颈淋巴结转移之间有显著相关性（P值均〈0．01）。结论MPA多见于中老年男性,好发于腮腺;临床表现多为无痛渐大性肿块,以近期生长迅速为特征;组织学表现为常同时具有良性多形性腺瘤成分和恶性肿瘤成分,侵袭性癌多见,恶性成分常多于良性成分,恶性成分以肌上皮癌和非特异性腺癌为多见;侵袭性癌、组织学分级高度恶性者易发生颈淋巴结转移。     

乳腺癌细胞核形态定量分析与临床病理特征的关系

目的：观察乳腺癌细胞核形态参数,探讨其与ER、PR、HER-2表达和临床病理特征的关系。方法收集388例乳腺癌标本,根据ER、PR和HER-2三种抗体的免疫组化标记结果,将乳腺癌分为管腔A( Luminal A)型、管腔B( Luminal B)型、HER-2过表达型和基底细胞样( Basal-like)型,各组行HE染色后通过图像分析软件测量细胞核参数,应用统计学分析各组间的差异,并通过电话或住院病例随访。结果各组乳腺癌细胞核等圆直径、面积及边缘周长差异有统计学意义( P均<0.05);ER+/PR+病例细胞核形态定量与ER-/PR-病例比较,差异有统计学意义( P<0.05);ER-/PR-病例组织学分级多为Ⅲ级,生存率低于ER+/PR+病例(P<0.05)。 Luminal A型乳腺癌的无病生存期高于Basal-like型(P<0.05),总生存期高于HER-2过表达型(P<0.05)和Basal-like型(P<0.05)。结论乳腺癌细胞核形态定量差异有显著性,对其分子分型有一定的参考价值。 ER、PR和HER-2免疫组化标记结合细胞核形态学测量结果对乳腺癌的治疗和预后的评估有重要意义。